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University of Texas Southwestern Medical Center
1.
D'Brot, Alejandro.
Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations.
Degree: 2014, University of Texas Southwestern Medical Center
URL: http://hdl.handle.net/2152.5/3311 
► It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, determinants that specify…
(more)
▼ It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, determinants that specify whether the apoptosome acts to kill or remodel have yet to be identified. I show here that Tango7 genetically interacts with the apoptotic machinery but instead of regulating cell death, collaborates with the apoptosome to drive caspase-dependent cellular remodeling. Specifically, Tango7 is required for non-apoptotic caspase activity during spermatid remodeling and localizes to the active apoptosome compartment in these cells via its C terminus. Furthermore, Tango7 directly stimulates activity of reconstituted apoptosomes in vitro. These and other data presented here suggest that Tango7 physically recruits the apoptosome to specify this complex for nonapoptotic cellular remodeling. In vivo genetic model systems are powerful tools to deconstruct activity of genes driving human disease. The tumor suppressor p53 is mutated more than any other gene in human cancer, but unlike other tumor suppressors, it acquires missense mutations which encode oncogenic variants. These gain-of-function mutants promote more aggressive and metastatic cancers in vivo but their oncogenic activity is not well understood. To address this problem, I have exploited Drosophila as a platform to study and stratify human p53 (hp53) mutants. I replaced fly p53 with either wild-type hp53 or 5 of the most prevalent hp53 mutations in cancer. In this system, hp53 is under control of endogenous Dp53 regulatory elements and can regulate in vivo transcriptional activation and apoptosis like its fly counterpart. Furthermore, wild-type hp53 forms foci in the germline that localize to the same subnuclear compartment as Dp53 foci. This property is compromised in all of the gain-of-function mutants and can thus be used to distinguish oncogenic variants from wild-type hp53. Future studies aim at finding whether this and other properties shared among the 5 mutants can help stratify oncogenic p53 mutations found in human cancer.
Advisors/Committee Members: Scaglioni, Pier Paolo, Shay, Jerry W., Yu, Hongtao.
Subjects/Keywords: Apoptosomes; Aryl Hydrocarbon Receptor Nuclear Translocator; Caspases; Drosophila melanogaster; Drosophila Proteins
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APA (6th Edition):
D'Brot, A. (2014). Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/3311
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
D'Brot, Alejandro. “Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations.” 2014. Thesis, University of Texas Southwestern Medical Center. Accessed January 28, 2021.
http://hdl.handle.net/2152.5/3311.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
D'Brot, Alejandro. “Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations.” 2014. Web. 28 Jan 2021.
Vancouver:
D'Brot A. Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2014. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/2152.5/3311.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
D'Brot A. Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations. [Thesis]. University of Texas Southwestern Medical Center; 2014. Available from: http://hdl.handle.net/2152.5/3311
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
2.
Hunter, Sarah Rachel.
Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids.
Degree: 2014, University of Toronto
URL: http://hdl.handle.net/1807/73165
► The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), a partner in the hypoxia and AHR signaling pathways, is induced in rat liver by dexamethasone (DEX),…
(more)
▼ The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), a partner in the hypoxia and AHR signaling pathways, is induced in rat liver by dexamethasone (DEX), a steroid that activates the glucocorticoid (GR) and pregnane X (PXR) receptors. I conducted in vivo rat studies to examine the roles of GR and PXR in ARNT regulation. A selective GR agonist or a low DEX dose activating GR but not PXR increased hepatic levels of ARNT mRNA and an unidentified ARNT antibody-reactive protein (UAARP). The trend for increased ARNT protein levels required high DEX doses activating GR and PXR. A GR antagonist prevented the induction of ARNT mRNA and UAARP levels by low-dose DEX and the increased ARNT protein levels by high-dose DEX. DEX-induced ARNT mRNA and protein levels did not differ between wild-type and PXR-knockout rats. These results support a role for GR in the DEX induction of rat hepatic ARNT expression.
M.Sc.
Advisors/Committee Members: Riddick, David S, Pharmacology.
Subjects/Keywords: aryl hydrocarbon receptor nuclear translocator; glucocorticoid receptor; glucocorticoids; pregnane X receptor; rat; signaling pathway; 0419
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APA (6th Edition):
Hunter, S. R. (2014). Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/73165
Chicago Manual of Style (16th Edition):
Hunter, Sarah Rachel. “Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids.” 2014. Masters Thesis, University of Toronto. Accessed January 28, 2021.
http://hdl.handle.net/1807/73165.
MLA Handbook (7th Edition):
Hunter, Sarah Rachel. “Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids.” 2014. Web. 28 Jan 2021.
Vancouver:
Hunter SR. Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids. [Internet] [Masters thesis]. University of Toronto; 2014. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1807/73165.
Council of Science Editors:
Hunter SR. Induction of the Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator by Glucocorticoids. [Masters Thesis]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/73165
University of Texas Southwestern Medical Center
3.
Card, Paul B.
PAS Domain-Mediated Dimerization of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in the Hypoxia Response Pathway.
Degree: 2005, University of Texas Southwestern Medical Center
URL: http://hdl.handle.net/2152.5/367
► PAS (Per-ARNT-SIM) domains are versatile protein-protein interaction domains that are often used as regulatory modules in a variety of important biological pathways. Although their importance…
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▼ PAS (Per-ARNT-SIM) domains are versatile protein-protein interaction domains that are often used as regulatory modules in a variety of important biological pathways. Although their importance in several of these pathways has been well established, only sparse structural data exists that could help elucidate a general mode of PAS-PAS interaction. As such, more examples of these domains must be studied using a variety of techniques to understand how these domains carry out viable functions within the cell.The
Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) is a constituent of heterodimeric transcriptional activation complexes used in several important biochemical pathways. One such complex is the hypoxia inducible transcription factor (HIF), which allows mammalian cells to respond to changes in oxygen availability. In HIF, ARNT dimerizes with HIFa to upregulate genes involved in the hypoxia response. The dimerization of ARNT and HIFa involves interactions between PAS domains in both proteins, but details regarding how these domains interact in this and other heterodimeric complexes have not previously been well characterized. To investigate these interactions within the context of the HIF/ARNT heterodimer, we expressed the C-terminal PAS domains from both proteins and characterized the complex using NMR-based methods. Solution structures of each domain are presented, as well as a model of the ARNT/HIF heterodimeric PAS complex. This model was used to identify of key interfacial residues, and the roles of these were tested in a variety of ways by sitedirected mutagenesis. In addition, extended constructs from ARNT that include other components of the full-length protein were investigated to establish the validity of a reductionist approach in the study of individual PAS domains from this system.
In many biological systems, PAS domains bind small molecules to regulate proteinprotein interactions. With this in mind, we also subjected PAS domains from HIFa and ARNT to an NMR-based screen against an in-house library of 800 compounds to determine the potential of these domains to bind small molecules. With have used this approach to identify compounds that can disrupt PAS-PAS interactions in the hypoxia pathway in order to help elucidate some of the molecular details of PAS domain-mediated signaling.
Advisors/Committee Members: Gardner, Kevin H..
Subjects/Keywords: Aryl Hydrocarbon Receptor Nuclear Translocator; Dimerization; Hypoxia, Cell
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APA (6th Edition):
Card, P. B. (2005). PAS Domain-Mediated Dimerization of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in the Hypoxia Response Pathway. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/367
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Card, Paul B. “PAS Domain-Mediated Dimerization of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in the Hypoxia Response Pathway.” 2005. Thesis, University of Texas Southwestern Medical Center. Accessed January 28, 2021.
http://hdl.handle.net/2152.5/367.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Card, Paul B. “PAS Domain-Mediated Dimerization of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in the Hypoxia Response Pathway.” 2005. Web. 28 Jan 2021.
Vancouver:
Card PB. PAS Domain-Mediated Dimerization of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in the Hypoxia Response Pathway. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2005. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/2152.5/367.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Card PB. PAS Domain-Mediated Dimerization of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in the Hypoxia Response Pathway. [Thesis]. University of Texas Southwestern Medical Center; 2005. Available from: http://hdl.handle.net/2152.5/367
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Texas Southwestern Medical Center
4.
Guo, Yirui.
Structural Characterization and Chemical Inhibition of the ARNT/TACC3 Complex.
Degree: 2014, University of Texas Southwestern Medical Center
URL: http://hdl.handle.net/2152.5/3939
► My research project focuses on mechanistic studies of a new group of transcriptional coactivators (coiled-coil coactivators: TACC3, TRIP230, CoCoA), involved in cancer development and progression.…
(more)
▼ My research project focuses on mechanistic studies of a new group of transcriptional coactivators (coiled-coil coactivators: TACC3, TRIP230, CoCoA), involved in cancer development and progression. Normally, these coactivators play an essential role in the HIF hypoxia response, directly interacting with the ARNT subunit of HIF in a novel and promoter-specific way. However, misregulation by overexpression or activating fusions (for example, FGFR-TACC3) is sufficient for transformation and associated with the development of glioblastoma, renal cell carcinoma and other cancers. In light of this connection between coiled-coil coactivators (CCCs) and HIF signaling, tools that inhibit HIF/CCC complex formation might present opportunities to interrogate the linkage between different CCC-containing pathways and may offer a novel route to blocking cancer formation and progression.
As a member of a new group of transcription coactivators, knowing how TACC3 interacts with ARNT is critical in understanding the general role of CCCs in HIF-dependent transcription machinery. In the first half of my study, I characterized the ARNT/TACC3 complex with various biophysical and biochemical methods including solution NMR, X-ray crystallography, circular dichroism, luminescence proximity and numerous cell-based assays. A 3.15 Å ARNT/TACC3 crystal structure was solved by molecular replacement, revealing details of this protein complex and providing a structural funcation for coactivator recruitment in HIF signaling pathway.
The second half of this study focuses on the search for ARNT/TACC3 inhibitors with in vitro screens to regulate ARNT/CCCs activity in a rapid and flexible way. From a fragment-based NMR screen, I identified small molecules that specifically bound within the second PER-ARNT-SIM (PAS) domain of ARNT and perturb its interaction with TACC3. However, these small molecules have drawbacks, such as low potency or unclear modes of action. To identify higher potency small molecules targeting ARNT/TACC3 complexes, I developed an AlphaScreen-based high throughput screen. Hopefully the discovery of artificial ligands with known mode-of-action that inhibit this typically "undruggable" protein complex will provide new perspectives in small molecule inhibitor development, and also serve as a very useful tool in cell biology for studying pathways utilizing ARNT/TACC3.
Advisors/Committee Members: Rosenbaum, Daniel M., Roth, Michael G., Rice, Luke M., Gardner, Kevin H..
Subjects/Keywords: Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Microtubule-Associated Proteins; Trans-Activators
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APA (6th Edition):
Guo, Y. (2014). Structural Characterization and Chemical Inhibition of the ARNT/TACC3 Complex. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/3939
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Guo, Yirui. “Structural Characterization and Chemical Inhibition of the ARNT/TACC3 Complex.” 2014. Thesis, University of Texas Southwestern Medical Center. Accessed January 28, 2021.
http://hdl.handle.net/2152.5/3939.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Guo, Yirui. “Structural Characterization and Chemical Inhibition of the ARNT/TACC3 Complex.” 2014. Web. 28 Jan 2021.
Vancouver:
Guo Y. Structural Characterization and Chemical Inhibition of the ARNT/TACC3 Complex. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2014. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/2152.5/3939.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Guo Y. Structural Characterization and Chemical Inhibition of the ARNT/TACC3 Complex. [Thesis]. University of Texas Southwestern Medical Center; 2014. Available from: http://hdl.handle.net/2152.5/3939
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Texas Southwestern Medical Center
5.
Evans, Matthew Ryan.
A Fragile Native State Structure: An Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Variant Exhibits Slow Interconversion Kinetics Between two Different Folds.
Degree: 2009, University of Texas Southwestern Medical Center
URL: http://hdl.handle.net/2152.5/749
► The aryl hydrocarbon receptor nuclear translocator (ARNT) is a promiscuous basic helix-loop-helix Period/ARNT/Single-minded (bHLH-PAS) protein that controls various biological pathways by forming heterodimeric transcriptional regulator…
(more)
▼ The
aryl hydrocarbon receptor nuclear translocator (ARNT) is a promiscuous basic helix-loop-helix Period/ARNT/Single-minded (bHLH-PAS) protein that controls various biological pathways by forming heterodimeric transcriptional regulator complexes with several other bHLH-PAS proteins via the beta-sheet surfaces of its two PAS domains. The beta-sheets of PAS domains are involved in many intermolecular interactions with other proteins and natural cofactors in order to detect environmental changes in sensor PAS proteins.
As part of a study of the HIF-2 alpha and ARNT PAS-B heterodimer, site-directed mutagenesis was performed on the ARNT PAS-B domain. Interestingly, one point mutation on the ARNT beta-sheet surface (Y456T) resulted in a new conformation of the domain that existed in equimolar concentrations with the wild-type conformation. Subsequent studies demonstrated that the two conformations are in equilibrium and that relative populations of the two conformations can be perturbed by additional mutations. Using solution NMR spectroscopy, we solved the high resolution solution structure of a mutant ARNT PAS-B domain in the new conformation, demonstrating that it contains a three-residue slip in register and accompanying inversion of the central beta-strand. In addition, this new conformer has a greater than hundred-fold reduction in affinity for HIF-2 alpha PAS-B, disrupting the hypoxia response pathway.
Solution NMR measurements of the interconversion kinetics have let us establish that these two conformations interconvert slowly (40 min at RT) with a linear Arrhenius temperature-dependence of the interconversion rate. Stopped-flow unfolding experiments using GdmHCl on Y456T, revealed a similarly slow unfolding rate (25 min at RT) and an energy barrier to unfold of approximately 13 kcal/mol, which is nearly identical to that for the interconversion process. These data indicate that the protein must undergo a global unfolding process in order to interconvert between conformations. Lastly, these relative populations of Y456T can be affected by compound preferentially binding into the core of one of these conformations.
This discovery highlights the malleability of PAS beta-sheets and suggests ARNT may act as a regulatory switch to control different biological pathways. Furthermore, this system presents a great opportunity to further understand the structural and kinetic impact of beta-strand slips observed in nature.
Advisors/Committee Members: Gardner, Kevin H..
Subjects/Keywords: Aryl Hydrocarbon Receptor Nuclear Translocator; Nuclear Magnetic Resonance, Biomolecular; Models, Molecular
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APA ·
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APA (6th Edition):
Evans, M. R. (2009). A Fragile Native State Structure: An Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Variant Exhibits Slow Interconversion Kinetics Between two Different Folds. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/749
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Evans, Matthew Ryan. “A Fragile Native State Structure: An Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Variant Exhibits Slow Interconversion Kinetics Between two Different Folds.” 2009. Thesis, University of Texas Southwestern Medical Center. Accessed January 28, 2021.
http://hdl.handle.net/2152.5/749.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Evans, Matthew Ryan. “A Fragile Native State Structure: An Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Variant Exhibits Slow Interconversion Kinetics Between two Different Folds.” 2009. Web. 28 Jan 2021.
Vancouver:
Evans MR. A Fragile Native State Structure: An Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Variant Exhibits Slow Interconversion Kinetics Between two Different Folds. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2009. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/2152.5/749.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Evans MR. A Fragile Native State Structure: An Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Variant Exhibits Slow Interconversion Kinetics Between two Different Folds. [Thesis]. University of Texas Southwestern Medical Center; 2009. Available from: http://hdl.handle.net/2152.5/749
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Oregon State University
6.
Phillips, Jessica Lynne.
Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression.
Degree: PhD, 2017, Oregon State University
URL: http://hdl.handle.net/1957/61709
► The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the basic helix-loop-helix PER/ARNT/SIM (bHLH/PAS) family and regulates a diverse set of genes. The…
(more)
▼ The
aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the basic helix-loop-helix PER/ARNT/SIM (bHLH/PAS) family and regulates a diverse set of genes. The AhR is best known for directing the transcription of drug-metabolizing enzymes, particularly upon activation by ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs). However, the AhR also regulates gene programs upstream of organismal development, cellular differentiation, cell proliferation, and programmed cell death. The roles of AhR in mediating cellular fate coupled with its ability to respond to both exogenous and endogenous chemical signals make its behavior in the context of cancer particularly interesting. Recently, we reported that low expression of AhR correlates with poor prognosis for breast cancer patients, adding to the accumulating evidence that AhR is able to mediate tumor suppressive effects in tissues.
The central hypothesis of this research is that the
aryl hydrocarbon receptor functions as a tumor suppressor, and that the tumor suppressive activities of AhR can be therapeutically activated with selective AhR ligands.
To test our hypothesis, we developed AhR-knockout mice lacking the tumor suppressor protein p53, mimicking the most common mutation event in the development of human cancers. The absence of AhR increased the tumor burden, tumor spectrum and reduced survival in p53-deficient mice, supporting a tumor modifier role for the AhR. Furthermore, the double-knockout of AhR and p53 resulted in reduced embryonic survival and neonatal fitness. These findings suggest important roles for the AhR in tumor suppression and development, and have significant clinical implications.
To test the hypothesis that AhR is a molecular target for anti-cancer therapeutics, we screened chemical libraries for small molecules capable of both activating the AhR and inhibiting the growth of cancer cells. Of interest were the compounds that caused growth arrest or apoptosis in triple-negative breast cancer (TNBC) cells, as patients with TNBC have an extremely bleak prognosis characterized by poor responses to currently available therapeutics and a rapid rate of relapse. A short list of compounds that induced AhR-dependent anti-cancer effects was investigated to determine their mechanisms of action. One compound activated AhR-dependent transcription of cyclin-dependent kinase inhibitor 1B (CDKN1B/p27Kip1), a cell cycle inhibitor and a tumor suppressor. As transcriptional regulation of p27Kip1 is a poorly understood phenomenon with implications for cancer treatment, we performed promoter analyses to determine regions critical to regulation of p27Kip1, and found evidence of transcriptional activation of p27Kip1 by the AhR. Given the potential for drug development, we then investigated the structural analogs of the p27Kip1-inducing compound for activation of AhR and subsequent transcriptional induction of p27Kip1, and restriction of TNBC cell growth. We selected ten analogs from a list of…
Advisors/Committee Members: Kolluri, Siva K. (advisor), Buermeyer, Andrew B. (committee member).
Subjects/Keywords: Aryl hydrocarbon receptor
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Phillips, J. L. (2017). Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression. (Doctoral Dissertation). Oregon State University. Retrieved from http://hdl.handle.net/1957/61709
Chicago Manual of Style (16th Edition):
Phillips, Jessica Lynne. “Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression.” 2017. Doctoral Dissertation, Oregon State University. Accessed January 28, 2021.
http://hdl.handle.net/1957/61709.
MLA Handbook (7th Edition):
Phillips, Jessica Lynne. “Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression.” 2017. Web. 28 Jan 2021.
Vancouver:
Phillips JL. Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression. [Internet] [Doctoral dissertation]. Oregon State University; 2017. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1957/61709.
Council of Science Editors:
Phillips JL. Roles for the Aryl Hydrocarbon Receptor in Tumor Suppression. [Doctoral Dissertation]. Oregon State University; 2017. Available from: http://hdl.handle.net/1957/61709
7.
Thiago Estevam Parente Martins.
Estudo comparativo da atividade catalítica e expressão protéica do citocromo P4501A (CYP1A) em cascudos (Loricariidae) e tilápias (Cichlidae).
Degree: 2008, Fundação Oswaldo Cruz
URL: http://www.bdtd.cict.fiocruz.br/tedesimplificado/tde_busca/arquivo.php?codArquivo=179
► Os citocromos P450 (CYP) desempenham importantes papéis na biotransformação de xenobióticos e no metabolismo de substâncias endógenas. A subfamília CYP1A foi bem conservada ao longo…
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▼ Os citocromos P450 (CYP) desempenham importantes papéis na biotransformação de xenobióticos e no metabolismo de substâncias endógenas. A subfamília CYP1A foi bem conservada ao longo da evolução dos vertebrados, tendo sido encontrada em todas as espécies de peixes mandibulados estudadas até o momento. Em trabalho anterior, verificamos que algumas espécies de cascudos da família Loricariidae não apresentavam atividade da etoxiresorufina-O-desetilase (EROD) em microssomos hepáticos. Como EROD é atividade catalisada predominantemente por CYP1A em diversos vertebrados, esse achado nos motivou a investigar em detalhe os CYP, em especial da subfamília 1A, em cascudos. Este trabalho é um estudo comparativo da capacidade de cascudos (Hyposthomus luetkeni e H. affinis), tilápias do Nilo (Oreochromis niloticus; Cichlidae) e camundongos, controles e tratados com indutores conhecidos de CYP1A [50 mg/kg ip; ßnaftoflavona (BNF), ou 7-12 dimetil-benzoantraceno (DMBA)] de: i catalisar diversas reações químicas sabidamente mediadas por CYP, ii expressar a proteína CYP1A no tecido hepático, e iii ativar o pró-mutágeno DMBA. Nos microssomos hepáticos das tilápias e dos camundongos, detectamos atividades constitutivas de EROD e também de desalquilação de outros ésteres da resorufina (MROD, PROD e BROD). Nessas duas espécies, as atividades dessas monooxigenases foram induzidas pelos tratamentos com BNF e DMBA. Nos cascudos, controles e tratados com os indutores de CYP1A, as atividades das alcoxi-resorufina-O-desalquilases não foram detectadas. A atividade da etoxicumarina desetilase (ECOD) foi cerca de cinco vezes maior no figado de cascudos e de camundongos do que no das tilápias. O CYP1A não parece ter papel importante na catálise de ECOD nessas duas espécies de peixes. Os resultados também mostraram que dois anticorpos anti-CYP1A de peixe reconheceram proteínas com massa molecular compatível com o de CYPs nos microssomos hepáticos de tilápias e camundongos tratados com indutores de CYP1A. Nos cascudos, entretanto, a detecção de CYP1A por immunoblotting com esses anticorpos não foi consistente. Com o emprego de espectrometria de massas, identificamos o CYP1A em microssomos hepáticos de tilápias induzidas, mas não nos cascudos controles ou induzidos. Em conjunto, os resultados sugerem que, em contraste com o observado com tilápias e camundongos, os cascudos não exibem atividade catalítica de CYP1A e não expressam as proteínas correspondentes no fígado, ou as expressam apenas em níveis constitutivos extremamente baixos. Apesar de não apresentarem atividade catalítica de CYP1A, os cascudos foram capazes de ativar o pró-mutágeno DMBA que, em outras espécies, é ativado por enzimas da família CYP1, em especial das subfamílias 1A e 1B.
The cytochrome P450 (CYP) superfamily plays important roles in the biotransformation of xenobiotic and endogenous compounds. The CYP1A subfamily is well conserved in vertebrates and has been found in all jawed fish studied to date. In a previous study, we had found that suckermouth armored catfishes of the…
Advisors/Committee Members: Francisco José Roma Paumgartten.
Subjects/Keywords: Sistema Enzimático do Citocromo P-450; Translocador Nuclear Receptor Aril Hidrocarboneto; Tilápia; Ecossistema; Xenobióticos; Peixes; CIENCIAS BIOLOGICAS; Estudo Comparativo; Animais; Camundongos; Cytochrome P-450 Enzyme System; Aryl Hydrocarbon Receptor Nuclear Translocator; Tilapia; Ecosystem; Xenobiotics; Fishes
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APA (6th Edition):
Martins, T. E. P. (2008). Estudo comparativo da atividade catalítica e expressão protéica do citocromo P4501A (CYP1A) em cascudos (Loricariidae) e tilápias (Cichlidae). (Thesis). Fundação Oswaldo Cruz. Retrieved from http://www.bdtd.cict.fiocruz.br/tedesimplificado/tde_busca/arquivo.php?codArquivo=179
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Martins, Thiago Estevam Parente. “Estudo comparativo da atividade catalítica e expressão protéica do citocromo P4501A (CYP1A) em cascudos (Loricariidae) e tilápias (Cichlidae).” 2008. Thesis, Fundação Oswaldo Cruz. Accessed January 28, 2021.
http://www.bdtd.cict.fiocruz.br/tedesimplificado/tde_busca/arquivo.php?codArquivo=179.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Martins, Thiago Estevam Parente. “Estudo comparativo da atividade catalítica e expressão protéica do citocromo P4501A (CYP1A) em cascudos (Loricariidae) e tilápias (Cichlidae).” 2008. Web. 28 Jan 2021.
Vancouver:
Martins TEP. Estudo comparativo da atividade catalítica e expressão protéica do citocromo P4501A (CYP1A) em cascudos (Loricariidae) e tilápias (Cichlidae). [Internet] [Thesis]. Fundação Oswaldo Cruz; 2008. [cited 2021 Jan 28].
Available from: http://www.bdtd.cict.fiocruz.br/tedesimplificado/tde_busca/arquivo.php?codArquivo=179.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Martins TEP. Estudo comparativo da atividade catalítica e expressão protéica do citocromo P4501A (CYP1A) em cascudos (Loricariidae) e tilápias (Cichlidae). [Thesis]. Fundação Oswaldo Cruz; 2008. Available from: http://www.bdtd.cict.fiocruz.br/tedesimplificado/tde_busca/arquivo.php?codArquivo=179
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Penn State University
8.
DiNatale, Brett C.
The role of the aryl hydrocarbon receptor in tumor cell phenotype.
Degree: 2011, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/11597
► The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely associated with its function in xenobiotic metabolism and its ability to bind environmental pollutants…
(more)
▼ The
aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely associated with its function in xenobiotic metabolism and its ability to bind environmental pollutants in the polycyclic aromatic
hydrocarbon family such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Upon ligand binding, the AHR translocates to the nucleus, exchanges its chaperone complex for its heterodimerization partner, the
aryl hydrocarbon receptor nuclear translocator, and binds to dioxin response elements (DREs) in the promoter of target genes, driving transcription. However, researchers have tied the AHR to a variety of cellular processes in addition to xenobiotic metabolism, not all of which occur through DRE binding and direct transcriptional activation. The studies presented here build upon the finding that combinatorial treatment with exogenous AHR ligands and IL1B leads to synergistic IL6 expression in some typically non-responsive tumor cell lines. The overall hypothesis was that the AHR plays a molecular role in IL6 transcription and represents a viable point of treatment to mediate tumor cell signaling. Analysis of the mechanism by which these two signals mediate IL6 induction revealed that the liganded AHR binds to DREs far upstream from the IL6 promoter, yet plays a role in the de-repression of the chromatin of the proximal promoter through dismissal of co-repressor complexes. Following this, IL1B-induced NFkB activity is able to positively affect transcription of the IL6 gene. Subsequently, the role played by the AHR in the relatively high basal and readily inducible cytokine expression of head and neck squamous cell carcinoma (HNSCC) cell lines was assessed. Multiple HNSCC cell lines derived from various loco-regional tumors showed a similar state of IL6 de-repression with AHR occupancy of the promoter in the absence of exogenous ligand. This promoter configuration could be reversed and transcription repressed through treatment of cells with an AHR antagonist and the resultant decrease in
receptor occupancy of the IL6 promoter. Next, the hypothesis was tested that basal AHR occupancy of the IL6 promoter in HNSCC cell lines is indicative of a constitutive level of
receptor activity, and that the role of the AHR in various cellular processes that enhance tumor cell phenotype were similarly occurring. Treatment of HNSCC cell lines with AHR antagonists decreased tumor cell proliferation, migration, invasive ability, and prevented the increase of an integral protein for a chemotherapy efflux pump. The significance of the results presented in these studies reflects on both the field of AHR biology and the potential for AHR-targeted treatment in cancer, including HNSCC. Uncovering a mechanism whereby AHR activation is one of two signals required for gene regulation opens a new field of research into combinatorial effects of the
receptor and points to previously undocumented genes as being AHR targets with or without DREs in the proximal promoter. Finally, AHR antagonist treatment is a viable…
Advisors/Committee Members: Gary H Perdew, Dissertation Advisor/Co-Advisor, Gary H Perdew, Committee Chair/Co-Chair, Jeffrey Maurice Peters, Committee Member, Craig Richard Baumrucker, Committee Member, Andrea Marie Mastro, Committee Member, Kumble Sandeep Prabhu, Committee Member.
Subjects/Keywords: ahr; aryl hydrocarbon receptor; cancer
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APA (6th Edition):
DiNatale, B. C. (2011). The role of the aryl hydrocarbon receptor in tumor cell phenotype. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11597
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
DiNatale, Brett C. “The role of the aryl hydrocarbon receptor in tumor cell phenotype.” 2011. Thesis, Penn State University. Accessed January 28, 2021.
https://submit-etda.libraries.psu.edu/catalog/11597.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
DiNatale, Brett C. “The role of the aryl hydrocarbon receptor in tumor cell phenotype.” 2011. Web. 28 Jan 2021.
Vancouver:
DiNatale BC. The role of the aryl hydrocarbon receptor in tumor cell phenotype. [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Jan 28].
Available from: https://submit-etda.libraries.psu.edu/catalog/11597.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
DiNatale BC. The role of the aryl hydrocarbon receptor in tumor cell phenotype. [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/11597
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Oulu
9.
Arpiainen, S. (Satu).
Transcriptional regulation of the hepatic cytochrome P450 2a5 gene.
Degree: 2007, University of Oulu
URL: http://urn.fi/urn:isbn:9789514285653
► Abstract Cytochrome P450 (CYP) enzymes are the major metabolizers of xenobiotics, e.g. drugs, and environmental toxins. Thus, changes in CYP expression have an important impact…
(more)
▼ Abstract
Cytochrome P450 (CYP) enzymes are the major metabolizers of xenobiotics, e.g. drugs, and environmental toxins. Thus, changes in CYP expression have an important impact on drug metabolism and susceptibility to chemical toxicity.
In the present study, the transcriptional mechanisms of both constitutive and inducible regulation of the Cyp2a5 gene in mouse liver were investigated. Mouse primary hepatocyte cultures were used as the main model system together with cell and molecular biology methods.
The key activation regions of the Cyp2a5 5' promoter were determined using reporter gene assays. Two major transcription activation sites of the Cyp2a5 5' promoter, called the proximal and the distal, were found. Transcription factors hepatocyte nuclear factor-4 (HNF-4) and nuclear factor I were shown to bind to the proximal promoter. Aryl hydrocarbon receptor nuclear translocator (ARNT) and upstream stimulatory factor bound to a common palindromic E-box element in the distal promoter region. All three response elements were shown to be essential for constitutive expression of CYP2A5 in murine hepatocytes. ARNT appeared to control Cyp2a5 transcription without a heterodimerization partner suggesting active involvement of the ARNT homodimer in mammalian gene regulation.
Aryl hydrocarbon receptor (AHR) ligands were shown to induce Cyp2a5 transcriptionally by an AHR-dependent mechanism, and established Cyp2a5 as a novel AHR-regulated gene. The AHR response element and the E-box, identified in these studies, were located near to each other and close to a separately defined nuclear factor (erythroid-derived 2)-like 2 binding site in the distal region of the Cyp2a5 promoter, suggesting cooperation between these elements.
Peroxisome proliferator-activated receptor gamma coactivator-1α was shown to up-regulate Cyp2a5 transcription through coactivation of HNF-4α. This indicates that xenobiotic metabolism can be regulated by modification of co-activation.
The present results show that CYP2A5 is regulated by several different cross-regulatory pathways. The regulatory mechanisms involved in the transcription of the Cyp2a5 gene may also control other CYP genes, especially the human ortholog CYP2A6, and may explain some of the individual variations in the metabolism of xenobiotics.
Subjects/Keywords: CYP2A5; aryl hydrocarbon receptor; aryl hydrocarbon receptor nuclear translocator; cytochrome P450 enzyme system; hepatocyte nuclear factor 4; nuclear factor I; peroxisome proliferator-activated receptor gamma coactivator-1alpha; upstream stimulatory factors
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APA ·
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APA (6th Edition):
Arpiainen, S. (. (2007). Transcriptional regulation of the hepatic cytochrome P450 2a5 gene. (Doctoral Dissertation). University of Oulu. Retrieved from http://urn.fi/urn:isbn:9789514285653
Chicago Manual of Style (16th Edition):
Arpiainen, S (Satu). “Transcriptional regulation of the hepatic cytochrome P450 2a5 gene.” 2007. Doctoral Dissertation, University of Oulu. Accessed January 28, 2021.
http://urn.fi/urn:isbn:9789514285653.
MLA Handbook (7th Edition):
Arpiainen, S (Satu). “Transcriptional regulation of the hepatic cytochrome P450 2a5 gene.” 2007. Web. 28 Jan 2021.
Vancouver:
Arpiainen S(. Transcriptional regulation of the hepatic cytochrome P450 2a5 gene. [Internet] [Doctoral dissertation]. University of Oulu; 2007. [cited 2021 Jan 28].
Available from: http://urn.fi/urn:isbn:9789514285653.
Council of Science Editors:
Arpiainen S(. Transcriptional regulation of the hepatic cytochrome P450 2a5 gene. [Doctoral Dissertation]. University of Oulu; 2007. Available from: http://urn.fi/urn:isbn:9789514285653
10.
Filiano, Anthony J.
The protective role of transglutaminase 2 in ischemic stroke.
Degree: PhD, 2009, University of Alabama – Birmingham
URL: http://contentdm.mhsl.uab.edu/u?/etd,496
► Stroke is a leading cause of long term disabilities in the US. Currently, administration of thrombolytics is the only approved therapy. Due to the variability,…
(more)
▼ Stroke is a leading cause of long term disabilities in the US. Currently,
administration of thrombolytics is the only approved therapy. Due to the variability,
small management time window, and lack of options for effective treatment, there is a
clear need for new compounds to alleviate cell death post-stroke. Transglutaminase 2
(TG2) can decrease apoptotic signaling during stroke and lead to increased neuronal
survival making it a potential target for therapeutic intervention. TG2, a multifunction
enzyme that has both transamidase (TG) and GTPase activities, amongst others, has
recently been shown to be upregulated in numerous neurodegenerative conditions,
including stroke. In the central nervous system, TG2 is predominately found in neurons
where it functions in neurite development and neuronal remodeling. Further, there is
increasing evidence that TG2 plays a pivotal role influencing life and death decisions of
the cell. In hypoxic environments, neurons adapt to decreases in oxygen by up-regulating
genes controlled by the hypoxia inducible factor 1 (HIF1). This transcription factor is
comprised of two subunits: HIF1α and HIF1β. Recent studies have provided evidence
that increased HIF1α can result in increased neuronal cell death in response to hypoxia, in
part due to upregulation of apoptotic genes. In this dissertation we analyzed the role of
TG2 in neuronal ischemia in two main studies.
In the first study, we show that TG2 protects primary cortical neurons from
oxygen and glucose deprivation (OGD). We identified HIF1β as a novel TG2 binding
partner and this binding leads to the attenuation of HIF controlled proapoptotic Bnip3 in
response to OGD yet cell survival factor VEGF remained elevated to an equal level as
controls.
In the second study, we show that TG2 translocates to the nucleus in both human
stroke samples and a mouse model of stroke. Using rat cortical cultures, we observed
this translocation to take place immediately after OGD and TG2 remained in the nucleus
up to 24 hours after oxygen and glucose were replenished. Furthermore, overexpression
of human TG2 (hTG2) in mouse neurons of the CNS decreased infarct volumes after
permanent middle cerebral artery (MCA) ligation.
vii, 127 p. : ill., digital, PDF file
Cell Biology
Joint Health Sciences
Transglutaminase 2, Ischemia
Neurons
Stroke
Hypoxia Inducible Factor
UNRESTRICTED
Advisors/Committee Members: Johnson, Gail V. W., Bailey, Shannon M.<br>, Clemens, Thomas<br>.
Subjects/Keywords: Aryl Hydrocarbon Receptor Nuclear Translocator – metabolism<; br>;
Cell Hypoxia<; br>;
GTP-Binding Proteins – metabolism<; br>;
Ischemia – prevention & control<; br>;
Neurons – metabolism<; br>;
Transglutaminases – metabolism
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APA ·
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APA (6th Edition):
Filiano, A. J. (2009). The protective role of transglutaminase 2 in ischemic stroke. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,496
Chicago Manual of Style (16th Edition):
Filiano, Anthony J. “The protective role of transglutaminase 2 in ischemic stroke.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed January 28, 2021.
http://contentdm.mhsl.uab.edu/u?/etd,496.
MLA Handbook (7th Edition):
Filiano, Anthony J. “The protective role of transglutaminase 2 in ischemic stroke.” 2009. Web. 28 Jan 2021.
Vancouver:
Filiano AJ. The protective role of transglutaminase 2 in ischemic stroke. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2021 Jan 28].
Available from: http://contentdm.mhsl.uab.edu/u?/etd,496.
Council of Science Editors:
Filiano AJ. The protective role of transglutaminase 2 in ischemic stroke. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,496
University of Stirling
11.
Dixon, Thomas James.
Molecular genetic studies of pollutant response in the European flounder, Platichthys flesus (L.).
Degree: PhD, School of Natural Sciences, 2003, University of Stirling
URL: http://hdl.handle.net/1893/57
► Effects of man made pollutants on an ecosystem are initiated at the cellular level where a prime determinant for survival of an organism is its…
(more)
▼ Effects of man made pollutants on an ecosystem are initiated at the cellular level where a prime determinant for survival of an organism is its ability to metabolise and excrete toxic chemicals or their metabolites, thereby preventing cellular toxicity or damage to germ cell DNA. Cytochrome P450 (CYP) enzymes are responsible (in concert with the remainder of the Ah battery enzymes) for the metabolism of numerous xenobiotics and endogenous compounds, including the metabolic activation of most environmental toxic chemicals and carcinogens. Genetic polymorphisms which affect performance of these enzymatic detoxification systems may alter tolerance to pollutants and thus survival in polluted environments. Alterations in the susceptibility of individuals and the development of resistant populations has arisen by forced selection of populations with variant genes, resulting in increased detoxification capacity. There is evidence for such scenarios of variations in activities of pollutant biotransforming enzymes of fish contributing to survival in polluted estuarine environments and several chemically resistant populations have been identified in the USA and Europe. In fish it has been demonstrated that CYP1A enzyme activity is required to activate some carcinogenic xenobiotics to a metabolic state in which they can form DNA adducts. The mechanism of reduced CYP1A expression in highly contaminated populations may therefore represent resistance to chemical stressors. European flounder (Platichthys flesus) from some waterways which have a long history of severe sedimentary contamination do not show elevated levels of CYP1A. The aim of the current study was to investigate whether any heritable differences were apparent between offspring from parents inhabiting long-term polluted and pristine areas. Flounder were obtained from a highly polluted estuary in the UK and crossed with fish from a relatively pristine environment. Offspring were raised in communal tanks in order to standardise environmental conditions, and allow investigations into the genetic variation of CYP1A. To allow identification of offspring to parental fish, polymorphic microsatellite loci were isolated and characterised for the flounder. Novel cDNA probes to transcription factors in the detoxification pathway (AhR2 and ARNT2) were cloned for flounder, and RT-PCR / Southern blot methods were developed for quantitation of gene transcript levels. A novel method of CYP1A quantification using real-time PCR was developed.
PAH and PCB exposure trials were carried out on mixed batch offspring, and CYP1A gene transcript levels assessed using Northern blot and real-time PCR techniques. Offspring were genotyped to their parents using the microsatellites obtained, and CYP1A transcript levels were correlated with clean and polluted areas. CYP1A was further correlated to transcription factor expression, and data are presented. Following exposure to the commercial PCB mixture, Aroclor 1254, CYP1A transcript levels were found to be significantly lower in families whose…
Subjects/Keywords: European flounder; Platichthys flesus; CYP1A; cytochrome P450; Fish; detoxification genes; pollutant response; marine environmental pollution; pollution; aryl hydrocarbon receptor; aryl hydrocarbon receptor repressor; aryl hydrocarbon receptor nuclear translocator; microsatellite; Plaice; Metabolic detoxification; Fishes Genetics; Pollutants Environmental aspects; Marine pollution
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APA (6th Edition):
Dixon, T. J. (2003). Molecular genetic studies of pollutant response in the European flounder, Platichthys flesus (L.). (Doctoral Dissertation). University of Stirling. Retrieved from http://hdl.handle.net/1893/57
Chicago Manual of Style (16th Edition):
Dixon, Thomas James. “Molecular genetic studies of pollutant response in the European flounder, Platichthys flesus (L.).” 2003. Doctoral Dissertation, University of Stirling. Accessed January 28, 2021.
http://hdl.handle.net/1893/57.
MLA Handbook (7th Edition):
Dixon, Thomas James. “Molecular genetic studies of pollutant response in the European flounder, Platichthys flesus (L.).” 2003. Web. 28 Jan 2021.
Vancouver:
Dixon TJ. Molecular genetic studies of pollutant response in the European flounder, Platichthys flesus (L.). [Internet] [Doctoral dissertation]. University of Stirling; 2003. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1893/57.
Council of Science Editors:
Dixon TJ. Molecular genetic studies of pollutant response in the European flounder, Platichthys flesus (L.). [Doctoral Dissertation]. University of Stirling; 2003. Available from: http://hdl.handle.net/1893/57
Cornell University
12.
Mohinta, Sonia.
Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function.
Degree: PhD, Immunology, 2014, Cornell University
URL: http://hdl.handle.net/1813/36177
► A number of autoimmune and chronic inflammatory diseases are related to environmental stress. Aryl hydrocarbon receptor (AHR) is regarded as an environmental sensor integrating immune…
(more)
▼ A number of autoimmune and chronic inflammatory diseases are related to environmental stress.
Aryl hydrocarbon receptor (AHR) is regarded as an environmental sensor integrating immune responses with environmental stress and thereby influencing the extent of host immune response. The physiological role of AHR, particularly, in the immune response remains a key question after the discovery that AHR can modulate Th17/Treg axis in a ligand specific manner. However, discovery of a non-DRE mediated AHR activation in addition to its canonical DRE-mediated pathway further adds to this complexity thereby necessitating a more critical approach in delineating the role of AHR in the context of Th17/Treg balance. Selective AHR modulators (SAHRMs) are a recently identified class of compounds that are capable of binding to AHR and repress cytokine- driven gene expression without activating DRE-driven responses We have used three classes of AHR ligands namely agonist, antagonist and partial antagonist (SAHRM) to delineate the role of AHR in the context of Th17/Treg regulation both in vitro and in vivo. Here, we show that inhibition of the DRE-driven response is sufficient to suppress the Th17 differentiation. Also, we show that the suppression of Treg differentiation is dependent on the inhibition of the non-DRE mediated pathway. We have also delineated the role of DRE vs non-DRE driven responses of Th17 regulation in both an acute vs a chronic Th17 mediated diseases. In an acute inflammation using C. rodentium model of IBD (Inflammatory Bowel Disease) AHR agonist enhanced Th17 production and thereby promoted resolution of infection. On the other hand, using S. rectivirgula in a chronic mouse model of Hypersensitivity Pneumonitis we show that inhibition of DRE and /or non-DRE mediated response had minimal effect on IL-17A production but precludes Th17 plasticity by enabling secretion of alternate lineage antiinflammatory cytokines. This work has profound implication in pharmacological intervention in autoimmune and chronic inflammatory diseases by developing AHR compounds which can modulate DRE and non-DRE driven responses.
Advisors/Committee Members: August, Avery (chair), Denkers, Eric Young (committee member), Bynoe, Margaret S. (committee member).
Subjects/Keywords: Aryl Hydrocarbon Receptor; Th17; Tcell differentiation
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APA (6th Edition):
Mohinta, S. (2014). Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36177
Chicago Manual of Style (16th Edition):
Mohinta, Sonia. “Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function.” 2014. Doctoral Dissertation, Cornell University. Accessed January 28, 2021.
http://hdl.handle.net/1813/36177.
MLA Handbook (7th Edition):
Mohinta, Sonia. “Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function.” 2014. Web. 28 Jan 2021.
Vancouver:
Mohinta S. Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1813/36177.
Council of Science Editors:
Mohinta S. Role Of Aryl Hydrocarbon Receptor (Ahr) And The Effect Of Selective Ahr Modulators (Sahrms) On T Cell Differentiation And Effector Function. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36177
Penn State University
13.
Smith, Kayla Jo.
THE ROLE OF THE ARYL HYDROCARBON RECEPTOR IN MODULATING SKIN AND INTESTINAL EPITHELIAL PHYSIOLOGY.
Degree: 2017, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/13833kjs5049
► Barrier tissues such as the skin and intestine are important for the first line of defense against injury and exposure to potentially harmful toxicants or…
(more)
▼ Barrier tissues such as the skin and intestine are important for the first line of defense against injury and exposure to potentially harmful toxicants or pathogens from the external environment. The cellular response in these tissues to stimuli often begins with altered levels of gene expression. Ligand-activated transcription factors such as the
aryl hydrocarbon receptor (AHR) are important mediators of this response. Due to the complex nature of AHR activation and its often context-specific role in health and disease, the use of relevant in vitro and in vivo models is necessary to fully elucidate its specific roles in a particular tissue. This dissertation describes the characterization of an AHR-regulated gene in the skin which is induced in response to AHR activation and inflammatory stimuli, the development of a mouse model for studying AHR activation during ultraviolet light exposure, and the development of a mouse model for use in determining the role of AHR expression in intestinal epithelial cells. The results of these studies confirm both the complex nature of AHR activation in different contexts and the importance of its expression in barrier tissues.
Advisors/Committee Members: Gary Perdew, Dissertation Advisor/Co-Advisor, Gary Perdew, Committee Chair/Co-Chair, Jeffrey Peters, Committee Member, Robert Paulson, Committee Member, Edward Dudley, Outside Member, Richard Frisque, Committee Member.
Subjects/Keywords: aryl hydrocarbon receptor; skin; intestine; inflammation; keratinocyte
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APA (6th Edition):
Smith, K. J. (2017). THE ROLE OF THE ARYL HYDROCARBON RECEPTOR IN MODULATING SKIN AND INTESTINAL EPITHELIAL PHYSIOLOGY. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13833kjs5049
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Smith, Kayla Jo. “THE ROLE OF THE ARYL HYDROCARBON RECEPTOR IN MODULATING SKIN AND INTESTINAL EPITHELIAL PHYSIOLOGY.” 2017. Thesis, Penn State University. Accessed January 28, 2021.
https://submit-etda.libraries.psu.edu/catalog/13833kjs5049.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Smith, Kayla Jo. “THE ROLE OF THE ARYL HYDROCARBON RECEPTOR IN MODULATING SKIN AND INTESTINAL EPITHELIAL PHYSIOLOGY.” 2017. Web. 28 Jan 2021.
Vancouver:
Smith KJ. THE ROLE OF THE ARYL HYDROCARBON RECEPTOR IN MODULATING SKIN AND INTESTINAL EPITHELIAL PHYSIOLOGY. [Internet] [Thesis]. Penn State University; 2017. [cited 2021 Jan 28].
Available from: https://submit-etda.libraries.psu.edu/catalog/13833kjs5049.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Smith KJ. THE ROLE OF THE ARYL HYDROCARBON RECEPTOR IN MODULATING SKIN AND INTESTINAL EPITHELIAL PHYSIOLOGY. [Thesis]. Penn State University; 2017. Available from: https://submit-etda.libraries.psu.edu/catalog/13833kjs5049
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Penn State University
14.
Narayanan, Gitanjali A.
Selective Modulation of the AH Receptor Leads to Repression of Complement Factor Gene Expression.
Degree: 2012, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/13944
► Modulation of aryl hydrocarbon receptor (AHR) activity by a class of ligands termed selective AHR modulators (SAhRMs) has been demonstrated to attenuate pro-inflammatory gene expression…
(more)
▼ Modulation of
aryl hydrocarbon receptor (AHR) activity by a class of ligands termed selective AHR modulators (SAhRMs) has been demonstrated to attenuate pro-inflammatory gene expression and signaling, including repression of cytokine-mediated induction of acute phase genes (e.g, Saa1) . These effects are observed to occur through an AHR-dependent mechanism that does not require canonical signaling through dioxin response elements (DREs). Previously, we have demonstrated that the SAhRM, 3´,4´-dimethoxy-α-napthoflavone (DiMNF) can repress the cytokine-mediated induction of complement factor genes. Here, we report that activation of the AHR with DiMNF can suppress the cytokine-mediated induction of the membrane complement regulatory protein (mCRP) CD55, which, when expressed on host cells, facilitates the decay of the complement component 3 (C3) convertase, thereby protecting the cell from complement mediated lysis. Furthermore, we also demonstrate that the cytokine-mediated expression of the mCRP, CD46, is also repressed by DiMNF. Tumor cells often exhibit elevated CD55 and CD46 expression on the cell surface in the inflammatory microenvironment of the tumor and it is thought that such enhanced expression represents a means of escaping immune surveillance. DiMNF can repress the cytokine-mediated induction of CD55 mRNA and protein. Luciferase reporter analysis have identified possible response elements on the CD55 promoter, which may be targets for this repression. CD97 is the
receptor for CD55 and this binding has been shown to play a role in the development of inflammation and leukocyte trafficking, as well as stimulate tumor cell migration and angiogenesis. We report here that DiMNF is capable of repressing cytokine-mediated induction of CD97 expression in addition to CD46 and CD55. A C3 deposition assay with [125I]-C3 revealed that repression of cytokine-mediated CD55 expression by DiMNF led to an increase of C3 deposition on the surface of Huh7 cells, which would likely stimulate the formation of the membrane attack complex (MAC) and lead to complement-mediated lysis. We thereby suggest that SAhRMs such as DiMNF have therapeutic potential in regulating the immune response to tumor formation.
Advisors/Committee Members: Gary H Perdew, Thesis Advisor/Co-Advisor.
Subjects/Keywords: Aryl Hydrocarbon Receptor; Complement; CD55; DiMNF
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Narayanan, G. A. (2012). Selective Modulation of the AH Receptor Leads to Repression of Complement Factor Gene Expression. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13944
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Narayanan, Gitanjali A. “Selective Modulation of the AH Receptor Leads to Repression of Complement Factor Gene Expression.” 2012. Thesis, Penn State University. Accessed January 28, 2021.
https://submit-etda.libraries.psu.edu/catalog/13944.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Narayanan, Gitanjali A. “Selective Modulation of the AH Receptor Leads to Repression of Complement Factor Gene Expression.” 2012. Web. 28 Jan 2021.
Vancouver:
Narayanan GA. Selective Modulation of the AH Receptor Leads to Repression of Complement Factor Gene Expression. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Jan 28].
Available from: https://submit-etda.libraries.psu.edu/catalog/13944.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Narayanan GA. Selective Modulation of the AH Receptor Leads to Repression of Complement Factor Gene Expression. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/13944
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Houston
15.
Butler, Ryan 1986-.
Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ.
Degree: PhD, Biology, 2013, University of Houston
URL: http://hdl.handle.net/10657/956
► Ligand-activated transcription factors are a diverse group of proteins that are involved a variety of physiological processes. The purpose of these studies was to investigate…
(more)
▼ Ligand-activated transcription factors are a diverse group of proteins that are involved a variety of physiological processes. The purpose of these studies was to investigate the
aryl hydrocarbon receptor (AhR) knockout mouse and the effects of hormone replacement therapy on the postmenopausal breast in order to better understand the functions of the ligand-activated transcription factors AhR and estrogen
receptor β (ERβ).
In the first part of these studies, we investigated the AhR knockout mouse in order to further elucidate the physiological functions of AhR. These mice developed stones in their urinary bladders composed of 100% uric acid while the serum uric acid levels remained normal. We determined these stones were formed by the breakdown of DNA into uric acid from a large number of dying cells. These mice also develop fibrosis of their ventral prostates and a phenotype in the immune system similar to chronic myeloid leukemia.
The second part of these studies was to investigate the effects of hormone replacement therapy on the histology and expression of various ligand-activated transcription factors in the postmenopausal breast. We treated postmenopausal women with estrogen or estrogen-progesterone therapy for 3 months and took biopsies of the breasts before and after treatment. Expression of several proteins including AhR, ERα, and ERβ were unchanged after treatment while expression of progesterone receptors was increased. Proliferation and breast density were unchanged by treatment in these breasts;
however, we show possible mechanisms leading to proliferation and development of density in non-cancerous breast tissue.
In conclusion, these studies revealed a role for AhR in prostatic development, uric acid formation, and leukemia, and have provided new information on the safety of short-term use of HRT.
Advisors/Committee Members: Gustafsson, Jan-Åke (advisor), Warner, Margaret (committee member), Ziburkus, Jokubas (committee member), Webb, Paul (committee member).
Subjects/Keywords: Aryl hydrocarbon receptor; Estrogen receptors; Transcription factors
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APA (6th Edition):
Butler, R. 1. (2013). Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/956
Chicago Manual of Style (16th Edition):
Butler, Ryan 1986-. “Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ.” 2013. Doctoral Dissertation, University of Houston. Accessed January 28, 2021.
http://hdl.handle.net/10657/956.
MLA Handbook (7th Edition):
Butler, Ryan 1986-. “Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ.” 2013. Web. 28 Jan 2021.
Vancouver:
Butler R1. Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ. [Internet] [Doctoral dissertation]. University of Houston; 2013. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/10657/956.
Council of Science Editors:
Butler R1. Physiological and pathological aspects of the ligand-activated transcription factors: AhR and ERβ. [Doctoral Dissertation]. University of Houston; 2013. Available from: http://hdl.handle.net/10657/956
16.
BIAN HAO SHENG.
Induction of Human Sulfotransferase1A3 (Sult1A3) by nuclear receptors.
Degree: 2009, National University of Singapore
URL: https://scholarbank.nus.edu.sg/handle/10635/16313
Subjects/Keywords: Sulfotransferase; transcriptional regulation; nuclear receptor; glucocorticoid receptor; aryl hydrocarbon receptor; response element
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APA (6th Edition):
SHENG, B. H. (2009). Induction of Human Sulfotransferase1A3 (Sult1A3) by nuclear receptors. (Thesis). National University of Singapore. Retrieved from https://scholarbank.nus.edu.sg/handle/10635/16313
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
SHENG, BIAN HAO. “Induction of Human Sulfotransferase1A3 (Sult1A3) by nuclear receptors.” 2009. Thesis, National University of Singapore. Accessed January 28, 2021.
https://scholarbank.nus.edu.sg/handle/10635/16313.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
SHENG, BIAN HAO. “Induction of Human Sulfotransferase1A3 (Sult1A3) by nuclear receptors.” 2009. Web. 28 Jan 2021.
Vancouver:
SHENG BH. Induction of Human Sulfotransferase1A3 (Sult1A3) by nuclear receptors. [Internet] [Thesis]. National University of Singapore; 2009. [cited 2021 Jan 28].
Available from: https://scholarbank.nus.edu.sg/handle/10635/16313.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
SHENG BH. Induction of Human Sulfotransferase1A3 (Sult1A3) by nuclear receptors. [Thesis]. National University of Singapore; 2009. Available from: https://scholarbank.nus.edu.sg/handle/10635/16313
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
17.
Rajendra, Sharanya.
The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor Alpha.
Degree: 2013, University of Toronto
URL: http://hdl.handle.net/1807/43310
► TiPARP is a PARP-like mART that is induced by and negatively regulates AHR transactivation. Despite these insights, not much is known about TiPARP. This study…
(more)
▼ TiPARP is a PARP-like mART that is induced by and negatively regulates AHR transactivation. Despite these insights, not much is known about TiPARP. This study aimed to characterize the regulation of TiPARP by AHR, PDGFR, and ERα, and investigate potential receptor interplay. Gene expression studies revealed that coactivation of AHR and PDGFR can enhance TiPARP expression after 3 h relative to activation of either receptor pathway alone. Gene expression and ChIP studies demonstrated that while co-activation of AHR and ER enhanced AHR, ARNT, and ERα recruitment to the regulatory region of TiPARP, TiPARP mRNA levels were not potentiated by co-activation relative to activation of either pathway. Dissection of the 5’ regulatory region of TiPARP using reporter gene assays revealed that a putative AHRE cluster and an ERE half-site were functional. Lastly, overexpression of TiPARP with an estrogen-responsive reporter revealed that TiPARP can repress ERα signalling and requires its catalytic activity.
MAST
Advisors/Committee Members: Matthews, Jason, Pharmacology.
Subjects/Keywords: Aryl Hydrocarbon Receptor; Estrogen Receptor Alpha; TCDD; TiPARP; Gene Regulation; 0419
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APA ·
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to Zotero / EndNote / Reference
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APA (6th Edition):
Rajendra, S. (2013). The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor Alpha. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/43310
Chicago Manual of Style (16th Edition):
Rajendra, Sharanya. “The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor Alpha.” 2013. Masters Thesis, University of Toronto. Accessed January 28, 2021.
http://hdl.handle.net/1807/43310.
MLA Handbook (7th Edition):
Rajendra, Sharanya. “The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor Alpha.” 2013. Web. 28 Jan 2021.
Vancouver:
Rajendra S. The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor Alpha. [Internet] [Masters thesis]. University of Toronto; 2013. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1807/43310.
Council of Science Editors:
Rajendra S. The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor Alpha. [Masters Thesis]. University of Toronto; 2013. Available from: http://hdl.handle.net/1807/43310
University of Alberta
18.
El Gendy, Mohamed, A M.
Identifying Aryl Hydrocarbon Receptor Modulators from a
Natural Source.
Degree: PhD, Faculty of Pharmacy and Pharmaceutical
Sciences, 2012, University of Alberta
URL: https://era.library.ualberta.ca/files/f7623d21k
► Dioxins are widespread environmental contaminants that have been linked to a variety of deleterious effects on human health including increased cancer rates via aryl hydrocarbon…
(more)
▼ Dioxins are widespread environmental contaminants that
have been linked to a variety of deleterious effects on human
health including increased cancer rates via aryl hydrocarbon
receptor (AhR)-dependent mechanism. AhR is a transcription factor
that regulates the expression of the carcinogen-activating enzyme,
cytochrome P450 1A1 (CYP1A1). Activation of AhR and its regulated
gene, CYP1A1, have been correlated with the incidence of several
cancers. Therefore, the use of AhR antagonists has been proposed as
a promising chemopreventative approach. Nonetheless, most of the
currently used AhR antagonists are not specific to AhR and some of
them act as partial agonists. Therefore, the search for new AhR
antagonists is still in progress. The specific objectives of the
present work were to identify new AhR modulators from a natural
source. In this regard, first we demonstrated that Peganum harmala,
a common traditional plant in Middle East, and North Africa,
significantly inhibited the dioxin-mediated induction of CYP1A1 at
mRNA, protein and activity levels using human and mouse hepatoma
cells. The role of AhR was confirmed using AhR-dependent luciferase
assay and electrophoretic mobility shift assay. Additionally, we
identified two β-carboline alkaloids (harmine and harmaline) as the
active constituents of the plant extract. Second, we demonstrated
that harman, a common β-carboline in several foods and drinks and
the parent structure of harmine, significantly induced CYP1A1
mainly through an AhR-dependent mechanism. Third, the active
constituents of Peganum harmala extract, harmine and harmaline, and
their metabolites, harmol and harmalol, significantly decreased the
dioxin-mediated induction of CYP1A1 at mRNA, protein and activity
levels via transcriptional (through AhR) and post-translational
(through ubiquitin-proteasomal pathway as well as a direct
inhibitory effect on CYP1A1 enzyme). Additionally, we demonstrated
that harmine, harmol, and harmalol can act as direct antagonists
for AhR, whereas harmalol affected AhR activation without a direct
interfering with AhR binding to its ligands. Finally, we confirmed
the effect of harmine and harmaline on dioxin-mediated induction of
Cyp1a1 in vivo using the responsive C57BL/6 mouse strain. In
conclusion, our data clearly demonstrate the promising effects of
Peganum harmala, harmine, harmol, harmaline, and harmalol to
prevent the toxicity and carcinogenicity of several AhR
ligands.
Subjects/Keywords: Cytochrome P450 1A1; harmol; Aryl Hydrocarbon Receptor; harmalol; harmine; Peganum harmala; Aryl Hydrocarbon Receptor antagonists from natural
source; harmaline; harman; Chemoprevention
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APA ·
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MLA ·
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Export
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Manager
APA (6th Edition):
El Gendy, Mohamed, A. M. (2012). Identifying Aryl Hydrocarbon Receptor Modulators from a
Natural Source. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/f7623d21k
Chicago Manual of Style (16th Edition):
El Gendy, Mohamed, A M. “Identifying Aryl Hydrocarbon Receptor Modulators from a
Natural Source.” 2012. Doctoral Dissertation, University of Alberta. Accessed January 28, 2021.
https://era.library.ualberta.ca/files/f7623d21k.
MLA Handbook (7th Edition):
El Gendy, Mohamed, A M. “Identifying Aryl Hydrocarbon Receptor Modulators from a
Natural Source.” 2012. Web. 28 Jan 2021.
Vancouver:
El Gendy, Mohamed AM. Identifying Aryl Hydrocarbon Receptor Modulators from a
Natural Source. [Internet] [Doctoral dissertation]. University of Alberta; 2012. [cited 2021 Jan 28].
Available from: https://era.library.ualberta.ca/files/f7623d21k.
Council of Science Editors:
El Gendy, Mohamed AM. Identifying Aryl Hydrocarbon Receptor Modulators from a
Natural Source. [Doctoral Dissertation]. University of Alberta; 2012. Available from: https://era.library.ualberta.ca/files/f7623d21k
INP Toulouse
19.
Malaisé, Yann.
Caractérisation chez la souris adulte des impacts immuno-modulateurs des bisphénols après exposition périnatale : conséquences sur la fonction "barrière" de l'intestin et la susceptibilité aux désordres métaboliques : Characterization of immuno-modulatory impacts of bisphenols after perinatal exposure in adult mice : consequences on the gut barrier function and the susceptibility to metabolic disorders.
Degree: Docteur es, Pathologie, Toxicologie, Génétique et Nutrition, 2017, INP Toulouse
URL: http://www.theses.fr/2017INPT0119
► Le bisphénol A (BPA) est un perturbateur endocrinien couramment employé dans l’industrie agroalimentaire, en particulier pour les matériaux en contact des denrées alimentaires. Son utilisation…
(more)
▼ Le bisphénol A (BPA) est un perturbateur endocrinien couramment employé dans l’industrie agroalimentaire, en particulier pour les matériaux en contact des denrées alimentaires. Son utilisation dans la fabrication de polycarbonates et de résines époxy, recouvrant la face interne des boîtes de conserve et des canettes, en fait un contaminant ubiquitaire de l’alimentation humaine. L’augmentation de l’exposition humaine à ce contaminant a été corrélée avec la récurrence de certains troubles comme l’intolérance alimentaire, l’obésité ou le diabète de type 2. Ces dernières années, une attention particulière a été portée sur sa capacité à perturber différentes fonctions physiologiques, dont celle du système immunitaire, après exposition périnatale à des niveaux environnementaux pertinents pour l’Homme. Dans une première étude, nous avons montré qu’une exposition périnatale au BPA à 50 µg/kg de poids corporel/jour induit une diminution de l’activité anti-microbienne corrélée à une chute de l’expression du lysozyme dans l’iléon de la descendance femelle. La perméabilité intestinale de ces individus augmente en association avec le niveau d’IFN- dans les muqueuses du côlon. De plus, nous observons une diminution des plasmocytes à IgA associée à une perte de sécrétion d’IgA dans les fèces, démontrant un défaut de la fonction barrière et des défenses de l’intestin chez la descendance BPA. De manière intéressante, une diminution de la fréquence des ILC3 intestinaux est observée chez ces individus, avec une augmentation du niveau d’IgG sanguin dirigé contre une E.coli commensale. Ces effets sont associés à un défaut de maturation et de capacité migratoire des cellules de la lamina propria (LP) et de la rate. L’exposition périnatale au BPA provoque une augmentation de la sécrétion d’IFN- et d’IL-17 après re-stimulation in vitro CD3/CD28 des cellules de la LP, et une réponse de type Th17 dans la rate. Réunis, ces effets confortent la capacité du BPA, lors d’une exposition périnatale, à induire une intolérance alimentaire chez la descendance femelle. Dans une seconde étude, nous avons mis en évidence que l’exposition périnatale au BPA, à la même dose, induit des perturbations de l’homéostasie du système immunitaire intestinal et systémique chez la descendance mâle au jour 45, via une diminution de la fréquence des Th1 et Th17 dans la LP et une augmentation de la réponse Th1 et Th17 dans la rate. Ces impacts apparaissent en parallèle avec une altération de la sensibilité au glucose, une diminution de la sécrétion d’IgA dans les fèces et un appauvrissement des bifodobacteria dans le microbiote intestinal de ces individus. L’ensemble de ces évènements précède l’infiltration de macrophages M1 pro-inflammatoires dans le tissu adipeux péri-gonadique, en association avec une diminution de la sensibilité à l’insuline et une augmentation du poids corporel apparaissant avec le vieillissement (jour 170) chez la descendance BPA. Cette étude longitudinale a permis de proposer une séquence d’évènements aboutissant à un phénotype obèse et au T2D…
Advisors/Committee Members: Piriou-Guzylack, Laurence (thesis director), Houdeau, Eric (thesis director).
Subjects/Keywords: Bisphénols; Système immunitaire; Intestin; Désordres métaboliques; Aryl hydrocarbon receptor; Bisphenols; Immune system; Gut; Metabolic disorders; Aryl hydrocarbon receptor
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APA ·
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MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Malaisé, Y. (2017). Caractérisation chez la souris adulte des impacts immuno-modulateurs des bisphénols après exposition périnatale : conséquences sur la fonction "barrière" de l'intestin et la susceptibilité aux désordres métaboliques : Characterization of immuno-modulatory impacts of bisphenols after perinatal exposure in adult mice : consequences on the gut barrier function and the susceptibility to metabolic disorders. (Doctoral Dissertation). INP Toulouse. Retrieved from http://www.theses.fr/2017INPT0119
Chicago Manual of Style (16th Edition):
Malaisé, Yann. “Caractérisation chez la souris adulte des impacts immuno-modulateurs des bisphénols après exposition périnatale : conséquences sur la fonction "barrière" de l'intestin et la susceptibilité aux désordres métaboliques : Characterization of immuno-modulatory impacts of bisphenols after perinatal exposure in adult mice : consequences on the gut barrier function and the susceptibility to metabolic disorders.” 2017. Doctoral Dissertation, INP Toulouse. Accessed January 28, 2021.
http://www.theses.fr/2017INPT0119.
MLA Handbook (7th Edition):
Malaisé, Yann. “Caractérisation chez la souris adulte des impacts immuno-modulateurs des bisphénols après exposition périnatale : conséquences sur la fonction "barrière" de l'intestin et la susceptibilité aux désordres métaboliques : Characterization of immuno-modulatory impacts of bisphenols after perinatal exposure in adult mice : consequences on the gut barrier function and the susceptibility to metabolic disorders.” 2017. Web. 28 Jan 2021.
Vancouver:
Malaisé Y. Caractérisation chez la souris adulte des impacts immuno-modulateurs des bisphénols après exposition périnatale : conséquences sur la fonction "barrière" de l'intestin et la susceptibilité aux désordres métaboliques : Characterization of immuno-modulatory impacts of bisphenols after perinatal exposure in adult mice : consequences on the gut barrier function and the susceptibility to metabolic disorders. [Internet] [Doctoral dissertation]. INP Toulouse; 2017. [cited 2021 Jan 28].
Available from: http://www.theses.fr/2017INPT0119.
Council of Science Editors:
Malaisé Y. Caractérisation chez la souris adulte des impacts immuno-modulateurs des bisphénols après exposition périnatale : conséquences sur la fonction "barrière" de l'intestin et la susceptibilité aux désordres métaboliques : Characterization of immuno-modulatory impacts of bisphenols after perinatal exposure in adult mice : consequences on the gut barrier function and the susceptibility to metabolic disorders. [Doctoral Dissertation]. INP Toulouse; 2017. Available from: http://www.theses.fr/2017INPT0119
Penn State University
20.
Patel, Rushang Dilipkumar.
REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION.
Degree: 2008, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/8497
► Adaptation in response to changes in internal as well as external environment is imperative to sustenance of life. Modulation of gene expression is a critical…
(more)
▼ Adaptation in response to changes in internal as well as external environment is imperative to sustenance of life. Modulation of gene expression is a critical component of this adaptive response and is mediated by activation of various transcription factors. Individual signaling pathways have been well characterized for many transcription factor systems.
Aryl hydrocarbon receptor (AHR) is a transcription factor that is activated by a variety of structurally diverse ligands, including the environmental contaminant dioxin, the cigarette smoke constituent benzo[a]pyrene and the therapeutically prescribed drug omeprazole. Prior to activation, AHR is primarily located in a cytoplasmic complex with chaperone and co-chaperone proteins. Ligand-binding is believed to initiate a conformational change that leads to
nuclear translocation, dissociation from the chaperones and heterodimerization with AHR-
nuclear translocator (ARNT). AHR-ARNT heterodimer recognizes and binds to a consensus DNA sequence (TNGCGTG), commonly referred to as a dioxin response element (DRE), to drive transcription of target genes. Phase I and II xenobiotic metabolism enzymes have been the well-characterized targets of AHR-mediated transactivation. This sequence of coordinate events has been described as the classical pathway of AHR activity. Different lines of evidence suggest that AHR serves physiologically relevant functions, though the details have not been elucidated. The goal of this research project was to identify previously uncharacterized targets of AHR-mediated gene regulation and to investigate the hypothesis that AHR functions through mechanisms that are independent of DNA-binding. The advances in performing genome-wide transcriptional profiling at the time of commencement of this project, encouraged the use of DNA-microarray technology for identifying new target genes. Epiregulin, a potent mitogen belonging to the epidermal growth factor family, was discovered to be regulated by AHR in immortalized murine hepatocytes. The fact that a number of AHR ligands have been associated with carcinogenesis signifies that the induction of growth factors like epiregulin might be a potential mechanism for AHR-mediated tumor enhancement. The next phase of this project led to the identification of the constitutive androstane
receptor (CAR), another
receptor involved in drug metabolism, as an in vivo target of AHR activation. This association between AHR-CAR highlights the possibility of crosstalk between AHR and other pathways. Exposure to divergent stimuli leads to simultaneous activation of multiple signaling pathways. This suggests that it is essential to study the networking of various pathways to be able to predict the biological outcomes. The third phase of this project focuses on the ability of AHR to modulate the inflammatory pathway and on the involved mechanism. AHR activation can repress the acute-phase response (APR) gene expression, implicated in disorders like septic shock and Alzheimer’s, partly by antagonizing NF-êB mediated gene regulation…
Advisors/Committee Members: Gary H Perdew, Committee Chair/Co-Chair, Curtis John Omiecinski, Committee Member, Jeffrey Maurice Peters, Committee Member, Robert Bruce Mitchell, Committee Member, Naomi S Altman, Committee Member, Peter John Hudson, Committee Member.
Subjects/Keywords: Aryl hydrocarbon receptor; Dioxin; Inflammation; Toxicology; Nuclear receptor; Gene regulation
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APA (6th Edition):
Patel, R. D. (2008). REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8497
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Patel, Rushang Dilipkumar. “REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION.” 2008. Thesis, Penn State University. Accessed January 28, 2021.
https://submit-etda.libraries.psu.edu/catalog/8497.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Patel, Rushang Dilipkumar. “REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION.” 2008. Web. 28 Jan 2021.
Vancouver:
Patel RD. REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Jan 28].
Available from: https://submit-etda.libraries.psu.edu/catalog/8497.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Patel RD. REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8497
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
21.
Yang, Yang.
Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells.
Degree: 2015, University of Toronto
URL: http://hdl.handle.net/1807/73180
► The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor best known for mediating the toxic actions of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).…
(more)
▼ The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor best known for mediating the toxic actions of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The aryl hydrocarbon receptor repressor (AHRR) is an AHR regulated gene and a negative regulator of AHR. Although the mechanism of AHRR-dependent repression of AHR is not clear, one of the proposed mechanisms is through direct competition or interaction with AHR at DNA sequences termed aryl hydrocarbon response elements (AHREs). This thesis aimed to compare the genome-wide binding profiles of AHR and AHRR in MCF-7 cells treated for 24 h with 10nM TCDD using ChIP-seq. Although AHRE was overrepresented in both AHR- and AHRR-bound regions, AHRR was shown to bind closer promoter regions than AHR. AHR- or AHRR-independent regulations of the identified genes were also confirmed. This work is the first genome-wide mapping of AHRR-bound regions which provides insight into potential novel functions for AHRR.
M.Sc.
Advisors/Committee Members: Matthews, Jason, Pharmacology.
Subjects/Keywords: Aryl hydrocarbon receptor (AHR); Aryl hydrocarbon receptor repressor (AHRR); Aryl hydrocarbon response element (AHRE); Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq); dioxin; DNA binding; 0383
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APA (6th Edition):
Yang, Y. (2015). Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/73180
Chicago Manual of Style (16th Edition):
Yang, Yang. “Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells.” 2015. Masters Thesis, University of Toronto. Accessed January 28, 2021.
http://hdl.handle.net/1807/73180.
MLA Handbook (7th Edition):
Yang, Yang. “Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells.” 2015. Web. 28 Jan 2021.
Vancouver:
Yang Y. Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1807/73180.
Council of Science Editors:
Yang Y. Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/73180
University of Toronto
22.
Crosby, Michael.
Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.
Degree: 2017, University of Toronto
URL: http://hdl.handle.net/1807/79379
► Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, triggering many biological effects typified by induction of cytochrome P450 1A1 (CYP1A1).…
(more)
▼ Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, triggering many biological effects typified by induction of cytochrome P450 1A1 (CYP1A1). Interestingly, little is known about their effects on human CYP3A4, despite this enzymeâ s clinical relevance. Controversially, studies have reported both inductive and suppressive effects of PAHs on CYP3A expression. The current study used 3-methylcholanthrene (3-MC) to study the effects of PAHs on CYP3A4 activity and expression in humanized PXR-CAR-CYP3A4/3A7 mice. Adult mice were treated by intraperitoneal injection with 3-MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours later. Basal hepatic CYP3A4 activity and expression was significantly higher in female vs. male mice. 3-MC decreased CYP3A4 activity and expression in female mice at 72 hours, whilemales showed similar, but non-statistically significant, trends. This mouse model will facilitate further in vivo studies of the mechanisms and consequences of CYP3A4 suppression by PAHs.
M.Sc.
Advisors/Committee Members: Riddick, David S, Pharmacology.
Subjects/Keywords: aryl hydrocarbon receptor; Cyp3a11; drug metabolism; drug metabolizing enzyme; P450; polycyclic aromatic hydrocarbon; 0419
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APA (6th Edition):
Crosby, M. (2017). Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/79379
Chicago Manual of Style (16th Edition):
Crosby, Michael. “Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.” 2017. Masters Thesis, University of Toronto. Accessed January 28, 2021.
http://hdl.handle.net/1807/79379.
MLA Handbook (7th Edition):
Crosby, Michael. “Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.” 2017. Web. 28 Jan 2021.
Vancouver:
Crosby M. Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1807/79379.
Council of Science Editors:
Crosby M. Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79379
University of Otago
23.
Kazantseva, Marina Grigorievna.
Smoking, genes and inflammation
.
Degree: 2012, University of Otago
URL: http://hdl.handle.net/10523/2496
► Rheumatoid arthritis (RA) is an, autoimmune disease where genetic predisposition and environmental factors increase the risk of developing RA and the severity of the disease.…
(more)
▼ Rheumatoid arthritis (RA) is an, autoimmune disease where genetic predisposition and environmental factors increase the risk of developing RA and the severity of the disease. Cigarette smoking is the major recognised environmental risk factor, and there is a combined effect from smoking and the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype on the risk of developing RA. This study sought to establish any direct effect of smoking and/or the genetic predisposition on the inflammation driving RA and to identify biological mechanism(s) that might explain epidemiological data linking smoking, genetics and RA.
The aim of initial work was to establish any involvement of
aryl hydrocarbon receptor (AHR)-mediated mechanisms within inflamed rheumatoid tissues. The expression of AHR, CYP1A1 and AHRR genes were quantified by real-time PCR in twenty synovial and eighteen subcutaneous nodule tissues. Patient’s smoking status was established at the time tissue was obtained. The results show smoking causes significant AHR activation in joint synovial tissue, but not in rheumatoid nodule tissues. A subset of synovial DCs show activated AHR in smokers, consistent with the sensitivity of human mo-DCs stimulated with the AHR agonist, benzo(a)pyrene (BaP) in vitro. It is concluded that DCs within the joint synovium are the principal immune cells that respond to cigarette smoke exposure.
Microarray analysis revealed that the expression of 547 synovial genes was up-regulated by smoking, including folate
receptor 1 (FOLR1), matrix metalloproteinases (MMP)9, MMP11 and MMP14, TNF-superfamily members, TNFSF10/TRAIL and TNFRSF10B/TRAILR2 and transcription factors, RUNX1 and RUNX2. Cell motility and adhesion were the biological processes in synovium most affected by smoking. The expression of 307 synovial genes was down-regulated by smoking, including the vascular “protective” genes, KLF2 and eNOS, suggesting that endothelial function is affected by smoking with implications for vasculitis and the development of rheumatoid nodules associated with severe RA.
Any effect of smoking and SE copy number on genes associated with AHR signalling and other immune-inflammatory genes was established. Results suggest there are solitary, reciprocal or synergistic effects from smoking and the SE in rheumatoid inflammation, which are gene dependent. Thus, smoking increases AHR activation in synovium; the SE has no effect. Furthermore, while smoking reduces IL17A expression in synovial tissue, indications are that SE copy number increases IL17A expression. In combination, smoking and the SE increase synovial MMP9 gene expression.
Human promonocytic U937 cells were used to model the effect of BaP exposure on MMP9 expression. PMA-activated U937 cells acquire an ability to respond to BaP, including with increased MMP9 gene expression. AHR-specific siRNA, confirmed that AHR regulates MMP9 gene expression.
Further data implicate different MMPs in rheumatoid tissue destruction. High MMP7 expression by macrophages occurs in a subset of nodule tissues.…
Advisors/Committee Members: Hessian, Paul A (advisor).
Subjects/Keywords: rheumatoid arthritis;
inflammation;
smoking;
aryl hydrocarbon receptor;
matrix metalloproteinases
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APA (6th Edition):
Kazantseva, M. G. (2012). Smoking, genes and inflammation
. (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/2496
Chicago Manual of Style (16th Edition):
Kazantseva, Marina Grigorievna. “Smoking, genes and inflammation
.” 2012. Doctoral Dissertation, University of Otago. Accessed January 28, 2021.
http://hdl.handle.net/10523/2496.
MLA Handbook (7th Edition):
Kazantseva, Marina Grigorievna. “Smoking, genes and inflammation
.” 2012. Web. 28 Jan 2021.
Vancouver:
Kazantseva MG. Smoking, genes and inflammation
. [Internet] [Doctoral dissertation]. University of Otago; 2012. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/10523/2496.
Council of Science Editors:
Kazantseva MG. Smoking, genes and inflammation
. [Doctoral Dissertation]. University of Otago; 2012. Available from: http://hdl.handle.net/10523/2496
Universiteit Utrecht
24.
Mooij, F.A. de.
The Aryl Hydrocarbon receptor and intestinal immunity: an overview of ligands derived from microbial metabolism and food.
Degree: 2015, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/309341
► Layman’s summary Everybody knows that eating vegetables and overall healthy food is beneficial for your health. In recent years advertisers also started to tell us…
(more)
▼ Layman’s summary
Everybody knows that eating vegetables and overall healthy food is beneficial for your health. In recent years advertisers also started to tell us that products such as Yakult© that contain bacteria can improve the wellbeing of our intestines1. This is why a lot of research has been going towards finding the mechanisms behind these healthy bacteria and the beneficial effects of healthy food. It is now suggested that there could be a link between these two.
Our bodies are built of cells that obtain their energy from food. In our intestines we have a lot of bacteria that helps us digest our food. This may sound weird, but in contrast to bacteria in other parts of our body, bacteria in the intestine are not harmful as long as there is a state of symbiosis. The cells of our intestines are not able to use all the food that we eat because they lack the machinery to make little pieces of it that can get absorbed into the cells. That’s where our resident bacteria come in. They have different machinery that help us process certain types of food into the small pieces we need. When these small pieces of food are taken up by the intestinal cells, they can start processes within the cells by binding to receptors. For instance, this could lead to the development and activation of the immune system. This can help to keep the balance between the intestine and the resident bacteria. Recent research has shown us that an important
receptor in this process is the
Aryl Hydrocarbon Receptor (AhR).
The AhR can assist in protecting our intestines from harm by activating part of our immune system. They do so by activating the cells to produce signaling molecules, one of the most important ones is interleukin 22 (IL-22). This IL-22 is on its own able to bind its own specific
receptor on other cells thereby amplifying the signal and activating these cells to start secreting small proteins such as defensins. As the name suggests, these defensins are small proteins that can kill the bacteria. With the secretion of defensins the amount of bacteria can be controlled, hereby keeping the balance to provide symbiosis. Next to the activation of cells to produce defensins, the activation of the AhR also leads to the development of other cells from our immune system, thereby making sure that we are well protected in the long run.
As described, via activation of the AhR we can modulate the health of our intestines. It is therefore very interesting to know how we can activate this
receptor. It is now suggested that the small molecules that bind the AhR can come from our food. For instance, tryptophan, which is an amino acid, gets cut by the gut bacteria into kynurenine which is then able to bind and activate the AhR. A particular group of bacteria, the lactobacilli, are very able to contribute to this process. Additionally, small molecules derived from food such as broccoli and cabbage have been shown to activate the AhR. One of these molecules is known as indole-3-carbinol.
In conclusion, activating the AhR in the intestines…
Advisors/Committee Members: Loonen, Dr. L., Wichers, Prof. H., Pieters, Dr. R..
Subjects/Keywords: ahr; aryl hydrocarbon receptor; probiotics; microbiotics; indole-3-carbinol; tryptophan
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APA (6th Edition):
Mooij, F. A. d. (2015). The Aryl Hydrocarbon receptor and intestinal immunity: an overview of ligands derived from microbial metabolism and food. (Masters Thesis). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/309341
Chicago Manual of Style (16th Edition):
Mooij, F A de. “The Aryl Hydrocarbon receptor and intestinal immunity: an overview of ligands derived from microbial metabolism and food.” 2015. Masters Thesis, Universiteit Utrecht. Accessed January 28, 2021.
http://dspace.library.uu.nl:8080/handle/1874/309341.
MLA Handbook (7th Edition):
Mooij, F A de. “The Aryl Hydrocarbon receptor and intestinal immunity: an overview of ligands derived from microbial metabolism and food.” 2015. Web. 28 Jan 2021.
Vancouver:
Mooij FAd. The Aryl Hydrocarbon receptor and intestinal immunity: an overview of ligands derived from microbial metabolism and food. [Internet] [Masters thesis]. Universiteit Utrecht; 2015. [cited 2021 Jan 28].
Available from: http://dspace.library.uu.nl:8080/handle/1874/309341.
Council of Science Editors:
Mooij FAd. The Aryl Hydrocarbon receptor and intestinal immunity: an overview of ligands derived from microbial metabolism and food. [Masters Thesis]. Universiteit Utrecht; 2015. Available from: http://dspace.library.uu.nl:8080/handle/1874/309341
University of Rochester
25.
Pena, Fanny Lys Casado.
Activation of the Aryl Hydrocarbon Receptor Signaling by
2,3,7,8 Tetra-chlorodibenzo-p-dioxin (TCDD) Alters Cell Function
and Pathway-specific Gene Modulation of Hematopoietic
Stem/Progenitor Cells.
Degree: PhD, 2011, University of Rochester
URL: http://hdl.handle.net/1802/15793
► The aryl hydrocarbon receptor (Ahr) mediates the toxicity of certain environmental pollutants including dioxins. Accidental dioxin exposure to humans has been correlated with blood malignancies…
(more)
▼ The aryl hydrocarbon receptor (Ahr) mediates the
toxicity of certain environmental pollutants including dioxins.
Accidental dioxin exposure to humans has been correlated with blood
malignancies such as leukemia and lymphoma. Dioxin exposure
suppresses immune responses in mammals via Ahr by several
mechanisms including altering the functional ability of
hematopoietic progenitors to seed the thymus. Also, exposure alters
population of the spleen and reconstitution of peripheral blood and
bone marrow. The Ahr is a ligand-activated transcription factor
without any established endogenous ligand or physiological role in
hematopoietic cells.
To explain the decreased reconstitution of
bone marrow, I hypothesized that dioxin exposure alters the numbers
of hematopoietic stem/progenitor cells and/or the trafficking of
these populations to the bone marrow. Furthermore, I hypothesized
that these cellular consequences of TCDD exposure are secondary to
an alteration of transcriptionally regulated pathways related to
cell-to-cell signaling and cellular movement. Colony-forming assays
and competitive repopulation experiments were used to quantify
sub-populations of LSKs. In vivo dioxin exposure increased the
numbers of multipotent progenitors but did not change the numbers
of functional hematopoietic stem cells (HSCs). Trafficking of LSKs
to the bone marrow in vivo, and to the chemokine Cxcl12 in vitro
were decreased. Transcripts involved in cell-to-cell signaling
(Ccl3, Cd69, Cxcl2, Cox-2, Mmp8) and cellular movement (Scin,
Mmp8), as well as hematological system development and function
(Egr-1, Ccl3, Cd69, Cxcl2, Cox-2) were altered in TCDD-exposed
LSKs. Altogether these data support a physiological role of the Ahr
to regulate homeostasis in HSCs. Disruption of Ahr expression or
activity may predispose more differentiated populations to acquire
malignant behaviors and reduce the ability of HSCs to respond to
stress or injury.
The mechanism of action for an Ahr ligand to
alter cell function and pathway-specific gene modulation of LSKs as
defined in this work provides a rationale to examine possible
preventive measures in populations exposed to Ahr ligands. Being
the Ahr a ligand-activated transcription factor, therapeutic
interventions that regulate the expansion, migration and
differentiation of HSCs or selective modulation of
specific-hematopoietic lineages may be explored.
Subjects/Keywords: Aryl Hydrocarbon Receptor; Hematopoiesis; Stem Cells; Toxicology; Dioxin
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APA (6th Edition):
Pena, F. L. C. (2011). Activation of the Aryl Hydrocarbon Receptor Signaling by
2,3,7,8 Tetra-chlorodibenzo-p-dioxin (TCDD) Alters Cell Function
and Pathway-specific Gene Modulation of Hematopoietic
Stem/Progenitor Cells. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/15793
Chicago Manual of Style (16th Edition):
Pena, Fanny Lys Casado. “Activation of the Aryl Hydrocarbon Receptor Signaling by
2,3,7,8 Tetra-chlorodibenzo-p-dioxin (TCDD) Alters Cell Function
and Pathway-specific Gene Modulation of Hematopoietic
Stem/Progenitor Cells.” 2011. Doctoral Dissertation, University of Rochester. Accessed January 28, 2021.
http://hdl.handle.net/1802/15793.
MLA Handbook (7th Edition):
Pena, Fanny Lys Casado. “Activation of the Aryl Hydrocarbon Receptor Signaling by
2,3,7,8 Tetra-chlorodibenzo-p-dioxin (TCDD) Alters Cell Function
and Pathway-specific Gene Modulation of Hematopoietic
Stem/Progenitor Cells.” 2011. Web. 28 Jan 2021.
Vancouver:
Pena FLC. Activation of the Aryl Hydrocarbon Receptor Signaling by
2,3,7,8 Tetra-chlorodibenzo-p-dioxin (TCDD) Alters Cell Function
and Pathway-specific Gene Modulation of Hematopoietic
Stem/Progenitor Cells. [Internet] [Doctoral dissertation]. University of Rochester; 2011. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1802/15793.
Council of Science Editors:
Pena FLC. Activation of the Aryl Hydrocarbon Receptor Signaling by
2,3,7,8 Tetra-chlorodibenzo-p-dioxin (TCDD) Alters Cell Function
and Pathway-specific Gene Modulation of Hematopoietic
Stem/Progenitor Cells. [Doctoral Dissertation]. University of Rochester; 2011. Available from: http://hdl.handle.net/1802/15793
University of Rochester
26.
Latchney, Sarah Elizabeth.
Pluripotent Neural Stem Cells are Targets for Dioxin
Toxicity: Novel Roles for the Aryl Hydrocarbon Receptor during
Neurogenesis.
Degree: PhD, 2012, University of Rochester
URL: http://hdl.handle.net/1802/19821
► The ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; Dioxin) has been linked to neurotoxicity in humans and experimental animals. TCDD exerts its toxicity by binding to the…
(more)
▼ The ubiquitous environmental contaminant
2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD; Dioxin) has been linked
to neurotoxicity in humans and experimental
animals. TCDD exerts
its toxicity by binding to the aryl hydrocarbon receptor (AhR),
a
ligand-activated bHLH/PAS transcription factor. Although the
endogenous
functions of AhR remain unknown, certain bHLH/PAS
proteins have been implicated
in cell proliferation,
differentiation, and cell fate decisions. Therefore, it is
conceivable that AhR plays similar roles during neurogenesis. TCDD,
through
binding and activating the AhR, causes numerous
neurological deficits. However, the
specific cellular targets and
mechanisms of AhR-mediated TCDD neurotoxicity are
not well
defined. Our laboratory has determined that AhR is robustly
expressed in
multipotent neural progenitor cells (NPCs) during
critical neurogenic periods,
implicating a mechanistic link
between TCDD-mediated toxicity and impaired brain
development.
This thesis project tested the hypothesis that NPCs are primary
targets for AhR-mediated TCDD neurotoxicity. As a result, AhR
activation by
TCDD impairs neurogenesis. A corollary to this
hypothesis is that AhR
intrinsically regulates neurogenesis in the
absence of an exogenous ligand.
Studies with the C17.2 NPC model
and primary cultures of NPCs from embryonic
mouse forebrain
demonstrate that NPCs possess an intact AhR pathway that is
responsive to TCDD. In these in vitro studies, TCDD reduced NPC
proliferation and
interfered with neuronal differentiation by
disrupting the expression of cell cycle
regulatory molecules.
Furthermore, in vivo TCDD exposure during a critical period of
NPC
expansion and peak AhR expression also diminished NPC birth in the
ventricular zone of the embryonic forebrain, confirming our in
vitro results. In adult
animals, AhR-deficient mice exhibited
significant impairments in contextual fear
memory, while
hippocampal-independent memory remained intact. AhR-deficient
mice
also exhibited reduced proliferation and neuronal differentiation
of adult-born
NPCs in the neurogenic dentate gyrus of the
hippocampus. Moreover, modulation of
AhR activity by TCDD in adult
wild-type mice disrupted hippocampal-dependent
contextual memory
and reduced cell birth and neuronal differentiation. Our findings
demonstrate the AhR is a novel transcriptional regulator during
developmental and
adult neurogenesis. As a result, modulation of
AhR activity by TCDD precludes the
AhR from performing its
endogenous function, leading to neurotoxicity and
dysfunction.
Subjects/Keywords: Hippocampus; Neurotoxicity; Neurogenesis; Neural Stem Cells; Dioxin; Aryl Hydrocarbon Receptor
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APA (6th Edition):
Latchney, S. E. (2012). Pluripotent Neural Stem Cells are Targets for Dioxin
Toxicity: Novel Roles for the Aryl Hydrocarbon Receptor during
Neurogenesis. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/19821
Chicago Manual of Style (16th Edition):
Latchney, Sarah Elizabeth. “Pluripotent Neural Stem Cells are Targets for Dioxin
Toxicity: Novel Roles for the Aryl Hydrocarbon Receptor during
Neurogenesis.” 2012. Doctoral Dissertation, University of Rochester. Accessed January 28, 2021.
http://hdl.handle.net/1802/19821.
MLA Handbook (7th Edition):
Latchney, Sarah Elizabeth. “Pluripotent Neural Stem Cells are Targets for Dioxin
Toxicity: Novel Roles for the Aryl Hydrocarbon Receptor during
Neurogenesis.” 2012. Web. 28 Jan 2021.
Vancouver:
Latchney SE. Pluripotent Neural Stem Cells are Targets for Dioxin
Toxicity: Novel Roles for the Aryl Hydrocarbon Receptor during
Neurogenesis. [Internet] [Doctoral dissertation]. University of Rochester; 2012. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1802/19821.
Council of Science Editors:
Latchney SE. Pluripotent Neural Stem Cells are Targets for Dioxin
Toxicity: Novel Roles for the Aryl Hydrocarbon Receptor during
Neurogenesis. [Doctoral Dissertation]. University of Rochester; 2012. Available from: http://hdl.handle.net/1802/19821
University of Rochester
27.
Bennett, John A.
Lack of Aryl Hydrocarbon Receptor Alters Gene Expression
and Functional Capacity of Murine Hematopoietic Stem
Cells.
Degree: PhD, 2015, University of Rochester
URL: http://hdl.handle.net/1802/30118
► All mature cell lineages of the peripheral blood and adaptive immune system are generated from bone marrow stem cells known as hematopoietic stem cells (HSCs).…
(more)
▼ All mature cell lineages of the peripheral blood
and adaptive immune system are generated from bone marrow stem
cells known as hematopoietic stem cells (HSCs). Lack of aryl
hydrocarbon receptor (AhR) signaling, or treatment with AhR
agonists such as TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin) , has
been shown to alter the phenotype and functional ability of HSCs,
suggesting a role for the AhR in regulating HSC function and
output. Most classical studies on AhR have been undertaken using
TCDD or other xenobiotic ligands to modulate AhR activity. While
these studies have revealed a wealth of information regarding AhR
target genes and signaling networks in a variety of cell types
(including HSCs), it has remained difficult to determine which
endpoints / regulatory target genes are adaptive or toxic responses
due to exposure to AhR ligands versus normal targets and functions
under homeostatic conditions.
Studies were performed using both
global AhR-null allele (AhR-KO) mice as well as hematopoietic
system restricted AhRfx/fxVav1-Cre (CKO) mice in order to better
understand the HSC-intrinsic physiological role of AhR in
regulating HSC function and output. These studies revealed a
surprising lack of phenocopy between the two strains. Aged KO
animals display an expansion of peripheral white blood cells which
is not found in aged CKO animals. KO animals have enhanced levels
of oxidative stress in bone marrow progenitors, as well as evidence
of DNA damage and decreased expression of p16. CKO animals only
display enhanced oxidative capacity at the time point examined.
Microarray studies on long term HSCs were undertaken in order to
examine
the differences in cell signaling and gene expression that
could be driving these unexpected differences in phenotype. The two
strains display very little overlap in genes with differential
expression relative to control at young ages, but become more
similar with aging. Gene Set Enrichment Analysis revealed
significant enrichment in a variety of gene sets that are related
to HSC function, or involved in the etiology of certain diseases
such as leukemia or myeloproliferation. A subset of differentially
expressed genes that changed expression due to both aging and lack
of AhR expression (Pdgf-D, Smo, Zbtb37, and Zfp382), and that
contain AhR binding sites in their upstream regulatory regions,
change expression when AhR expression is silenced in wild-type
hematopoietic cells. Taken together, these data reveal potential
genes that AhR may intrinsically regulate in HSCs throughout aging
of the hematopoietic system. Given the lack of phenocopy and the
small degree of overlap differentially expressed genes in HSCs
between KO and CKO mice, these data also implicate AhR in
non-hematopoietic stromal cells of the bone marrow as having a
regulatory effect on HSC function and output.
Subjects/Keywords: AhR; Aryl Hydrocarbon Receptor; Hematopoiesis; Hematopoietic Stem Cell
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APA (6th Edition):
Bennett, J. A. (2015). Lack of Aryl Hydrocarbon Receptor Alters Gene Expression
and Functional Capacity of Murine Hematopoietic Stem
Cells. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/30118
Chicago Manual of Style (16th Edition):
Bennett, John A. “Lack of Aryl Hydrocarbon Receptor Alters Gene Expression
and Functional Capacity of Murine Hematopoietic Stem
Cells.” 2015. Doctoral Dissertation, University of Rochester. Accessed January 28, 2021.
http://hdl.handle.net/1802/30118.
MLA Handbook (7th Edition):
Bennett, John A. “Lack of Aryl Hydrocarbon Receptor Alters Gene Expression
and Functional Capacity of Murine Hematopoietic Stem
Cells.” 2015. Web. 28 Jan 2021.
Vancouver:
Bennett JA. Lack of Aryl Hydrocarbon Receptor Alters Gene Expression
and Functional Capacity of Murine Hematopoietic Stem
Cells. [Internet] [Doctoral dissertation]. University of Rochester; 2015. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1802/30118.
Council of Science Editors:
Bennett JA. Lack of Aryl Hydrocarbon Receptor Alters Gene Expression
and Functional Capacity of Murine Hematopoietic Stem
Cells. [Doctoral Dissertation]. University of Rochester; 2015. Available from: http://hdl.handle.net/1802/30118
University of Rochester
28.
Boule , Lisbeth A.
Characterizing the Effects of Developmental Activation of
the Aryl Hydrocarbon Receptor on CD4+ T Cell Responses Later in
Life.
Degree: PhD, 2015, University of Rochester
URL: http://hdl.handle.net/1802/30128
► Developmental exposures have been shown to alter immune-mediated processes later in life, yet the mechanism by which this occurs is unknown. In fact, in most…
(more)
▼ Developmental exposures have been shown to alter
immune-mediated processes
later in life, yet the mechanism by
which this occurs is unknown. In fact, in most cases it
is unclear
which cell types and molecular machinery are affected. Many studies
have
examined early life exposures to chemicals that activate the
aryl hydrocarbon receptor
(AhR). Cells of the immune system
express this receptor, and AhR activation in the fully
mature
immune system (i.e., non-developmental exposure) alters CD4+ T
cell-dependent
immune responses. However, little is known about
how activation of the AhR during
development changes the function
of CD4+ T cells in adult offspring. Therefore, using
mouse models
of human disease, we determined whether developmental exposure to
the
prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) affects CD4+ T cell
responses in adult offspring. For the
majority of work in this project, we used influenza A
virus
infection to initiate an immune response. Developmentally exposed
adult mice
infected with influenza virus had fewer conventional
effector CD4+ T cells in draining
lymph nodes of the lung, yet an
increase in regulatory CD4+ T cells (Tregs). In contrast,
the
lungs of these mice had an increase in all CD4+ T cell subsets.
Using a combination
of tools, including adoptive transfers and the
cre-loxP system, we determined that the
altered CD4+ T cell
response to infection in developmentally exposed mice reflects a
combination of intrinsic and extrinsic changes in CD4+ T cells,
which are revealed in a
tissue-specific manner. While the
extrinsic factors triggered by developmental exposure
that
influence CD4+ T cell function later in life remain to be
elucidated, we determined
that these changes require live,
replicating virus in the lung, suggesting a novel effect of
developmental exposure on the structural cells of the lung. The
implications of this work
extend beyond influenza virus infection,
as we observe changes in disease progression in
developmentally
exposed offspring in a CD4+ T cell dependent model of systemic
autoimmunity. Together, this work establishes that CD4+ T cells are
changed by
activation of the AhR during development, and that
these modifications have the
potential to mediate the persistent
alterations in immune responses observed in exposed
human
populations.
Subjects/Keywords: Aryl Hydrocarbon Receptor; CD4 T Cell; Developmental Exposure
Record Details
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Boule , L. A. (2015). Characterizing the Effects of Developmental Activation of
the Aryl Hydrocarbon Receptor on CD4+ T Cell Responses Later in
Life. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/30128
Chicago Manual of Style (16th Edition):
Boule , Lisbeth A. “Characterizing the Effects of Developmental Activation of
the Aryl Hydrocarbon Receptor on CD4+ T Cell Responses Later in
Life.” 2015. Doctoral Dissertation, University of Rochester. Accessed January 28, 2021.
http://hdl.handle.net/1802/30128.
MLA Handbook (7th Edition):
Boule , Lisbeth A. “Characterizing the Effects of Developmental Activation of
the Aryl Hydrocarbon Receptor on CD4+ T Cell Responses Later in
Life.” 2015. Web. 28 Jan 2021.
Vancouver:
Boule LA. Characterizing the Effects of Developmental Activation of
the Aryl Hydrocarbon Receptor on CD4+ T Cell Responses Later in
Life. [Internet] [Doctoral dissertation]. University of Rochester; 2015. [cited 2021 Jan 28].
Available from: http://hdl.handle.net/1802/30128.
Council of Science Editors:
Boule LA. Characterizing the Effects of Developmental Activation of
the Aryl Hydrocarbon Receptor on CD4+ T Cell Responses Later in
Life. [Doctoral Dissertation]. University of Rochester; 2015. Available from: http://hdl.handle.net/1802/30128
Penn State University
29.
Girer, Nathaniel Gabriel.
AN EXAMINATION OF THE ARYL HYDROCARBON RECEPTOR IN LIVER METABOLISM.
Degree: 2016, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/13610nug128
► The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor from the basic helix-loop-helix PER/ARNT/SIM family of proteins that is evolutionarily conserved in both vertebrates…
(more)
▼ The
aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor from the basic helix-loop-helix PER/ARNT/SIM family of proteins that is evolutionarily conserved in both vertebrates and invertebrates. Known as a "promiscuous"
receptor, AHR can bind to several different classes of chemical compounds such as polycyclic aromatic hydrocarbons (PAH) and flavonoids. When not bound to ligand, AHR resides in a cytosolic complex containing two molecules of heat shock protein 90, one molecule of X-associated protein 2, and a molecule of p23. Upon ligand binding, this complex is transported to the nucleus via
nuclear importins and AHR dissociates to form a heterodimer with
aryl hydrocarbon nuclear translocator (ARNT). The AHR/ARNT heterodimer then binds to specific DNA sequences known as dioxin response elements (DRE) within the promoter region of target genes (e.g. cytochrome P450 enzyme 1A1, CYP1A1) to activate their transcription.
Previous studies have primarily examined AHR within the context of ligand-mediated transcriptional activation of its prototypical target gene, Cyp1a1. However, the AHR can also influence gene transcription in the absence of exogenous ligand and/or Cyp1a1 expression. Using a conditional AHR knockout mouse model that lacks hepatocyte-specific AHR expression (Ahrfx/fxAlbCre), this dissertation examines how basal AHR activity in the absence of Cyp1a1 transcription can influence metabolic homeostasis. In particular, the data reveal that the loss of hepatocyte-specific AHR expression correlates with reduced body and liver mass relative to congenic AHR-expressing mice (Ahrfx/fx). Additionally, Ahrfx/fxAlbCre mice maintained on purified AIN-93M diet display impaired glucose tolerance without any perturbations of insulin sensitivity. Conversely, Ahrfx/fxAlbCre mice challenged with a high-sucrose dietary modification of AIN-93M exhibit reduced insulin sensitivity without any difference in glucose tolerance. Most notably, Ahrfx/fxAlbCre mice challenged with a high-fat/high-sucrose (HF/HS) diet exhibit significantly decreased gene/protein expression of key enzymes involved in de novo fatty acid synthesis and fatty acid import, as well as significantly increased expression of key fatty acid export genes. Furthermore, inflammatory gene expression is also significantly reduced in HF/HS-fed Ahrfx/fxAlbCre mice relative to Ahrfx/fx. Together, the data suggest that basal hepatocyte-specific AHR signaling may promote diet-induced steatohepatitis in Ahrfx/fx mice.
Utilizing the Ahrfx/fxAlbCre mouse model, this dissertation also explores the role of AHR in regulating hepatic fibroblast growth factor 21 (FGF21) production. FGF21 is an important metabolic hormone and regulator of the fasting response. Notably, FGF21 can attenuate obesity-associated morbidities when administered to various genetic and diet-induced mouse models of the disease. In the absence of exogenous AHR ligand, non-fasted Ahrfx/fxAlbCre mice exhibit 4-fold greater hepatic Fgf21 expression relative to Ahrfx/fx, along with elevated…
Advisors/Committee Members: Gary Perdew, Dissertation Advisor/Co-Advisor, Gary Perdew, Committee Chair/Co-Chair, Andrew Patterson, Committee Member, Jeffrey Peters, Committee Member, Connie Rogers, Outside Member, Ross Hardison, Committee Member, Ross Hardison, Committee Member.
Subjects/Keywords: Aryl Hydrocarbon Receptor; Fibroblast growth factor 21; Liver Metabolism
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Girer, N. G. (2016). AN EXAMINATION OF THE ARYL HYDROCARBON RECEPTOR IN LIVER METABOLISM. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13610nug128
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Girer, Nathaniel Gabriel. “AN EXAMINATION OF THE ARYL HYDROCARBON RECEPTOR IN LIVER METABOLISM.” 2016. Thesis, Penn State University. Accessed January 28, 2021.
https://submit-etda.libraries.psu.edu/catalog/13610nug128.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Girer, Nathaniel Gabriel. “AN EXAMINATION OF THE ARYL HYDROCARBON RECEPTOR IN LIVER METABOLISM.” 2016. Web. 28 Jan 2021.
Vancouver:
Girer NG. AN EXAMINATION OF THE ARYL HYDROCARBON RECEPTOR IN LIVER METABOLISM. [Internet] [Thesis]. Penn State University; 2016. [cited 2021 Jan 28].
Available from: https://submit-etda.libraries.psu.edu/catalog/13610nug128.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Girer NG. AN EXAMINATION OF THE ARYL HYDROCARBON RECEPTOR IN LIVER METABOLISM. [Thesis]. Penn State University; 2016. Available from: https://submit-etda.libraries.psu.edu/catalog/13610nug128
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Penn State University
30.
Hubbard, Troy David.
Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor.
Degree: 2017, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/13677tdh176
► The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor of the basic region helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) homology super family. The AHR was first identified…
(more)
▼ The
aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor of the basic region helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) homology super family. The AHR was first identified as the primary mediator of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity and regulator of xenobiotic metabolism. Further investigation revealed AHR possesses a promiscuous ligand binding domain (LBD) that is able to bind to an array of exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs). Following ligand-binding, the AHR forms a functional heterodimeric transcription factor with AHR
nuclear translocator (ARNT) and regulates expression of target genes via binding of dioxin response elements (DREs) within their promoters.
The physiological activity of the AHR has expanded to include pivotal roles within immune regulation, mucosal barrier function, cell cycle progression, organogenesis, circadian rhythm, and cellular differentiation pathways. However, these functions often require the ligand activated form of the
receptor and are known to occur in the absence of exogenous ligand. This finding led to the premise and eventual characterization of endogenous AHR ligands. The catabolism of the amino acid tryptophan by commensal microorganisms, endogenous enzymes, and radical oxidation is a known source of numerous AHR ligands.
The studies presented in here build upon previously published data establishing microbial metabolism as a reservoir of endogenous ligand production. In our research we have identified the microbial tryptophan metabolite indole as a human AHR selective agonist through SAR studies and in silico modeling of AHR-ligand molecular docking. In silico molecular docking models support observations of differential indole responsiveness between species through a unique bi-molecular (2:1) binding stoichiometry that is sterically permissive within the human AHR, but not its mouse homolog. The capacity for host cells to sense microbial indole through the AHR may be paramount to the establishment of an inter-kingdom signaling pathway that affects maintenance of intestinal homeostasis.
Molecular functionalities of the AHR, such as heterodimerization with ARNT and binding of DREs, are conserved among vertebrate and invertebrate species. However, ligand specificity of the AHR can vary between species. Comparative studies have shown that the human AHR displays reduced binding capacity with regard to prototypical PAH agonists when compared to rodent homologs. Such differences suggest that divergence of the AHR ligand binding domain (LBD) structure during the course of mammalian evolution facilitated interspecies variation in ligand selectivity.
Here we present evidence supporting the hypothesis that selective desensitization of the human AHR to PAHs arose during speciation of Homo sapiens. Interspecies AHR analyses, through utilization of ligand binding assay, DNA binding assay, and AHR-dependent gene expression identified a single amino acid substitution (A381V)…
Advisors/Committee Members: Dr. Gary Perdew, Dissertation Advisor/Co-Advisor, Dr. Andrew Patterson, Committee Chair/Co-Chair, Dr. Jeffrey Peters, Committee Member, Dr. Ming Tien, Committee Member, Dr. Edward Dudley, Outside Member.
Subjects/Keywords: aryl hydrocarbon receptor; AHR; Evolution; Ligand selectivity; PAHs; Toxicity
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hubbard, T. D. (2017). Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13677tdh176
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Hubbard, Troy David. “Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor.” 2017. Thesis, Penn State University. Accessed January 28, 2021.
https://submit-etda.libraries.psu.edu/catalog/13677tdh176.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hubbard, Troy David. “Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor.” 2017. Web. 28 Jan 2021.
Vancouver:
Hubbard TD. Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor. [Internet] [Thesis]. Penn State University; 2017. [cited 2021 Jan 28].
Available from: https://submit-etda.libraries.psu.edu/catalog/13677tdh176.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hubbard TD. Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor. [Thesis]. Penn State University; 2017. Available from: https://submit-etda.libraries.psu.edu/catalog/13677tdh176
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
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Open Access Theses and Dissertations