You searched for subject:(nuclear receptor).
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University of Illinois – Urbana-Champaign
1.
Parent, Alexander A.
Second-site inhibitors of the estrogen and androgen hormone receptors.
Degree: PhD, 0335, 2012, University of Illinois – Urbana-Champaign
URL: http://hdl.handle.net/2142/29523 
► The estrogen and androgen receptors are members of the nuclear hormone receptor protein superfamily and play an important role in the development of primary and…
(more)
▼ The estrogen and androgen receptors are members of the
nuclear hormone
receptor protein superfamily and play an important role in the development of primary and secondary female and male sexual characteristics. Although necessary for proper development, in certain contexts activation of these receptors contributes to the formation and progression of hyperplastic diseases, namely breast and prostate cancers. Current treatment for metastatic hormone responsive breast and prostate tumors involves either chemical ‘castration’ techniques which target the synthesis of the endogenous estrogen and androgen agonists, or the administration of hormone antagonists which displace endogenous agonist from the ligand binding domain of the
receptor causing a conformational change such that the transcriptional activity of the protein is inhibited. While efficacious for a duration ranging from a few months to years, breast and prostate tumors eventually cease to respond to these treatments, entering a hormone-refractory state for which there is no adequate treatment.
Multiple new approaches to estrogen and androgen
receptor inhibition have been reported in recent years. Among these are efforts to directly disrupt the
nuclear receptor/coactivator and the
nuclear receptor/DNA interactions, and to increase degradation of
receptor through binding of small-molecules at non-traditional binding sites. Due to the essential nature of these interactions for estrogen and androgen
receptor signaling, it has been proposed that such second-site inhibition may be less susceptible to the mutations and
receptor and coregulator overexpression that are currently exhibited in hormone-refractory breast and prostate cancers.
As described herein, we have investigated a number of chemical systems for their ability to disrupt the estrogen and androgen
receptor/steroid
receptor coactivator interaction. In chapters 2 and 3 we describe the structure-based design of pyrimidine-core small-molecules that mimic the three interacting leucine/phenylalanine residues of the estrogen and androgen
receptor coactivators. Members of this library bind to both
nuclear receptors and disrupt the
nuclear receptor/coactivator complex with Ki’s in the low micromolar range. In our screening against the two subtypes of the estrogen
receptor, we discovered a only few compounds that exhibited binding to the estrogen
receptor beta, and the vast majority show strong preference for estrogen
receptor alpha inhibition. Based on its ability to accommodate larger aromatic residues at the coactivator binding site, we anticipated that pyrimidine-core molecules with bulky aromatic substituents would selectively bind to the androgen
receptor. Indeed, this approach produced multiple coactivator binding inhibitors that displayed potent and selective inhibition of the androgen
receptor, without concomitant disruption of the estrogen
receptor/coactivator complex.
During the synthesis of the pyrimidine-core coactivator binding inhibitors, a tetra-aryl cyclobutane compound that showed potent…
Advisors/Committee Members: Katzenellenbogen, John A. (advisor), Katzenellenbogen, John A. (Committee Chair), van der Donk, Wilfred A. (committee member), Hergenrother, Paul J. (committee member), Gennis, Robert B. (committee member).
Subjects/Keywords: estrogen receptor; androgen receptor; inhibitor; nuclear receptor
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APA (6th Edition):
Parent, A. A. (2012). Second-site inhibitors of the estrogen and androgen hormone receptors. (Doctoral Dissertation). University of Illinois – Urbana-Champaign. Retrieved from http://hdl.handle.net/2142/29523
Chicago Manual of Style (16th Edition):
Parent, Alexander A. “Second-site inhibitors of the estrogen and androgen hormone receptors.” 2012. Doctoral Dissertation, University of Illinois – Urbana-Champaign. Accessed January 22, 2021.
http://hdl.handle.net/2142/29523.
MLA Handbook (7th Edition):
Parent, Alexander A. “Second-site inhibitors of the estrogen and androgen hormone receptors.” 2012. Web. 22 Jan 2021.
Vancouver:
Parent AA. Second-site inhibitors of the estrogen and androgen hormone receptors. [Internet] [Doctoral dissertation]. University of Illinois – Urbana-Champaign; 2012. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/2142/29523.
Council of Science Editors:
Parent AA. Second-site inhibitors of the estrogen and androgen hormone receptors. [Doctoral Dissertation]. University of Illinois – Urbana-Champaign; 2012. Available from: http://hdl.handle.net/2142/29523
UCLA
2.
Sallam, Tamer.
Characterization of Novel Liver X Receptor Regulatory Circuits.
Degree: Molec, Cell, & Integ Physiology, 2014, UCLA
URL: http://www.escholarship.org/uc/item/1608s1wp
► The liver X receptors (LXRs) are members of the nuclear receptors superfamily of transcription factors. Multiple lines of evidence established LXRs as crucial regulators of…
(more)
▼ The liver X receptors (LXRs) are members of the nuclear receptors superfamily of transcription factors. Multiple lines of evidence established LXRs as crucial regulators of metabolic homeostasis. Upon activation by cholesterol intermediates, LXRs induce the expression of a cluster of genes involved in cholesterol efflux, catabolism, and storage. In addition, activation of LXRs represses inflammatory signaling and enhances cellular survival against noxious stimuli. The diverse biologic roles of LXRs have made them attractive targets for pharmacologic manipulation.In this work, we utilized unbiased high-throughput genome-wide screens to identify novel LXR target genes.
Subjects/Keywords: Medicine; Cholesterol; Nuclear Receptor
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APA (6th Edition):
Sallam, T. (2014). Characterization of Novel Liver X Receptor Regulatory Circuits. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/1608s1wp
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):
Sallam, Tamer. “Characterization of Novel Liver X Receptor Regulatory Circuits.” 2014. Thesis, UCLA. Accessed January 22, 2021.
http://www.escholarship.org/uc/item/1608s1wp.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sallam, Tamer. “Characterization of Novel Liver X Receptor Regulatory Circuits.” 2014. Web. 22 Jan 2021.
Vancouver:
Sallam T. Characterization of Novel Liver X Receptor Regulatory Circuits. [Internet] [Thesis]. UCLA; 2014. [cited 2021 Jan 22].
Available from: http://www.escholarship.org/uc/item/1608s1wp.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sallam T. Characterization of Novel Liver X Receptor Regulatory Circuits. [Thesis]. UCLA; 2014. Available from: http://www.escholarship.org/uc/item/1608s1wp
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Southern California
3.
Lee, Janet M.
The mechanism of recruitment of Tip60 to ER target
genes.
Degree: MS, Biochemistry & Molecular Biology, 2011, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/441052/rec/6984
► The steroid receptors in the nuclear receptor superfamily are responsible for regulating many different functions including transcription. However, in order to completely and correctly activate…
(more)
▼ The steroid receptors in the
nuclear receptor
superfamily are responsible for regulating many different functions
including transcription. However, in order to completely and
correctly activate transcription, the steroid receptors must
recruit not only the general initiation factors but also other
coregulatory factors, such chromatin remodelers and coactivators.
Tip60, a 60 kD protein with an N-terminal chromodomain, a central
intrinsic histone acetyltransferase (HAT) activity, and a
C-terminal
nuclear receptor binding domain (NR box) was previously
reported to be a coactivator for androgen
receptor, in addition to
being able to bind to the estrogen
receptor in vivo. Subsequently,
Tip60 was identified to be recruited very early on to the pS2
estrogen response element1 (ERE1) site, hormone binding enhancer
elements involved in transactivation, upon hormone treatment. Here,
it is shown that the interaction between Tip60 and the estrogen
receptor, both in vivo and in vitro, requires ligand binding to
estrogen
receptor and also interacts via the C-terminal NR box,
specifically the LXXLL motif. Furthermore, the abolishment of the
LXXLL motif compromises Tip60’s recruitment to certain estrogen
response elements (EREs) of ER target genes. In addition, the
N-terminal chromodomain is shown to preferentially bind to histone
H3 mono-methylated and di-methylated at lysine4. Finally, it is
shown that a competition for methylated histones between the
wildtype Tip60 and the exogenously expressed Tip60 chromodomain
fragment also compromises its recruitment to certain EREs of ER
target genes. Thus, the stable recruitment and association of Tip60
at the EREs is dependent upon the normal function of its N-terminal
chromodomain and C-terminal NR box.
Advisors/Committee Members: (Committee Chair), Stallcup, Michael R. (Committee Member), Tokes, Zoltan A. (Committee Member), Rice, Judd C. (Committee Member).
Subjects/Keywords: Tip60; coactivator; nuclear receptor
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APA (6th Edition):
Lee, J. M. (2011). The mechanism of recruitment of Tip60 to ER target
genes. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/441052/rec/6984
Chicago Manual of Style (16th Edition):
Lee, Janet M. “The mechanism of recruitment of Tip60 to ER target
genes.” 2011. Masters Thesis, University of Southern California. Accessed January 22, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/441052/rec/6984.
MLA Handbook (7th Edition):
Lee, Janet M. “The mechanism of recruitment of Tip60 to ER target
genes.” 2011. Web. 22 Jan 2021.
Vancouver:
Lee JM. The mechanism of recruitment of Tip60 to ER target
genes. [Internet] [Masters thesis]. University of Southern California; 2011. [cited 2021 Jan 22].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/441052/rec/6984.
Council of Science Editors:
Lee JM. The mechanism of recruitment of Tip60 to ER target
genes. [Masters Thesis]. University of Southern California; 2011. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/441052/rec/6984
4.
Caiozzi, Gianella C.
Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract.
Degree: 2013, University of Nevada – Reno
URL: http://hdl.handle.net/11714/3044
► Hypertriglyceridemia is a prevalent condition that is associated with cardiovascular disease. Grape seed procyanidin extract (GSPE), a natural compound rich in procyanidins, has recently been…
(more)
▼ Hypertriglyceridemia is a prevalent condition that is associated with cardiovascular disease. Grape seed
procyanidin extract (GSPE), a natural compound rich in procyanidins, has recently been shown to reduce
serum triglyceride (TG) levels in vivo in normolipidemic animals. This effect was shown to be mediated
via farnesoid X
receptor (FXR), a member of the
nuclear hormone
receptor (NHR) superfamily. NHRs
are ligand-inducible, and in some cases ligand-independent, transcription factors that interact with DNA
to regulate gene expression. Activation of FXR by its endogenous ligand, bile acids (BA), modulates TG
and BA homeostasis via regulation of hepatic and intestinal gene expression. Activation of FXR in the
liver by BAs increases the expression of small heterodimer partner (SHP), which then acts as a repressor
to decrease hepatic expression of sterol response element binding protein 1c (SREBP1c), a key
transcription factor regulating lipogenic gene expression, thereby lowering serum TG levels. Studies have
shown that in the liver, GSPE acts as a co-agonist ligand for FXR resulting in enhancement of BA-bound
FXR activation in vitro, and that the TG-lowering ability of GSPE is lost in vivo in both, FXR and SHP
knockout mouse models. Recently, utilizing a FXRE-luciferase reporter mouse model, it was shown that
the intestine has the highest bile acid-induced FXR signaling under physiological conditions. FXR
activation in the intestine induces the expression of several FXR target-genes including intestinal bile
acid-binding protein (IBABP), organic solute transporters (OST) α/β, and fibroblast growth factor (FGF)
15/19, while repressing the expression of the apical sodium dependent bile acid transporter (ASBT),
which contributes to bile acid enterohepatic recirculation and bile acid homeostasis.
The overall aim of this research was to further investigate the effects of GSPE to aid in the understanding
of its molecular hypotriglyceridemic mode of action. Based on the fact that FXR is a bridge between the
liver and the intestine to control bile acid levels and to regulate bile acid synthesis and enterohepatic flow,
the first aim was to discern whether or not GSPE exerts any effects on intestinal FXR which could then
contribute to the TG-lowering effect of GSPE. Therefore, the effects of GSPE on the regulation of known FXR target-genes in the intestine was investigated, to provide further insight into the inter-relationship
between the intestine and the liver in the regulation of lipid homeostasis by GSPE.
Studies have previously established the ability of GSPE to lower serum TG levels in a normolipidemic
state, therefore, the second aim was to determine the potential of GSPE to lower serum TG levels in a
hypertriglyceridemic state, and to identify the underlying molecular events.
Our results indicate that in the intestine, GSPE may act as a gene-selective bile acid
receptor modulator
(BARM), rather than a bile acid-dependent co-agonist of FXR, as previously reported to occur in the
liver. In…
Advisors/Committee Members: Ricketts, Marie-Louise (advisor), Omaye, Stanley (committee member), Teglas, Mike (committee member), Shintani, David (committee member).
Subjects/Keywords: Nuclear hormone receptor; Procyanidins
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Manager
APA (6th Edition):
Caiozzi, G. C. (2013). Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract. (Thesis). University of Nevada – Reno. Retrieved from http://hdl.handle.net/11714/3044
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):
Caiozzi, Gianella C. “Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract.” 2013. Thesis, University of Nevada – Reno. Accessed January 22, 2021.
http://hdl.handle.net/11714/3044.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Caiozzi, Gianella C. “Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract.” 2013. Web. 22 Jan 2021.
Vancouver:
Caiozzi GC. Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract. [Internet] [Thesis]. University of Nevada – Reno; 2013. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/11714/3044.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Caiozzi GC. Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract. [Thesis]. University of Nevada – Reno; 2013. Available from: http://hdl.handle.net/11714/3044
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
5.
Batista, Fernanda Aparecida Heleno.
Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPARδ.
Degree: PhD, Física Aplicada, 2012, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01062012-175615/
;
► Os PPARs são fatores de transcrição ativados por ligantes, pertencentes à superfamília dos receptores nucleares, que são considerados sensores de lipídeos capazes de transformar alterações…
(more)
▼ Os PPARs são fatores de transcrição ativados por ligantes, pertencentes à superfamília dos receptores nucleares, que são considerados sensores de lipídeos capazes de transformar alterações nos padrões de lipídeos/ácidos graxos dos organismos em atividade metabólica. Com isto, os 3 isotipos (α, δ e γ) estão associados a diferentes desordens metabólicas como doenças vasculares, diabetes, obesidade, câncer e certas doenças mentais que constituem um grave problema de saúde pública mundial, o que torna esta classe de proteínas, um valioso alvo para a indústria farmacêutica. Embora a importância do hPPARδ na regulação da transcrição de genes relacionados a uma série de processos metabólicos seja conhecida, não há ainda nenhum fármaco no mercado cujo alvo seja este receptor. O maior conhecimento a respeito da estrutura deste receptor pode trazer esclarecimentos capazes de auxiliar o desenvolvimento racional de fármacos. Desta forma, no presente trabalho, buscou-se encontrar características estruturais importantes para a seletividade e especificidade dos ligantes pelo isotipo δ. Para tal, determinou-se as condições de expressão e purificação da proteína hPPARδ LBD, bem como as condições apropriadas de manutenção da mesma por meio da técnica de dicroísmo circular. O estado oligomérico deste receptor foi determinado em solução através das técnicas de cromatografia por exclusão de tamanho e por espalhamento dinâmico de luz, onde se concluiu que a proteína é monomérica nas condições testadas. Além disto, através de uma estrutura de alta resolução da proteína hPPARδ LBD com o ligante GW 0742, propôs-se a construção de dois mutantes, V312M e I328M, através dos quais concluiu-se que estes dois resíduos são potencialmente importantes para interação de ligantes estruturalmente relacionados com GW 0742, ao isotipo δ, indicando dois determinantes relacionados à seletividade de ligantes por este isotipo. Como existem poucos relatos sobre a estrutura completa deste receptor, e consequentemente da influência que os domínios N-terminal e DBD apresentam sobre o domínio LBD, um breve estudo da interação diferencial entre o receptor nuclear hPPARδ Full e três diferentes cofatores, em presença de ligante agonista e antagonista foi realizado. Para isto, determinou-se as condições de expressão e purificação da proteína hPPARδ Full, e prosseguiu-se com ensaios de anisotropia de fluorescência, através dos quais ficou claro que cada cofator apresenta um padrão diferente de interação com a proteína que pode ser dependente de outras regiões da proteína além daquelas já classicamente descritas. Isto é um forte indicativo de que diferentes regiões do hPPARδ podem ser chave no processo de regulação por intermédio de cofatores.
PPARs are transcription factors activated by ligands, belonging to the superfamily of nuclear receptors, which are considered to be lipid sensors capable of making changes in patterns of lipid/fatty acid metabolic activity of organisms. The three isotypes…
Advisors/Committee Members: Polikarpov, Igor.
Subjects/Keywords: Ligand; Ligantes; Nuclear Receptor; PPAR; PPAR; Receptor Nuclear
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APA ·
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APA (6th Edition):
Batista, F. A. H. (2012). Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPARδ. (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01062012-175615/ ;
Chicago Manual of Style (16th Edition):
Batista, Fernanda Aparecida Heleno. “Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPARδ.” 2012. Doctoral Dissertation, University of São Paulo. Accessed January 22, 2021.
http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01062012-175615/ ;.
MLA Handbook (7th Edition):
Batista, Fernanda Aparecida Heleno. “Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPARδ.” 2012. Web. 22 Jan 2021.
Vancouver:
Batista FAH. Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPARδ. [Internet] [Doctoral dissertation]. University of São Paulo; 2012. [cited 2021 Jan 22].
Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01062012-175615/ ;.
Council of Science Editors:
Batista FAH. Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPARδ. [Doctoral Dissertation]. University of São Paulo; 2012. Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01062012-175615/ ;
6.
Liberato, Marcelo Vizoná.
Ácidos graxos de cadeia média como ligantes da proteína PPAR.
Degree: Mestrado, Física Aplicada, 2009, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-19032009-111236/
;
► Receptores ativados da proliferação de peroxissomos (PPAR) são receptores nucleares que regulam o metabolismo de gordura e glicose, adipogênese e polarização de macrófagos, e são…
(more)
▼ Receptores ativados da proliferação de peroxissomos (PPAR) são receptores nucleares que regulam o metabolismo de gordura e glicose, adipogênese e polarização de macrófagos, e são os mediadores da ação de uma grande classe de fármacos usada no tratamento de diabetes tipo 2, as tiazolidinadionas (TZD). Enquanto as TZDs reduzem a glicose do sangue e aumentam efetivamente a sensibilidade à insulina, elas podem também apresentar efeitos colaterais como aumento do risco de complicações cardiovasculares, ganho de peso, retenção de fluido e toxicidade hepática. Por causa disso, novos fármacos que possuem respostas mais favoráveis devem ser desenvolvidos, e o mecanismo de ativação do PPAR por ligantes vem sendo intensamente examinado. Para entender a relação entre a ligação de agonistas ao PPAR e a ativação transcricional, pretendíamos primeiramente obter cristais de PPAR-LBD (domínio de ligação ao ligante) humano na forma apo. Porém, surpreendentemente, a análise do sítio de ligação ao ligante revelou a presença de três pequenas moléculas, identificadas como ácidos nonanoicos e octanoicos. Este trabalho reporta a análise da estrutura cristalográfica do PPAR LBD complexado simultaneamente com três ácidos graxos de cadeia média (AGCM), provindos de bactérias (organismo de expressão), localizados no sítio de ligação ao ligante. A análise estrutural e funcional sugere que os AGCM são agonistas parciais que estabilizam a conformação do LBD do PPAR por mecanismo independente da hélice 12.
PPARs (peroxisome proliferator activated receptors) are nuclear receptors that regulate glucose and fat metabolism, adipogenesis and macrophage polarization and mediate actions of a major class of drugs that are used to treat type 2 diabetes, the thiazolidinediones. While TZDs reduce blood glucose and improve insulin sensitivity effectively, they can also exhibit deleterious side effects such as increased cardiovascular risk, weight gain, fluid retention and liver toxicity. Because it is desirable to develop new PPAR drugs with more favorable spectrums of response, mechanisms of PPAR ligand activation have come under intense scrutiny. To understand relationships between PPAR ligand binding and transcriptional activation, we sought to obtain apo human PPAR-LBD (ligand binding domain) crystals that diffract to high resolution. More surprisingly, close analysis of the ligand binding pocket revealed the presence of three small molecules, identified as nonanoic acid and octanoic acid. Here, we report the X-ray structural analysis of the PPAR LBD complexed with three bacterial (expression organism) medium chain fatty acids (MCFAs) that simultaneously occupy the buried ligand binding pocket (LBP). Structural and functional analysis suggests that MCFAs are partial agonists that stabilize PPAR LBD conformation, through a helix 12 independent mechanism.
Advisors/Committee Members: Polikarpov, Igor.
Subjects/Keywords: Nuclear receptor. PPAR. Medium chain fatty acids. Receptor-ligand interaction.; Receptor nuclear. PPAR. Ácidos graxos de cadeia média. Interação receptor-ligante.
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Liberato, M. V. (2009). Ácidos graxos de cadeia média como ligantes da proteína PPAR. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/76/76132/tde-19032009-111236/ ;
Chicago Manual of Style (16th Edition):
Liberato, Marcelo Vizoná. “Ácidos graxos de cadeia média como ligantes da proteína PPAR.” 2009. Masters Thesis, University of São Paulo. Accessed January 22, 2021.
http://www.teses.usp.br/teses/disponiveis/76/76132/tde-19032009-111236/ ;.
MLA Handbook (7th Edition):
Liberato, Marcelo Vizoná. “Ácidos graxos de cadeia média como ligantes da proteína PPAR.” 2009. Web. 22 Jan 2021.
Vancouver:
Liberato MV. Ácidos graxos de cadeia média como ligantes da proteína PPAR. [Internet] [Masters thesis]. University of São Paulo; 2009. [cited 2021 Jan 22].
Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-19032009-111236/ ;.
Council of Science Editors:
Liberato MV. Ácidos graxos de cadeia média como ligantes da proteína PPAR. [Masters Thesis]. University of São Paulo; 2009. Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-19032009-111236/ ;
Universidade Estadual de Campinas
7.
da Silva, Julio Cesar Araujo, 1974-.
Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular: Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations.
Degree: 2012, Universidade Estadual de Campinas
URL: http://repositorio.unicamp.br/jspui/handle/REPOSIP/248861
► Abstract: Androgen receptors (AR) are members of the superfamily of nuclear receptors that includes the steroid receptors, among others. AR binds the male endogenous sex…
(more)
▼ Abstract: Androgen receptors (AR) are members of the superfamily of
nuclear receptors that includes the steroid receptors, among others. AR binds the male endogenous sex steroids, dihydrotestosterone and testosterone. Normal development of the male phenotype and reproductive system requires pre- and postnatal actions promoted by AR interaction with these hormones. Mutations in the androgen
receptor gene may lead to several diseases like prostate cancer (PCa) and the androgen insensitivity syndrome (AIS). Different substitutions at the same amino acid residue may result in variable impact on the activity of the
receptor leading to different degrees of AIS. A number of mutations have been reported for the AR in AIS and PCa tumor cells and their location and function may help us to understand how these diseases should be treated. Nevertheless, not much is known about how the mutations change the structure and dynamics of the AR since only a few crystallographic structures of mutants were obtained. In this work we present molecular dynamics simulation (MD) studies of some human AR mutations located in the ligand binding domain (LBD) in comparison with wild type (WT) structure in complex with the synthetic ligand methyltrienolone (R1881). Our goal is to investigate the molecular basis of subtle changes in the
receptor caused by mutations in the AR-LBD/R1881 affinity. Although the mutated residues do not interact with the ligand, the simulations results indicated that the mutants cause structural and dynamical changes in the AR-LBD in the region in which the mutation is placed and in the binding pocket (LBP). The principal change observed was the displacement of residue Arg752, facilitating water penetration in LBP, and the repositioning of F-domain side chains, which makes important contributions to the stability of the AR-LBD structure and helix 12 active conformation. The results obtained show that these naturally occurring mutations are examples of residues that are not in contact with the ligand and do not belong to coactivator recruitment region, but which do have an important role in ligand binding and
receptor activation by stabilizing the helix H12 and the F-domain in the active conformation
Advisors/Committee Members: UNIVERSIDADE ESTADUAL DE CAMPINAS (CRUESP), Skaf, Munir Salomão, 1963- (advisor), Universidade Estadual de Campinas. Instituto de Química (institution), Programa de Pós-Graduação em Química (nameofprogram), Araujo, Alexandre Suman de (committee member), Neto, Mario de Oliveira (committee member), Martínez, Leandro (committee member), Custodio, Rogério (committee member).
Subjects/Keywords: Receptor nuclear; Receptor de androgênio; Simulação de dinâmica molecular; Nuclear receptor; Androgen receptor; Molecular dynamics simulations
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APA (6th Edition):
da Silva, Julio Cesar Araujo, 1. (2012). Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular: Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations. (Thesis). Universidade Estadual de Campinas. Retrieved from http://repositorio.unicamp.br/jspui/handle/REPOSIP/248861
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):
da Silva, Julio Cesar Araujo, 1974-. “Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular: Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations.” 2012. Thesis, Universidade Estadual de Campinas. Accessed January 22, 2021.
http://repositorio.unicamp.br/jspui/handle/REPOSIP/248861.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
da Silva, Julio Cesar Araujo, 1974-. “Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular: Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations.” 2012. Web. 22 Jan 2021.
Vancouver:
da Silva, Julio Cesar Araujo 1. Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular: Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations. [Internet] [Thesis]. Universidade Estadual de Campinas; 2012. [cited 2021 Jan 22].
Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/248861.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
da Silva, Julio Cesar Araujo 1. Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular: Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations. [Thesis]. Universidade Estadual de Campinas; 2012. Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/248861
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
North Carolina State University
8.
Hannas, Bethany Reeves.
Mechanistic evaluation of the reproductive and developmental toxicity of nitrate and nitrite.
Degree: PhD, Toxicology, 2009, North Carolina State University
URL: http://www.lib.ncsu.edu/resolver/1840.16/5758
► This research investigates the mechanism for reproductive and developmental toxicity associated with the aquatic contaminants nitrate and nitrite, in the crustacean Daphnia magna. Two hypotheses…
(more)
▼ This research investigates the mechanism for reproductive and developmental toxicity associated with the aquatic contaminants nitrate and nitrite, in the crustacean Daphnia magna. Two hypotheses were tested: 1) Nitrate and nitrite are converted to nitric oxide(NO), resulting in disruption of endocrine-related processes; and 2) NO interferes with endocrine signaling by lowering steroid hormone levels or by binding a heme-containing
nuclear receptor involved in steroid signaling.
In the first study, the developmental and reproductive toxicity of nitrate and nitrite to daphnids was consistent with toxicity elicited by the NO donor, sodium nitroprusside and was ameliorated by the NO-scavenger ß-carotene. Drosophila S2 cells converted nitrate and nitrite to NO in a substrate and cell concentration-dependent manner. Together, these results are consistent with nitrate and nitrite eliciting toxicity via intracellular conversion to NO. Although toxicity was indicative of an anti-ecdysteroid mechanism of action, we did not detect significant, consistent decreases in 20-hydroxyecdysone levels in exposed daphnids.
The next study characterized a potential target of NO toxicity in the ecdysteroid signaling pathway. The
nuclear receptors E75 (group NR1D) and HR3 (NR1F) were cloned and sequenced from Daphnia magna. E75 possessed amino acid residues in the ligand-binding domain that likely bind heme, a common target of NO binding. HR3 was significantly induced by 20-hydroxyecdysone, whereas E75 was minimally responsive. These results implicate both E75 and HR3 of daphnids as potential targets of the anti-ecdysteroid action of exogenous NO.
Finally, we characterized E75 and HR3 regulation of gene transcription, to determine if NO alters this regulatory activity. HR3 activated transcription of a retinoid orphan
receptor element (RORE)-driven luciferase reporter. E75 did not activate the reporter, but served to repress HR3 activation. Experiments revealed no evidence that NO interferes with E75 repression of HR3. Therefore, the mechanism by which nitrate and nitrite-derived NO elicits developmental and reproductive toxicity remains unknown.
This research highlights the potential threat posed to the reproductive and developmental success of aquatic organisms exposed to nitrate and nitrite. It additionally advances understanding of crustacean endocrinology, while demonstrating the need for further information to identify the mechanism of action for interfering environmental contaminants.
Advisors/Committee Members: Dr. R. Michael Roe, Committee Member (advisor), Dr. Gerald A. LeBlanc, Committee Chair (advisor), Dr. David Buchwalter, Committee Member (advisor), Dr. Jun Tsuji, Committee Member (advisor).
Subjects/Keywords: nuclear receptor; endocrine disruption; ecdysteroid; arthropod; aquatic
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APA (6th Edition):
Hannas, B. R. (2009). Mechanistic evaluation of the reproductive and developmental toxicity of nitrate and nitrite. (Doctoral Dissertation). North Carolina State University. Retrieved from http://www.lib.ncsu.edu/resolver/1840.16/5758
Chicago Manual of Style (16th Edition):
Hannas, Bethany Reeves. “Mechanistic evaluation of the reproductive and developmental toxicity of nitrate and nitrite.” 2009. Doctoral Dissertation, North Carolina State University. Accessed January 22, 2021.
http://www.lib.ncsu.edu/resolver/1840.16/5758.
MLA Handbook (7th Edition):
Hannas, Bethany Reeves. “Mechanistic evaluation of the reproductive and developmental toxicity of nitrate and nitrite.” 2009. Web. 22 Jan 2021.
Vancouver:
Hannas BR. Mechanistic evaluation of the reproductive and developmental toxicity of nitrate and nitrite. [Internet] [Doctoral dissertation]. North Carolina State University; 2009. [cited 2021 Jan 22].
Available from: http://www.lib.ncsu.edu/resolver/1840.16/5758.
Council of Science Editors:
Hannas BR. Mechanistic evaluation of the reproductive and developmental toxicity of nitrate and nitrite. [Doctoral Dissertation]. North Carolina State University; 2009. Available from: http://www.lib.ncsu.edu/resolver/1840.16/5758
Wesleyan University
9.
Kilinc Avsaroglu, Seda.
Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes.
Degree: Molecular Biology and Biochemistry, 2016, Wesleyan University
URL: https://wesscholar.wesleyan.edu/etd_diss/68
► Mammalian olfaction depends on the development of specialized olfactory sensory neurons (OSNs) that each expresses one odorant receptor (OR) protein from a large family…
(more)
▼ Mammalian olfaction depends on the development of specialized olfactory sensory neurons (OSNs) that each expresses one odorant
receptor (OR) protein from a large family of OR genes encoded in the genome. The molecular mechanisms underlying mutually exclusive OR gene expression is poorly understood. I focused on the role of
nuclear organization and epigenetic mechanisms that restrict expression to one of >1000 OR genes in developing OSNs. A current working model proposed in the field is that sequestration and silencing of OR genes within repressive chromocenters is crucial for restricting expression to only one OR gene per cell. However, my work showed that in an olfactory placode (OP) cell line derived from a founder cell whose transcriptional profile is consistent with early post-progenitor cells of olfactory epithelium OR genes are not sequestered within chromocenters but nevertheless exhibit singular OR expression. This surprising result suggests that OR sequestration might only be needed for maintenance of singularity in mature OSNs, but not as a mechanism to ensure the establishment of this singularity. Next, I investigated alternative explanations that might contribute to the establishment of singular OR transcription. Recently, we showed that LSD1, a histone lysine demethylase known to play a role in OR gene regulation, exhibits variable organization within nuclei of developing OSNs, and tends to consolidate into a single dominant compartment at the edges of chromocenters within nuclei of early post-mitotic cells of the mouse olfactory epithelium (MOE). Using the OP cell line, I show that consolidation of LSD1 appears to be cell-cycle regulated, with a peak occurrence in early G1. LSD1 co-compartmentalizes with CoREST, a protein known to collaborate with LSD1 to carry out a variety of chromatin-modifying functions. I show that LSD1 compartments co-localize with 1-3 OR loci at the exclusion of most OR genes, and commonly associate with Lhx2, a transcription factor involved in OR regulation. Together, these findings suggest that LSD1 is sequestered into a distinct
nuclear space that might restrict a histone-modifying function to a narrow developmental time window and/or range of OR gene targets.
Advisors/Committee Members: Robert P. Lane.
Subjects/Keywords: olfactory receptor genes; nuclear organization; epigenetics
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APA (6th Edition):
Kilinc Avsaroglu, S. (2016). Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes. (Doctoral Dissertation). Wesleyan University. Retrieved from https://wesscholar.wesleyan.edu/etd_diss/68
Chicago Manual of Style (16th Edition):
Kilinc Avsaroglu, Seda. “Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes.” 2016. Doctoral Dissertation, Wesleyan University. Accessed January 22, 2021.
https://wesscholar.wesleyan.edu/etd_diss/68.
MLA Handbook (7th Edition):
Kilinc Avsaroglu, Seda. “Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes.” 2016. Web. 22 Jan 2021.
Vancouver:
Kilinc Avsaroglu S. Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes. [Internet] [Doctoral dissertation]. Wesleyan University; 2016. [cited 2021 Jan 22].
Available from: https://wesscholar.wesleyan.edu/etd_diss/68.
Council of Science Editors:
Kilinc Avsaroglu S. Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes. [Doctoral Dissertation]. Wesleyan University; 2016. Available from: https://wesscholar.wesleyan.edu/etd_diss/68
University of Toronto
10.
Lee, Richard Heungki.
An In Vivo System for the Identification of Ligands for Peroxisome Proliferator-activated Receptors.
Degree: 2015, University of Toronto
URL: http://hdl.handle.net/1807/70369
► Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors (NRs) that play major roles in metabolism and development and, when disrupted, lead to disorders…
(more)
▼ Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors (NRs) that play major roles in metabolism and development and, when disrupted, lead to disorders such as cancer, diabetes and obesity. Our laboratory has established a transgenic Ligand Trap system in zebrafish for high throughput screening of drugs to identify novel activators of human NRs. We have identified Coenzyme Q10 (CoQ10) as an activator of PPAR-gamma in a presumed tissue specific manner. To demonstrate that CoQ10 directly binds to PPARs, we expressed PPARs in bacteria and zebrafish embryos and treated with CoQ10. Ligand-bound receptors were purified and analyzed by denaturing mass spectrometry. Data suggest that CoQ10 binds to PPAR-alpha and PPAR-gamma, but not to PPAR-beta. Future experiments will focus to confirm direct binding to PPAR subtypes. Once verified, subsequent studies will explore the significance of CoQ10 as a PPAR ligand in the context of transcription machinery complex formation.
M.Sc.
Advisors/Committee Members: Krause, Henry, Molecular and Medical Genetics.
Subjects/Keywords: Coenzyme Q10; Nuclear Receptor; PPAR; 0307
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APA (6th Edition):
Lee, R. H. (2015). An In Vivo System for the Identification of Ligands for Peroxisome Proliferator-activated Receptors. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/70369
Chicago Manual of Style (16th Edition):
Lee, Richard Heungki. “An In Vivo System for the Identification of Ligands for Peroxisome Proliferator-activated Receptors.” 2015. Masters Thesis, University of Toronto. Accessed January 22, 2021.
http://hdl.handle.net/1807/70369.
MLA Handbook (7th Edition):
Lee, Richard Heungki. “An In Vivo System for the Identification of Ligands for Peroxisome Proliferator-activated Receptors.” 2015. Web. 22 Jan 2021.
Vancouver:
Lee RH. An In Vivo System for the Identification of Ligands for Peroxisome Proliferator-activated Receptors. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/1807/70369.
Council of Science Editors:
Lee RH. An In Vivo System for the Identification of Ligands for Peroxisome Proliferator-activated Receptors. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/70369
Oregon State University
11.
Yang, Liping.
Effects of small molecule ligands on the conformational dynamics of the Farnesoid X Receptor ligand binding domain (FXR-LBD).
Degree: PhD, Chemistry, 2014, Oregon State University
URL: http://hdl.handle.net/1957/49982
► The Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of…
(more)
▼ The Farnesoid X
Receptor (FXR) is a member of the
nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. This dissertation focuses on the development and application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) to characterize the impact of various ligands on the structural dynamics of the FXR-LBD. Additionally, fluorescence spectroscopy is used to complement the HDX studies.
Firstly, we explored the use of amide HDX coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon binding of three well known ligands: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. Ligand-specific deuterium incorporation profiles were obtained for the FXR LBD upon interaction with the diverse ligand chemotypes. Comparison of the HDX profiles of the ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed.
Secondly, several functional studies focusing on the health promoting effects of prenylflavonoids have suggested that prenylflavonoids, including xanthohumol (XN), isoxanthohumol (IX), and 8-prenylnaringenin (8-PN), are capable of modulating lipid metabolism possibly via modulating expression of FXR target genes. Therefore, we hypothesize that prenylflavonoid-type molecules might be FXR ligands that exert their regulatory effects by binding to the FXR-LBD thereby inducing changes in structural dynamics in a ligand-specific manner. Under identical experimental solution-phase conditions, we determined the effects of binding of prenylflavonoid-type compounds on the structural dynamics of FXR-LBD. Deuterium incorporation profiles were obtained for the four prenylflavonoids: XN, IX, 8-PN, and one derivative of XN, tetrahydroxanthohumol (TX). The HDX protection profiles of the FXR-LBD in presence of the diverse prenylflavonoids indicated partial conformational stabilization of the LBD in particular in regions that would be consistent with a model in which the prenylflavonoids interact with the canonical ligand binding cavitiy. In silico molecular docking studies predicted that the series of prenylflavonoids tested can act indeed as ligands of the FXR-LBD, in agreement with our HDX data. We discuss the prenylflavonoid-induced conformational changes in the context of the conformational changes that were observed with the known…
Advisors/Committee Members: Maier, Claudia (advisor), Hsu, Victor (committee member).
Subjects/Keywords: Farnesoid X Receptor; Nuclear receptors (Biochemistry)
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APA (6th Edition):
Yang, L. (2014). Effects of small molecule ligands on the conformational dynamics of the Farnesoid X Receptor ligand binding domain (FXR-LBD). (Doctoral Dissertation). Oregon State University. Retrieved from http://hdl.handle.net/1957/49982
Chicago Manual of Style (16th Edition):
Yang, Liping. “Effects of small molecule ligands on the conformational dynamics of the Farnesoid X Receptor ligand binding domain (FXR-LBD).” 2014. Doctoral Dissertation, Oregon State University. Accessed January 22, 2021.
http://hdl.handle.net/1957/49982.
MLA Handbook (7th Edition):
Yang, Liping. “Effects of small molecule ligands on the conformational dynamics of the Farnesoid X Receptor ligand binding domain (FXR-LBD).” 2014. Web. 22 Jan 2021.
Vancouver:
Yang L. Effects of small molecule ligands on the conformational dynamics of the Farnesoid X Receptor ligand binding domain (FXR-LBD). [Internet] [Doctoral dissertation]. Oregon State University; 2014. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/1957/49982.
Council of Science Editors:
Yang L. Effects of small molecule ligands on the conformational dynamics of the Farnesoid X Receptor ligand binding domain (FXR-LBD). [Doctoral Dissertation]. Oregon State University; 2014. Available from: http://hdl.handle.net/1957/49982
University of Iowa
12.
Weatherford, Eric Thomas.
Regulation of renin gene expression by CTCF, Nr2f2, Nr2f6, Nr4a1 and maintenance of the renin expressing cell.
Degree: PhD, Molecular Physiology and Biophysics, 2011, University of Iowa
URL: https://ir.uiowa.edu/etd/1104
► The renin angiotensin system (RAS) is critical for the regulation of blood pressure, electrolyte/fluid, and metabolic homeostasis. Regulation of the RAS is important in…
(more)
▼ The renin angiotensin system (RAS) is critical for the regulation of blood pressure, electrolyte/fluid, and metabolic homeostasis. Regulation of the RAS is important in the development and treatment of hypertension. As part of the rate-limiting step in a cascade of events ending in the production of angiotensin II, renin is a major regulator of the RAS. Its expression is localized to the juxtaglomerular (JG) cells of the JG apparatus where it is exquisitely located to respond to various physiological cues. Understanding the regulation of renin expression and development of the juxtaglomerular cells is critical. Two regulatory elements, the enhancer and proximal promoter, have been found to be important in controlling cell- and tissue- specific baseline expression of the renin gene. Within the enhancer is a hormone response element (HRE) which confers a high level of activity to the enhancer.
Nuclear receptors that bind this element have been found to bind the HRE and regulate renin promoter transcriptional activity. We have previously characterized the role of the orphan
nuclear receptor Nr2f6 as a negative regulator of renin expression that mediates its effects through the HRE. However, gel shift assays indicate that there are other transcription factors binding this element. We have identified other orphan
nuclear receptors that regulate renin expression. The first, Nr2f2 acts as a negative regulator of renin promoter activity but does not appear to affect baseline expression of the endogenous renin gene. The other, Nr4a1, is a positive regulator of renin expression, but it does not appear to mediate its effects through the HRE. The transcriptional regulation of gene expression is controlled by regulatory elements separated by large distances from promoters. We and others have found that short transgenes of the human renin (hREN) locus are not sufficient to protect them from positional effects that can be exerted upon them by neighboring regulatory elements. We discovered a random truncation in a large genomic construct of the hREN gene that resulted in ubiquitous expression of renin not seen with the intact form. By locating the genomic insertion site of that transgene in the Zbtb20 gene, we found that the hREN promoter had come under control of that gene's regulatory elements. The gene downstream of renin however maintained its tissue-specific expression. We found that CCCTC-binding factor (CTCF) bound to chromatin in and around the renin locus. The presence of CTCF suggests that insulator elements are present in the renin locus, and their loss likely explains the results above. Finally, we assessed the role of microRNAs in the development of renin expressing cells in the mouse kidneys by cell-specific deletion of the processing enzyme Dicer. This resulted in reduction of renin expression and a decrease in the number of renin expressing cells in the kidney. Mice were hypotensive and had several kidney abnormalities including a hypertrophied vasculature and striped fibrosis. These results…
Advisors/Committee Members: Sigmund, Curt Daniel (supervisor).
Subjects/Keywords: CTCF; Dicer; Nuclear Receptor; Renin; Transcription; Biophysics
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APA (6th Edition):
Weatherford, E. T. (2011). Regulation of renin gene expression by CTCF, Nr2f2, Nr2f6, Nr4a1 and maintenance of the renin expressing cell. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/1104
Chicago Manual of Style (16th Edition):
Weatherford, Eric Thomas. “Regulation of renin gene expression by CTCF, Nr2f2, Nr2f6, Nr4a1 and maintenance of the renin expressing cell.” 2011. Doctoral Dissertation, University of Iowa. Accessed January 22, 2021.
https://ir.uiowa.edu/etd/1104.
MLA Handbook (7th Edition):
Weatherford, Eric Thomas. “Regulation of renin gene expression by CTCF, Nr2f2, Nr2f6, Nr4a1 and maintenance of the renin expressing cell.” 2011. Web. 22 Jan 2021.
Vancouver:
Weatherford ET. Regulation of renin gene expression by CTCF, Nr2f2, Nr2f6, Nr4a1 and maintenance of the renin expressing cell. [Internet] [Doctoral dissertation]. University of Iowa; 2011. [cited 2021 Jan 22].
Available from: https://ir.uiowa.edu/etd/1104.
Council of Science Editors:
Weatherford ET. Regulation of renin gene expression by CTCF, Nr2f2, Nr2f6, Nr4a1 and maintenance of the renin expressing cell. [Doctoral Dissertation]. University of Iowa; 2011. Available from: https://ir.uiowa.edu/etd/1104
University of Southern California
13.
Ianculescu, Irina.
One play, many actors: the many roles coregulators play in
nuclear receptor mediated transcription.
Degree: PhD, Genetic, Molecular and Cellular Biology, 2011, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/175732/rec/4568
► It is becoming increasingly evident that transcriptional coregulators are a diverse group of proteins of central importance to gene expression. Although some appear to be…
(more)
▼ It is becoming increasingly evident that
transcriptional coregulators are a diverse group of proteins of
central importance to gene expression. Although some appear to be
just scaffold proteins used to tether the
nuclear receptor to RNA
polymerase quite a few possess enzymatic activities that are
required for gene expression. Here we explored the roles of various
coactivators in
nuclear receptor mediated transcription. ❧ Hic-5 is
perhaps the least well studied coactivator of the group
investigated. A coactivator for both the androgen
receptor (AR) and
glucocorticoid
receptor (GR), its depletion in A549 lung cancer
cells failed to show any changes in GR target gene expression for
the 25 genes that we examined. Similar results were observed for
the depletion of the well known histone and protein
methyltransferase PRMT1 in A549 and MCF-7 cells. ❧ The histone
acetyltransferases p300 and CBP appeared to be selectively required
for androgen-regulated genes in the C4-2B prostate cancer cells.
Illumina microarray expression data showed that 47% of androgen
regulated genes are p300 dependent, while only 0.3% are CBP
dependent. Actually, p300 is important for both androgen dependent
pol II and TBP recruitment to the AR target genes, TMPRSS2 and PSA.
CBP expression cannot compensate for the loss of p300 on these two
genes. Likewise, androgen induced increases in histone H3 Lys 18,
Lys 27 and histone H4 acetylation rely on the presence of p300.
Although previously thought to have many overlapping functions in
gene expression, our data suggests that in C4-2B cells they exhibit
many separate and defining roles critical for proper androgen
regulated gene expression. Our data also suggests that p300 is the
dominant member of the pair, appearing to be more important for
androgen-mediated gene expression. CBP depletion in our cell line
did not affect the androgen regulated expression of nearly as many
genes as loss of p300 did. This suggests a distinct role for p300
in an advanced prostate cancer cell model.
Advisors/Committee Members: Stallcup, Michael R. (Committee Chair), Coetzee, Gerhard (Gerry) A. (Committee Member), Rice, Judd C. (Committee Member).
Subjects/Keywords: transcriptional regulation; nuclear receptor coactivators; p300/CBP
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APA (6th Edition):
Ianculescu, I. (2011). One play, many actors: the many roles coregulators play in
nuclear receptor mediated transcription. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/175732/rec/4568
Chicago Manual of Style (16th Edition):
Ianculescu, Irina. “One play, many actors: the many roles coregulators play in
nuclear receptor mediated transcription.” 2011. Doctoral Dissertation, University of Southern California. Accessed January 22, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/175732/rec/4568.
MLA Handbook (7th Edition):
Ianculescu, Irina. “One play, many actors: the many roles coregulators play in
nuclear receptor mediated transcription.” 2011. Web. 22 Jan 2021.
Vancouver:
Ianculescu I. One play, many actors: the many roles coregulators play in
nuclear receptor mediated transcription. [Internet] [Doctoral dissertation]. University of Southern California; 2011. [cited 2021 Jan 22].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/175732/rec/4568.
Council of Science Editors:
Ianculescu I. One play, many actors: the many roles coregulators play in
nuclear receptor mediated transcription. [Doctoral Dissertation]. University of Southern California; 2011. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/175732/rec/4568
University of Southern California
14.
Mah, In Kyoung.
Roles of three domains of CCAR1 in transcription activation
by nuclear receptors.
Degree: MS, Biochemistry & Molecular Biology, 2008, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/51656/rec/5655
► Nuclear receptors are ligand dependent transcription factors that activate target genes involved in diverse physiological processes such as metabolism, development, reproduction through the recruitment of…
(more)
▼ Nuclear receptors are ligand dependent transcription
factors that activate target genes involved in diverse
physiological processes such as metabolism, development,
reproduction through the recruitment of multiple coactivators.;
Cell cycle and apoptosis regulator 1 (CCAR1) is a
nuclear receptor
coactivator and helps to enhance the transcription activation by
nuclear receptors. CCAR1 is also associated with the mediator
complex, which recruits RNA polymerase II to the target gene
promoters.; One of three domains of CCAR1 interacts with estrogen
receptor. Deletions of three domains diminish the coactivator
function of CCAR1. One domain is required for cooperation with
CoCoA. In addition, three domains are required for collaboration
with TRAP220 in estrogen
receptor mediated transcription. One of
three domains of CCAR1 is not necessary for the multiple
coactivator complexes activity. Two domains of CCAR1 play important
roles in TRAP220 associated GR dependent activity. Thus, three
domains of CCAR1 might work differently in different
conditions.
Advisors/Committee Members: Stallcup, Michael R. (Committee Chair), Tokes, Zoltan A. (Committee Member), Stellwagen, Robert H. (Committee Member).
Subjects/Keywords: nuclear receptor; coactivator
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APA (6th Edition):
Mah, I. K. (2008). Roles of three domains of CCAR1 in transcription activation
by nuclear receptors. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/51656/rec/5655
Chicago Manual of Style (16th Edition):
Mah, In Kyoung. “Roles of three domains of CCAR1 in transcription activation
by nuclear receptors.” 2008. Masters Thesis, University of Southern California. Accessed January 22, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/51656/rec/5655.
MLA Handbook (7th Edition):
Mah, In Kyoung. “Roles of three domains of CCAR1 in transcription activation
by nuclear receptors.” 2008. Web. 22 Jan 2021.
Vancouver:
Mah IK. Roles of three domains of CCAR1 in transcription activation
by nuclear receptors. [Internet] [Masters thesis]. University of Southern California; 2008. [cited 2021 Jan 22].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/51656/rec/5655.
Council of Science Editors:
Mah IK. Roles of three domains of CCAR1 in transcription activation
by nuclear receptors. [Masters Thesis]. University of Southern California; 2008. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/51656/rec/5655
University of Toronto
15.
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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MLA ·
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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 22, 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. 22 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 22].
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 Toronto
16.
Tan, Susanna Shu Xian.
Characterizing the Role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose Polymerase (TIPARP) in Estrogen Receptor Signalling.
Degree: 2016, University of Toronto
URL: http://hdl.handle.net/1807/76045
► Estrogens exert their effects by activating estrogen receptor alpha (ERα) and beta (ERβ). A number of different co-regulator proteins regulate the activities of both receptors.…
(more)
▼ Estrogens exert their effects by activating estrogen receptor alpha (ERα) and beta (ERβ). A number of different co-regulator proteins regulate the activities of both receptors. Identifying new ER co-regulators could lead to improved treatments for diseases, such as breast cancer. This study aimed to characterize the role of TIPARP, a mono-ADP-ribosyltransferase and novel co-regulator of ERs. Gene expression and ChIP studies revealed that TIPARP mRNA levels were regulated by ERs, and that ERα was recruited to TIPARP. TIPARP in turn repressed ERα, but co-activated ERβ activity. Furthermore, TIPARP was recruited to the regulatory regions of estrogen target genes. TIPARP mono-ADP-ribosylated both ERα and ERβ and reversed the effects of the mono-ADP-ribosylase, MacroD1, on ERα/β transactivation. Taken together, this work showed that TIPARP is a mixed function co-regulator of ERs, revealing that TIPARP and MacroD1 dynamically regulate the activities of ERα/β through ADP-ribosylation.
M.Sc.
Advisors/Committee Members: Matthews, Jason, Pharmacology.
Subjects/Keywords: Estrogen; Estrogen Receptor; Nuclear transcription factors; Receptor Signalling; TIPARP; 0307
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APA (6th Edition):
Tan, S. S. X. (2016). Characterizing the Role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose Polymerase (TIPARP) in Estrogen Receptor Signalling. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/76045
Chicago Manual of Style (16th Edition):
Tan, Susanna Shu Xian. “Characterizing the Role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose Polymerase (TIPARP) in Estrogen Receptor Signalling.” 2016. Masters Thesis, University of Toronto. Accessed January 22, 2021.
http://hdl.handle.net/1807/76045.
MLA Handbook (7th Edition):
Tan, Susanna Shu Xian. “Characterizing the Role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose Polymerase (TIPARP) in Estrogen Receptor Signalling.” 2016. Web. 22 Jan 2021.
Vancouver:
Tan SSX. Characterizing the Role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose Polymerase (TIPARP) in Estrogen Receptor Signalling. [Internet] [Masters thesis]. University of Toronto; 2016. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/1807/76045.
Council of Science Editors:
Tan SSX. Characterizing the Role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose Polymerase (TIPARP) in Estrogen Receptor Signalling. [Masters Thesis]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/76045
University of Ottawa
17.
Carrigan, Amanda.
Sequence and Effects of Glucocorticoid Receptor Nuclear Retention: An Aid to Understanding Nuclear Retention in Other Proteins?
.
Degree: 2011, University of Ottawa
URL: http://hdl.handle.net/10393/19719
► Corticosteroid ligands activate the glucocorticoid receptor (GR). GR plays a role in glucose homeostasis, adipogenesis, inflammation, and mood and cognitive functions. Understanding the interplay of…
(more)
▼ Corticosteroid ligands activate the glucocorticoid receptor (GR). GR plays a role in glucose homeostasis, adipogenesis, inflammation, and mood and cognitive functions. Understanding the interplay of diverse forms of receptor regulation (including post-translational modification, cofactor interactions, ligand binding, and receptor localization) and their effects is important for understanding and developing more effective treatment for a variety of conditions. Prior to ligand binding, the naïve GR is primarily cytoplasmic, residing in a chaperone complex containing heat-shock proteins and immunophilins. Upon ligand-binding, alterations to the complex allow the receptor to dimerize and import into the nucleus. Nuclear GR interacts with transcriptional regulatory sequences and recruits cofactors to regulate specific gene expression. Upon hormone withdrawal, the original chaperone complex is reassembled and the receptor is exported to the cytoplasm. Interestingly, while the import of GR into the nucleus occurs very rapidly (t ½ = 5 min), the re-export is significantly slower (t ½ = 12-24h). Previous work by our lab and others has indicated the existence of a nuclear retention signal (NRS) within the GR. The NRS sequence of the GR, its interaction partners, and the role it might play in the activity of the receptor have not yet been fully defined. Work in the Hache lab indicates that mutation of the GR nuclear localization signal 1 (NL1) increases the export rate of nuclear GR to the cytoplasm, as well as compromising receptor import, suggesting that the NL1 overlapped an NRS sequence. In this work, I made a series of GR mutants, based on sequence from the SV40 large T antigen NLS, which lacks nuclear retention activity. Using these mutants, I found that GR nuclear retention is influenced by both specific residues within the hinge region and the location of the sequence within the receptor, as reintroduction of the NLS sequence at the N-terminus of the receptor retention mutant failed to reconstitute the retention activity. Agonist liganded and hormone-withdrawn receptor mutants showed a similar decrease in retention. By contrast, antagonist-withdrawn GR mutants were retained in the nucleus, possibly due to altered receptor configuration and interactions. Assays of GR-responsive promoter activation by receptor retention mutants showed that while no difference in the ability of retention mutants to activate transcription was seen at a simple promoter, activation of a complex promoter was compromised. This impaired transactivation for the SV506-523 mutant correlated with decreased histone H4 acetylation and PolII recruitment, while GR DNA-binding at the target promoter appeared to be unaffected. These results suggested that promoter-specific cofactor interactions might be implicated in GR nuclear retention. Loss of GR hinge interaction with Oct cofactors produced an incomplete loss of retention, suggesting overlapping signals, but not supporting Oct as a primary factor in GR retention. The overlap between important residues…
Subjects/Keywords: glucocorticoid receptor;
nuclear retention;
steroid hormone receptor;
export;
NLS;
trafficking
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Manager
APA (6th Edition):
Carrigan, A. (2011). Sequence and Effects of Glucocorticoid Receptor Nuclear Retention: An Aid to Understanding Nuclear Retention in Other Proteins?
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/19719
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):
Carrigan, Amanda. “Sequence and Effects of Glucocorticoid Receptor Nuclear Retention: An Aid to Understanding Nuclear Retention in Other Proteins?
.” 2011. Thesis, University of Ottawa. Accessed January 22, 2021.
http://hdl.handle.net/10393/19719.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Carrigan, Amanda. “Sequence and Effects of Glucocorticoid Receptor Nuclear Retention: An Aid to Understanding Nuclear Retention in Other Proteins?
.” 2011. Web. 22 Jan 2021.
Vancouver:
Carrigan A. Sequence and Effects of Glucocorticoid Receptor Nuclear Retention: An Aid to Understanding Nuclear Retention in Other Proteins?
. [Internet] [Thesis]. University of Ottawa; 2011. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/10393/19719.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Carrigan A. Sequence and Effects of Glucocorticoid Receptor Nuclear Retention: An Aid to Understanding Nuclear Retention in Other Proteins?
. [Thesis]. University of Ottawa; 2011. Available from: http://hdl.handle.net/10393/19719
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
18.
Williams-Dautovich, Jasmine.
The Role of LXR in Glucocorticoid-Induced Osteoporosis and Muscle Wasting.
Degree: 2015, University of Toronto
URL: http://hdl.handle.net/1807/81006
► Synthetic glucocorticoids (GCs) have unparalleled anti-inflammatory and immunosuppressive properties that are crucial for the treatment of many inflammatory diseases. Unfortunately, a remaining limitation for the…
(more)
▼ Synthetic glucocorticoids (GCs) have unparalleled anti-inflammatory and immunosuppressive properties that are crucial for the treatment of many inflammatory diseases. Unfortunately, a remaining limitation for the long-term therapeutic use of GCs is the development of major metabolic side effects, including Cushing’s syndrome, a disease characterized by metabolic dysregulations such as hyperglycemia, muscle wasting and osteoporosis. The glucocorticoid receptor (GR) and liver X receptor (LXR) are members of the nuclear receptor superfamily that regulate distinct but overlapping transcriptional programs. Using a Cushing’s mouse model of GC excess, as well as in vitro cell lines treated with synthetic GCs, we find that LXR antagonism is protective from GC-induced osteoclast activation, but not from the anti-osteoblastogenic or muscle atrophy effect of GCs; suggesting a cell type specific effect. Together, these studies show the selective regulation of LXR antagonism may be useful in preventing GC-induced osteoclast activation.
M.Sc.
2017-12-21 00:00:00
Advisors/Committee Members: Cummins, Carolyn L, Pharmaceutical Sciences.
Subjects/Keywords: Bone; Cushing's syndrome; Glucocorticoids; Liver X Receptor; Muscle; Nuclear Receptor; 0572
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APA (6th Edition):
Williams-Dautovich, J. (2015). The Role of LXR in Glucocorticoid-Induced Osteoporosis and Muscle Wasting. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/81006
Chicago Manual of Style (16th Edition):
Williams-Dautovich, Jasmine. “The Role of LXR in Glucocorticoid-Induced Osteoporosis and Muscle Wasting.” 2015. Masters Thesis, University of Toronto. Accessed January 22, 2021.
http://hdl.handle.net/1807/81006.
MLA Handbook (7th Edition):
Williams-Dautovich, Jasmine. “The Role of LXR in Glucocorticoid-Induced Osteoporosis and Muscle Wasting.” 2015. Web. 22 Jan 2021.
Vancouver:
Williams-Dautovich J. The Role of LXR in Glucocorticoid-Induced Osteoporosis and Muscle Wasting. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/1807/81006.
Council of Science Editors:
Williams-Dautovich J. The Role of LXR in Glucocorticoid-Induced Osteoporosis and Muscle Wasting. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/81006
19.
Berrabah, Wahiba.
Régulation du récepteur nucléaire Farnesoid X Receptor par la voie de biosynthèse des hexosamines : Regulation of nuclear receptor Farnesoid X Receptor through the hexosamine biosynthesis pathway.
Degree: Docteur es, Biochimie et biologie moléculaire, 2013, Université Lille II – Droit et Santé
URL: http://www.theses.fr/2013LIL2S020
► Chez les patients diabétiques, le flux hépatique du glucose est perturbé affectant les voies qui lui sont associées telle que la voie de biosynthèse des…
(more)
▼ Chez les patients diabétiques, le flux hépatique du glucose est perturbé affectant les voies qui lui sont associées telle que la voie de biosynthèse des hexosamines (HBP). Cette voie permet la production d’UDP-GlcNAc à partir du glucose. Ce substrat est engagé dans une modification post-traductionnelle (PTM) réversible des protéines appelée O-GlcNAcylation. Elle consiste à transférer du GlcNAc à partir d’UDP-GlcNAc sur un résidu serine ou thréonine. Une O-GlcNAcylation anormale des protéines contribue à la glucotoxicité hépatique et au diabète de type 2. FXR (Farnesoid X Receptor), un récepteur nucléaire fortement exprimé dans le foie, contrôle le métabolisme des acides biliaires ainsi que l'homéostasie glucidique et lipidique. Après son activation par un ligand et son hétérodimérisaton avec RXR (Retinoid X Receptor), FXR régule la transcription de gènes cibles en se fixant sur ses éléments de réponse. L’expression génique de FXR est augmentée dans des modèles animaux de diabète et ses activités transcriptionnelles en font une cible thérapeutique potentielle dans le contrôle des troubles métaboliques. Considérant ces informations, nous avons émis l’hypothèse que FXR est un substrat de la HBP et que les variations des flux hépatiques de glucose affectent son activité transcriptionnelle. Nous avons démontré, par différentes techniques, que FXR est O-GlcNAcylé in vitro et in vivo et que le glucose augmente sa fixation sur ces éléments de réponse et son activité transcriptionnelle. En outre, nous avons montré que l’inhibition de la voie HBP diminue l’expression génique et protéique de FXR mais également que la sérine 62 joue un rôle important dans la MPT de ce récepteur nucléaire. En conclusion, nos résultats montrent que le récepteur nucléaire FXR est sensible aux variations hépatiques des flux de glucose et que la O-GlcNAcylation de FXR augmente son activité transcriptionnelle ainsi que son expression génique et protéique dans différents modèles hépatiques humains et murins.
In diabetic patients, hepatic glucose flux is disrupted affecting associated pathways such as the hexosamine biosynthesis pathway (HBP). This pathway allows the production of UDP-GlcNAc from glucose. This substrate is engaged in a reversible post-translational modification (PTM) of proteins called O-GlcNAcylation. This PTM involves the transfer of GlcNAc from UDP-GlcNAc to serine or threonine residue of proteins. Abnormal O-GlcNAcylation of proteins contributes to liver glucotoxicity and type 2 diabetes. FXR (Farnesoid X Receptor), a nuclear receptor highly expressed in the liver controls the bile acids metabolism, glucose and lipid homeostasis. After its activation by ligand and its hétérodimérisaton with RXR (Retinoid X Receptor), FXR regulates the transcription of target genes by binding to its response elements. The FXR gene expression is increased in diabetes animal models and its transcriptional activities are a potential therapeutic target in the control of metabolic disorders. Considering this information, we hypothesized that FXR is a…
Advisors/Committee Members: Aumercier, Pierrette (thesis director).
Subjects/Keywords: FXR; O-GlcNAcylation; Récepteurs nucléaires; Farnesoid X Receptor; Nuclear receptor
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APA (6th Edition):
Berrabah, W. (2013). Régulation du récepteur nucléaire Farnesoid X Receptor par la voie de biosynthèse des hexosamines : Regulation of nuclear receptor Farnesoid X Receptor through the hexosamine biosynthesis pathway. (Doctoral Dissertation). Université Lille II – Droit et Santé. Retrieved from http://www.theses.fr/2013LIL2S020
Chicago Manual of Style (16th Edition):
Berrabah, Wahiba. “Régulation du récepteur nucléaire Farnesoid X Receptor par la voie de biosynthèse des hexosamines : Regulation of nuclear receptor Farnesoid X Receptor through the hexosamine biosynthesis pathway.” 2013. Doctoral Dissertation, Université Lille II – Droit et Santé. Accessed January 22, 2021.
http://www.theses.fr/2013LIL2S020.
MLA Handbook (7th Edition):
Berrabah, Wahiba. “Régulation du récepteur nucléaire Farnesoid X Receptor par la voie de biosynthèse des hexosamines : Regulation of nuclear receptor Farnesoid X Receptor through the hexosamine biosynthesis pathway.” 2013. Web. 22 Jan 2021.
Vancouver:
Berrabah W. Régulation du récepteur nucléaire Farnesoid X Receptor par la voie de biosynthèse des hexosamines : Regulation of nuclear receptor Farnesoid X Receptor through the hexosamine biosynthesis pathway. [Internet] [Doctoral dissertation]. Université Lille II – Droit et Santé 2013. [cited 2021 Jan 22].
Available from: http://www.theses.fr/2013LIL2S020.
Council of Science Editors:
Berrabah W. Régulation du récepteur nucléaire Farnesoid X Receptor par la voie de biosynthèse des hexosamines : Regulation of nuclear receptor Farnesoid X Receptor through the hexosamine biosynthesis pathway. [Doctoral Dissertation]. Université Lille II – Droit et Santé 2013. Available from: http://www.theses.fr/2013LIL2S020
20.
Muniz, Amanda Bernardes.
Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos.
Degree: PhD, Física Aplicada, 2013, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-31072013-141118/
;
► Os receptores ativadores da proliferação de peroxissomos (PPARs) pertencem à superfamília de receptores nucleares que funcionam como fatores transcricionais. Eles exercem um papel fundamental em…
(more)
▼ Os receptores ativadores da proliferação de peroxissomos (PPARs) pertencem à superfamília de receptores nucleares que funcionam como fatores transcricionais. Eles exercem um papel fundamental em processos que envolvem, principalmente, o metabolismo lipídico, em resposta à ativação por ligantes naturais e sintéticos como os ácidos graxos e os fibratos, respectivamente. A crescente descoberta de importantes funções fisiológicas, coordenadas pelos PPARs, e a necessidade de se conhecer como os agonistas, atualmente disponíveis, atuam nesses receptores, têm incitado pesquisas que vislumbram sua melhor exploração nos tratamentos de doenças metabólicas e inflamatórias, minimizando os efeitos adversos de ativações suprafisiológicas. Nesse cenário, o presente trabalho buscou compreender melhor as bases estruturais envolvidas nas funções atribuídas aos PPARs e explicar como as interações com seus ligantes ocorrem. Para isso, foram realizadas a subclonagem do domínio de ligação ao ligante do PPARα, sua expressão e purificação, seguidas de ensaios cristalográficos e biofísicos, além da abordagem de testes funcionais. Uma vez que a formação de oligômeros está relacionada à funcionalidade desses receptores, foram abordados estudos de oligomerização dos PPARs α e γ, compreendendo tanto o processo de homo- quanto o de heterodimerização. Os ensaios de cristalização do hPPARα LBD complexado a ligantes naturais e sintéticos, resultaram em estruturas cristalográficas que permitiram a identificação dos resíduos envolvidos no reconhecimento dos ligantes e a caracterização de sítios de ligação nunca antes descritos. A presença de ligantes nessas regiões afeta a conformação da proteína e, consequentemente, a modulação de sua função e o recrutamento da maquinaria transcricional. Adicionalmente, as estruturas cristalográficas da proteína complexada a ácidos graxos auxiliaram na compreensão de como essa importante classe de ligantes naturais possui efeitos farmacológicos similares aos de ligantes sintéticos. Esses resultados têm imediato impacto na procura racional de agonistas para esses receptores e se inserem em uma perspectiva de promoção do desenvolvimento científico-tecnológico na área de endocrinologia molecular.
The peroxisome proliferation-activated receptors (PPARs) belong to the nuclear receptors superfamily, acting as transcriptional factors. They play a key role in processes involving essentially lipid metabolism in response to activation by natural and synthetic ligands such as fatty acids and fibrates, respectively. The rising discovery of important physiological functions coordinated by PPARs and the necessity to know how the currently available agonists act on these receptors, have encouraged researches envisioning a better receptor exploration in the treatment of metabolic and inflammatory diseases, minimizing the adverse effects of supraphysiological activations. In this scenario, the present study aimed to better understand the structural basis involved in PPARs functions and elucidates how the…
Advisors/Committee Members: Polikarpov, Igor.
Subjects/Keywords: Cristalografia de proteínas; Interação proteína: ligante; Nuclear receptor; Oligomerização de proteínas; Peroxisome proliferator-activated receptor; Protein crystallography; Protein oligomerization; Protein:ligand interaction; Receptor ativador da proliferação de peroxissomos; Receptor nuclear
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APA (6th Edition):
Muniz, A. B. (2013). Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos. (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/76/76132/tde-31072013-141118/ ;
Chicago Manual of Style (16th Edition):
Muniz, Amanda Bernardes. “Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos.” 2013. Doctoral Dissertation, University of São Paulo. Accessed January 22, 2021.
http://www.teses.usp.br/teses/disponiveis/76/76132/tde-31072013-141118/ ;.
MLA Handbook (7th Edition):
Muniz, Amanda Bernardes. “Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos.” 2013. Web. 22 Jan 2021.
Vancouver:
Muniz AB. Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos. [Internet] [Doctoral dissertation]. University of São Paulo; 2013. [cited 2021 Jan 22].
Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-31072013-141118/ ;.
Council of Science Editors:
Muniz AB. Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos. [Doctoral Dissertation]. University of São Paulo; 2013. Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-31072013-141118/ ;
University of Toronto
21.
Costa, Selina.
Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish.
Degree: 2018, University of Toronto
URL: http://hdl.handle.net/1807/89513
► Nuclear receptors (NRs) are ligand activated transcription factors that are involved in variety of processes, such as metabolism, development, and reproduction. The farnesoid x receptor…
(more)
▼ Nuclear receptors (NRs) are ligand activated transcription factors that are involved in variety of processes, such as metabolism, development, and reproduction. The farnesoid x receptor (FXR) is a NR that is involved in maintaining lipid homeostasis in the liver. When FXR is downregulated in the liver, diseases such as fatty liver disease can arise. Using the ligand-trap system in zebrafish, a novel ligand for FXR, 8215 Ethyl, was identified. This ligand was characterized and it was discovered that 8215 Ethyl induces FXR expression robustly and selectively in the liver at non-toxic concentrations. 8215 Ethyl is also able to induce activation of the NRs PPARγ and RORγ in zebrafish. FXR, PPARγ, and RORγ are regulated by 8215 Ethyl through the direct binding of the ligand to the ligand binding domains of these NRs. These findings indicate that 8215 Ethyl may have therapeutic potential to treat diseases associated with downregulation of FXR.
M.Sc.
Advisors/Committee Members: Krause, Henry, Molecular and Medical Genetics.
Subjects/Keywords: Drug Screening; Farnesoid X Receptor; Ligand Characterization; Ligand Trap System; Nuclear Receptor; 0369
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APA (6th Edition):
Costa, S. (2018). Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/89513
Chicago Manual of Style (16th Edition):
Costa, Selina. “Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish.” 2018. Masters Thesis, University of Toronto. Accessed January 22, 2021.
http://hdl.handle.net/1807/89513.
MLA Handbook (7th Edition):
Costa, Selina. “Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish.” 2018. Web. 22 Jan 2021.
Vancouver:
Costa S. Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish. [Internet] [Masters thesis]. University of Toronto; 2018. [cited 2021 Jan 22].
Available from: http://hdl.handle.net/1807/89513.
Council of Science Editors:
Costa S. Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish. [Masters Thesis]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/89513
University of Western Ontario
22.
Sun, Man-Ger.
Liver X Receptor and Retinoid X Receptor in Cartilage Development and Homeostasis.
Degree: 2017, University of Western Ontario
URL: https://ir.lib.uwo.ca/etd/5175
► Osteoarthritis (OA) is a heterogeneous and multifactorial degenerative disease characterized by cartilage degradation in the joint. Available treatment options target symptoms but do not address…
(more)
▼ Osteoarthritis (OA) is a heterogeneous and multifactorial degenerative disease characterized by cartilage degradation in the joint. Available treatment options target symptoms but do not address the underlying issue of joint tissue degeneration. A better understanding of the molecular mechanisms maintaining cartilage health is essential for developing novel therapeutic strategies. Previous studies have shown the nuclear receptor Liver X Receptor (LXR) to possess protective roles against cartilage breakdown in OA, however the underlying mechanisms behind this process remain unknown. Since LXR regulates transcription by forming obligate heterodimers with another nuclear receptor, the Retinoid X Receptor (RXR), I hypothesized that LXR and RXR regulate cartilage development, maturation and lipid homeostasis.
The first study of this thesis investigated the effect of LXR activation on chondrocyte differentiation in order to elucidate the molecular mechanisms behind LXR’s protection against OA. Three different chondrogenic culture systems were treated with the specific LXR agonist, GW3965, and it was found that LXR activation suppressed chondrocyte hypertrophy, in part through the delay of cell-cycle exit and consequent retention of chondrocyte proliferation.
To further identify the intracellular changes that occur to elicit this suppression in hypertrophy, I conducted microarray analysis on growth plate chondrocytes treated with GW3965 in my second study. LXR activation caused differential regulation of various genes involved in lipid metabolism, including central players mediating cellular cholesterol efflux. These findings demonstrate a potential link between LXR’s role in lipid metabolism and the differentiation of developing chondrocytes.
Lastly, to gain insight into LXR and RXR’s transcriptional effects in articular chondrocytes, I conducted microarray analysis on immature murine articular chondrocytes (IMACs) treated with either a LXR or RXR agonist. Both LXR and RXR activation differentially regulated cellular lipid metabolism. However, they appear to exert opposing effects on cellular oxidative stress response and maintenance of extracellular matrix (ECM) homeostasis, suggesting contrasting roles in OA progression.
Collectively, these data demonstrate that LXR and RXR regulate various cellular mechanisms involved in metabolic homeostasis of both growth plate and articular chondrocytes. Deeper understanding of nuclear receptor function in chondrocytes will contribute to better understanding of the molecular pathways controlling cartilage health and disease.
Subjects/Keywords: Liver X Receptor; Retinoid X Receptor; Nuclear Receptors; Chondrocyte Differentiation; Osteoarthritis; Transcriptional Regulation; Musculoskeletal Diseases
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APA ·
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APA (6th Edition):
Sun, M. (2017). Liver X Receptor and Retinoid X Receptor in Cartilage Development and Homeostasis. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/5175
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):
Sun, Man-Ger. “Liver X Receptor and Retinoid X Receptor in Cartilage Development and Homeostasis.” 2017. Thesis, University of Western Ontario. Accessed January 22, 2021.
https://ir.lib.uwo.ca/etd/5175.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sun, Man-Ger. “Liver X Receptor and Retinoid X Receptor in Cartilage Development and Homeostasis.” 2017. Web. 22 Jan 2021.
Vancouver:
Sun M. Liver X Receptor and Retinoid X Receptor in Cartilage Development and Homeostasis. [Internet] [Thesis]. University of Western Ontario; 2017. [cited 2021 Jan 22].
Available from: https://ir.lib.uwo.ca/etd/5175.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sun M. Liver X Receptor and Retinoid X Receptor in Cartilage Development and Homeostasis. [Thesis]. University of Western Ontario; 2017. Available from: https://ir.lib.uwo.ca/etd/5175
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
23.
Breuker, Cyril.
Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte.
Degree: Docteur es, Sciences du médicament, 2010, Université Montpellier I
URL: http://www.theses.fr/2010MON13522
► CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X Receptor, NR1I2) sont deux récepteurs nucléaires dédiés à la reconna issance et à l'élimination de molécules…
(more)
▼ CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X Receptor, NR1I2) sont deux récepteurs nucléaires dédiés à la reconna issance et à l'élimination de molécules lipophiles potentiellement toxiques pour l'organisme. Ces facteurs de transcription peuvent être activés par des ligands d'origines et de structures diverses (médicaments, polluants environnementaux, produits de l'alimentation et de phytothérapies). L'activation de ces récepteurs entraîne l'expression des gènes majeurs de la fonction de détoxication entéro-hépatique (CYP450, transférases, transporteurs) permettant l'élimination de ces toxiques. Dans ce travail, nous avons dans un premier temps 1) montré que CAR contrôle l'expression de Spot14, une protéine pro-lipogénique, et 2) nous avons identifié une nouvelle isoforme de PXR (PXR-small) codant uniquement pour le domaine de liaison des ligands de PXR. Nous avons pu déterminer les origines de transcription par 5'-RACE PCR et montrer que PXR-small représente environ 10% de l'ensemble des transcrits de PXR dans le tissu hépatique sain par une approche de PCR qua ntitative. Nous avons pu détecter sa présence par western-blot sur des extraits de protéines nucléaires issus de tissus hépatiques et de lignées cellulaires hépatiques. Par des expériences de gel retard, nous avons observé que cette nouvelle isoforme tronquée, qui ne code que pour le LBD de PXR, ne peut pas se lier à l'ADN. Des expériences de gènes rapporteurs suggèrent que cette isoforme se comporte comme un dominant négatif de PXR. Enfin, la présence d'un ilot CpG situé juste en amont de PXR-small suggère que cette nouvelle isoforme pourrait être régulée épigénétiquement par méthylation, notamment dans les cellules tumorales.
CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) are two nuclear receptors devoted to the recognition and elimination of lipohilic molecules potentially toxic to the body.These transcription factors can be activated by ligands of different origins and structures (drugs, environmental pollutants, food products and herbal medicine...). The activation of these receptors leads to the expression of major genes of the detoxification process (CYP450, transferases, transporters) leading to the elimination of these toxics. In this work, we 1) showed that Spot14, a pro-lipogenic protein, is a target gene of CAR, then 2) we identified a novel isoform of PXR (PXR-small), coding only the ligand binding domain of PXR. By using 5'-RACE PXR, we established the origins of transcription of PXR-small and by quantitative PCR we observed that PXR-small represents about 10% of all PXR transcripts in human liver. By using western blo t, we detect its presence on nuclear protein extracts from liver tissues and hepatic cell lines. In Electromobility shift essays experiments, we observed that PXR-small cannot bind to DNA, while reporter essay experiments suggest that this isoform acts as a dominant negative of PXR. Finally, the presence of a CpG island just upstream of PXR-small suggests that this novel…
Advisors/Committee Members: Pascussi, Jean-Marc (thesis director), Lumbroso, Serge (thesis director).
Subjects/Keywords: Récepteur nucléaire; Pregnane X Receptor; Constitutive Androstane Receptor; Métabolisme des médicaments; Perturbateur métabolique; Nuclear receptor; Pregnane X Receptor; Constitutive Androstane Receptor; Drugs metabolism; Metabolic disruptive
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APA ·
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APA (6th Edition):
Breuker, C. (2010). Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte. (Doctoral Dissertation). Université Montpellier I. Retrieved from http://www.theses.fr/2010MON13522
Chicago Manual of Style (16th Edition):
Breuker, Cyril. “Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte.” 2010. Doctoral Dissertation, Université Montpellier I. Accessed January 22, 2021.
http://www.theses.fr/2010MON13522.
MLA Handbook (7th Edition):
Breuker, Cyril. “Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte.” 2010. Web. 22 Jan 2021.
Vancouver:
Breuker C. Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte. [Internet] [Doctoral dissertation]. Université Montpellier I; 2010. [cited 2021 Jan 22].
Available from: http://www.theses.fr/2010MON13522.
Council of Science Editors:
Breuker C. Etude des xénorécepteurs CAR (NR1I3) et PXR (NR1I2) : identification d’un nouveau gène cible de CAR (SPOT14) et d’une nouvelle isoforme de PXR (PXR-small) dans l'hépatocyte humain : Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte. [Doctoral Dissertation]. Université Montpellier I; 2010. Available from: http://www.theses.fr/2010MON13522
24.
Bendo, Luana.
Estudo da imobilização do receptor tireoidiano humano TRβ1 em filmes finos nanoestruturados e aplicações em detecção de hormônios tireoidianos.
Degree: Mestrado, Ciência e Engenharia de Materiais, 2010, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/88/88131/tde-06072010-175249/
;
► A manipulação de materiais em escala nanométrica representa uma das fronteiras em nanociência e nanotecnologia, devido à possibilidade de controle de propriedades específicas do material.…
(more)
▼ A manipulação de materiais em escala nanométrica representa uma das fronteiras em nanociência e nanotecnologia, devido à possibilidade de controle de propriedades específicas do material. No caso de materiais biológicos, em particular, a manipulação e imobilização na forma de filmes ou camadas ultrafinas é crucial para seu emprego em dispositivos biotecnológicos. Neste trabalho, objetivou-se o estudo de detecção de diferentes hormônios tireoidianos (HTs) e análogos a partir da imobilização da região LBD do receptor de hormônio tireoidiano humano TRTRβ1 em um eletrodo interdigitado, para o desenvolvimento de um biossensor capacitivo. Este sistema consiste em um arranjo estrutural na forma de filme fino capaz de distinguir a interação específica receptor-ligante de outras interações possivelmente interferentes, visando a quantificação dos níveis de HTs. Para isto, a técnica de SAMs (Self-Assembled Monolayers) foi empregada, por permitir um alto controle da espessura e ordenamento molecular dos filmes, assim como a preservação das atividades das biomoléculas. Análises espectroscópicas e morfológicas foram realizadas para o estudo de adsorção das biomoléculas no filme. As interações específicas receptor-ligante foram avaliadas por meio de respostas elétricas (impedância) do biossensor contendo o TRβ1-LBD imobilizado em um filme orgânico ultrafino, e também por SPR (Surface Plasmon Resonance). Os resultados mostraram a capacidade dos eletrodos contendo TRTRβ1-LBD de detectar e diferenciar entre diferentes HTs em concentrações da ordem de nanomolar, compatível com níveis fisiológicos, evidenciando o grande potencial de aplicação para este sistema no diagnóstico e tratamento de disfunções tireoidianas.
Manipulation of materials at the nanoscale represents one of the frontiers in nanoscience and nanotechnology, mainly due to the possibility of specific controlling, improved properties, not observed if conventional bulk processing is applied. For biomolecules, in particular, processing via immobilization in the form of nanostructured films has allowed their use in biotechnological applications and devices. In this master dissertation, we aimed at investigating the immobilization of the LBD domain of human thyroid hormone receptor TRTRβ1 on interdigitated electrodes, to be used as capacitive biosensors for thyroid hormones (THs) and analogues detection. The nuclear receptors were immobilized via SAMs (Self-Assembled Monolayers), since this technique allows a high control of molecular order and thickness of the films, as well as the preservation of biological activities. Spectroscopic and morphological analyses were performed to investigate the adsorption of biomolecules on the nanostructured film. The interactions between receptor - ligand were also evaluated by means of electrical response (impedance) and SPR (Surface Plasmon Resonance). The bioelectrodes containing immobilized TRTRβ1 were capable of detecting and distinguishing among different HTs, including T3, T4, TRIAC and GC-1 at…
Advisors/Committee Members: Zucolotto, Valtencir.
Subjects/Keywords: Biosensor; Biossensor; Hormônios tireoidianos; Human thyroid nuclear receptor; Imobilização; Nanomedicina; Nanomedicine; Protein immobilization; Receptor nuclear tireoidiano humano; Thyroid hormones
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APA (6th Edition):
Bendo, L. (2010). Estudo da imobilização do receptor tireoidiano humano TRβ1 em filmes finos nanoestruturados e aplicações em detecção de hormônios tireoidianos. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/88/88131/tde-06072010-175249/ ;
Chicago Manual of Style (16th Edition):
Bendo, Luana. “Estudo da imobilização do receptor tireoidiano humano TRβ1 em filmes finos nanoestruturados e aplicações em detecção de hormônios tireoidianos.” 2010. Masters Thesis, University of São Paulo. Accessed January 22, 2021.
http://www.teses.usp.br/teses/disponiveis/88/88131/tde-06072010-175249/ ;.
MLA Handbook (7th Edition):
Bendo, Luana. “Estudo da imobilização do receptor tireoidiano humano TRβ1 em filmes finos nanoestruturados e aplicações em detecção de hormônios tireoidianos.” 2010. Web. 22 Jan 2021.
Vancouver:
Bendo L. Estudo da imobilização do receptor tireoidiano humano TRβ1 em filmes finos nanoestruturados e aplicações em detecção de hormônios tireoidianos. [Internet] [Masters thesis]. University of São Paulo; 2010. [cited 2021 Jan 22].
Available from: http://www.teses.usp.br/teses/disponiveis/88/88131/tde-06072010-175249/ ;.
Council of Science Editors:
Bendo L. Estudo da imobilização do receptor tireoidiano humano TRβ1 em filmes finos nanoestruturados e aplicações em detecção de hormônios tireoidianos. [Masters Thesis]. University of São Paulo; 2010. Available from: http://www.teses.usp.br/teses/disponiveis/88/88131/tde-06072010-175249/ ;
Universidade Estadual de Campinas
25.
Souza, Paulo Cesar Telles de, 1982-.
Modelagem molecular de receptores nucleares : estrutura, dinâmica e interação com ligantes: Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands.
Degree: 2013, Universidade Estadual de Campinas
URL: http://repositorio.unicamp.br/jspui/handle/REPOSIP/248869
► Abstract: Nuclear receptors (NRs) are proteins that regulate the gene transcription and thus are important targets for drug development. NRs are composed of four structural…
(more)
▼ Abstract:
Nuclear receptors (NRs) are proteins that regulate the gene transcription and thus are important targets for drug development. NRs are composed of four structural domains. The most important of them is the Ligand Binding Domain (LBD), responsible for the selective recognition of ligands and activation of NR function. In this Doctoral Thesis, Molecular Dynamics (MD) Simulation are used to study two important NRs LBD: Thyroid Hormone
Receptor (TR) and Estrogen
Receptor (ER). Studies involving TR began by investigating a new second binding site of thyroid hormones (T3 and T4) in the TR LBD. It has been shown that hormones remain anchored to the second site and have high mobility and multiple binding modes. Estimates of dissociation DG indicate that this new site can exist in aqueous solution. T4 has the higher affinity and may be the natural ligand of this site. The second objetive of the Thesis was the molecular modeling of the TR LBD structure without ligands (apo-TR) by combining results of MD simulations and hydrogen deuterium exchange experiments. The obtained model of apo-TR shows that H12 a-helix is anchored in H3 which explains the hydration changes in this region indicated by the experiments. The third goal was to elucidate the molecular mechanisms that lead to changes in the activity of two TR mutations: M369Ra and P452Lb. Simulations of M369Ra indicate that the mutated residue can interact directly with T3 in the second binding site, explaining the increase of its affinity. Simulations of P452Lbsuggested that this mutation changes the H12 position, leading to loss of ligand interaction with the rst binding site and reduction of coactivator cavity. The last study investigated a new alternative conformation of ERb LBD, which has the potential to explain how this subtype promotes the partial repression of ERagene transcription. Calculation of DG between classic and alternative conformations indicate that the alternative is stable and the global minimum of free energy.
Advisors/Committee Members: UNIVERSIDADE ESTADUAL DE CAMPINAS (CRUESP), Skaf, Munir Salomão, 1963- (advisor), Universidade Estadual de Campinas. Instituto de Química (institution), Programa de Pós-Graduação em Química (nameofprogram), Pascutti, Pedro Geraldo (committee member), Garratt, Richard Charles (committee member), Ramos, Carlos Henrique Inacio (committee member), Pessine, Francisco Benedito Teixeira (committee member).
Subjects/Keywords: Dinâmica molecular; Proteínas; Receptor nuclear; Hormônios tireoidianos; Estrogênios; Molecular dynamics; Protein; Nuclear receptor; Thyroid hormone; Estrogen hormone
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APA (6th Edition):
Souza, Paulo Cesar Telles de, 1. (2013). Modelagem molecular de receptores nucleares : estrutura, dinâmica e interação com ligantes: Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands. (Thesis). Universidade Estadual de Campinas. Retrieved from http://repositorio.unicamp.br/jspui/handle/REPOSIP/248869
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):
Souza, Paulo Cesar Telles de, 1982-. “Modelagem molecular de receptores nucleares : estrutura, dinâmica e interação com ligantes: Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands.” 2013. Thesis, Universidade Estadual de Campinas. Accessed January 22, 2021.
http://repositorio.unicamp.br/jspui/handle/REPOSIP/248869.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Souza, Paulo Cesar Telles de, 1982-. “Modelagem molecular de receptores nucleares : estrutura, dinâmica e interação com ligantes: Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands.” 2013. Web. 22 Jan 2021.
Vancouver:
Souza, Paulo Cesar Telles de 1. Modelagem molecular de receptores nucleares : estrutura, dinâmica e interação com ligantes: Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands. [Internet] [Thesis]. Universidade Estadual de Campinas; 2013. [cited 2021 Jan 22].
Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/248869.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Souza, Paulo Cesar Telles de 1. Modelagem molecular de receptores nucleares : estrutura, dinâmica e interação com ligantes: Molecular modeling of nuclear receptors : structure, dynamics and interaction with ligands. [Thesis]. Universidade Estadual de Campinas; 2013. Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/248869
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Universidade Federal de Santa Maria
26.
Luciana Benetti.
RECEPTOR DE ANGIOTENSINA II ENVOLVIDO NA REGULAÇÃO DA MATURAÇÃO NUCLEAR DE OÓCITO BOVINO.
Degree: 2008, Universidade Federal de Santa Maria
URL: http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=2022
► O objetivo deste estudo foi de verificar o tipo de receptor da angiotensina II (AngII) envolvido na maturação nuclear de oócitos bovinos e a possível…
(more)
▼ O objetivo deste estudo foi de verificar o tipo de receptor da angiotensina II (AngII) envolvido na maturação nuclear de oócitos bovinos e a possível participação da bradicinina (BK) como mediadora da AngII nesse processo. O primeiro experimento foi conduzido para analisar o tipo de receptor, para isso os complexos cumulus-oócitos (CCOs) foram cultivados por 7 ou 12h na presença de hemiseções foliculares e AngII (10-11M), com ou sem os antagonistas losartan (10-6M; seletivo para receptores AT1), PD123319 (10-6M; seletivo para receptores AT2) ou saralasina (10-7M; antagonista AT1 e AT2). Adicionalmente, foram utilizados dois grupos controle, onde os oócitos foram cultivados na ausência ou na presença de hemiseções foliculares (controle positivo e negativo, respectivamente). Oócitos cultivados por 7h em presença de AngII atingiram 70,4% de rompimento da vesícula germinativa (RVG). Quando o losartan foi adicionado ao meio de cultivo com AngII, não houve diferença na percentagem de oócitos em RVG (73,2%), porém, quando os CCOs foram incubados na presença de AngII + PD123319, houve queda significativa na maturação nuclear (52,1%; P<0,05). O cultivo dos oócitos por um período maior (12h) não causou diferença significativa em relação a esses tratamentos quando foram realizados às 7h (P<0,05). Esses dados indicam que os receptores AT2 mediam as ações da AngII na maturação nuclear em bovinos. Em um segundo experimento, foi verificado o efeito de diferentes concentrações de PD123319 na maturação nuclear dos oócitos na presença de AngII (10-11M) e hemiseções foliculares. O cultivo foi realizado por 7h em um delineamento similar ao do experimento anterior e verificou-se que a inibição induzida pelo antagonista ocorreu de maneira dosedependente e há relação linear entre concentração de PD e índices de RVG obtidos (P=0,0306). Para verificar a participação da BK no mecanismo de ação dos receptores AT2, os oócitos foram cultivados na presença de AngII (10-11M) e hemiseções foliculares com ou sem Hoe-140 (antagonista de receptores B2 da BK) em diferentes concentrações (10-6, 10-7, 10-8 e 10-9M) por 7h. Nesse experimento, não houve diferença nos índices de oócitos que atingiram RVG entre os grupos tratados com o antagonista e o grupo AngII (P>0,05). Esses dados permitem inferir que a AngII atua na maturação nuclear dos oócitos bovinos ativando os receptores AT2 e que a via BK/receptor B2 não está envolvida nesse processo.
The aim of this study was to verify the type of angiotensin II (AngII) receptor involved in nuclear maturation of bovine oocytes and the possible participation of bradykinin (BK) as a mediator of AngII in this process. The first experiment was conducted to analyze the type of AngII receptor, for this cumulus-oocyte complexes (COCs) were cultured for 7 or 12h in the presence of follicular hemisections and AngII (10-11M), with or without the antagonists losartan (10-6M; selective for AT1 receptor), PD123319 (10-6M; selective for AT2 receptor) or saralasin (10-7M; AT1 and AT2 antagonist). Additionally, two control…
Advisors/Committee Members: Katia Padilha Barreto, Juliano Ferreira, José Ricardo de Figueiredo.
Subjects/Keywords: oócito bovino; angiotensina II; receptor AT2; bradicinina; maturação nuclear; FARMACIA; oocyte bovine; angiotensin II; AT2 receptor; bradykinin; nuclear maturation
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APA (6th Edition):
Benetti, L. (2008). RECEPTOR DE ANGIOTENSINA II ENVOLVIDO NA REGULAÇÃO DA MATURAÇÃO NUCLEAR DE OÓCITO BOVINO. (Thesis). Universidade Federal de Santa Maria. Retrieved from http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=2022
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):
Benetti, Luciana. “RECEPTOR DE ANGIOTENSINA II ENVOLVIDO NA REGULAÇÃO DA MATURAÇÃO NUCLEAR DE OÓCITO BOVINO.” 2008. Thesis, Universidade Federal de Santa Maria. Accessed January 22, 2021.
http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=2022.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Benetti, Luciana. “RECEPTOR DE ANGIOTENSINA II ENVOLVIDO NA REGULAÇÃO DA MATURAÇÃO NUCLEAR DE OÓCITO BOVINO.” 2008. Web. 22 Jan 2021.
Vancouver:
Benetti L. RECEPTOR DE ANGIOTENSINA II ENVOLVIDO NA REGULAÇÃO DA MATURAÇÃO NUCLEAR DE OÓCITO BOVINO. [Internet] [Thesis]. Universidade Federal de Santa Maria; 2008. [cited 2021 Jan 22].
Available from: http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=2022.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Benetti L. RECEPTOR DE ANGIOTENSINA II ENVOLVIDO NA REGULAÇÃO DA MATURAÇÃO NUCLEAR DE OÓCITO BOVINO. [Thesis]. Universidade Federal de Santa Maria; 2008. Available from: http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=2022
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cambridge
27.
Frei, Jan Niclas.
Characterisation of the conformational landscape of the β1-adrenergic receptor and development of a strategy towards NMR studies of the protease-activated receptor 1.
Degree: PhD, 2020, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/303160
► The research conducted for this thesis was aimed at providing a comprehensive description of the dynamic and conformational landscape of the minimally thermostabilised avian β1-adrenergic…
(more)
▼ The research conducted for this thesis was aimed at providing a comprehensive
description of the dynamic and conformational landscape of the minimally
thermostabilised avian β1-adrenergic receptor (tβ1AR) using solution state nuclear
magnetic resonance (NMR) spectroscopy. The tβ1AR is a class A G-protein-coupled
receptor (GPCR) and the human counterpart is an important drug target in diseases of
the heart. In chapter 2, a wide range of constructs, labelling reagents and conditions
were tested to make the tβ1AR accessible to 19F NMR spectroscopy. The conditions
optimised in chapter 2 were used in chapter 3 to conduct comprehensive 19F NMR
studies investigating the conformational plasticity of the cytoplasmic ends of
transmembrane domains 6 and 7. Both domains have previously been proposed to be
important structural hotspots for conformational changes during the activation of the
receptor. The work described in chapter 3 tests the conformational response of both
domains in response to a range of ligands and a Gs protein mimicking nanobody. The
data obtained suggested that the cytoplasmic ends of the receptor sample through
several inactive, pre-active and signalling active states and the populations of these
states are tightly controlled by the Gs efficacies of ligands and the binding of
intracellular binding partners. The results will help to explain how extracellular signals
are conformationally transmitted through the receptor to the cytoplasmic face of the
receptor.
In chapter 4, I complemented the results obtained in the NMR spectroscopic studies of
chapter 3 with structural data obtained through second harmonic generation (SHG)
spectroscopy.
In a final step in chapter 5, the knowledge gained from working with the tβ1AR has
been applied to initiate an investigation of the conformational plasticity of a second
GPCR target, the human Protease activated receptor 1 (PAR1). The PAR1 is mostly
associated with regulation of haemostasis and as such a high potential target for
clinical research. I established the construct, expression, purification and 19F labelling
of the PAR1 and obtained initial 19F NMR spectra. The work is an important step
towards understanding the PAR1 conformational landscape.
Subjects/Keywords: G protein-coupled receptor; Nuclear magnetic resonance spectroscopy; β1-adrenergic receptor; Protease-activated receptor 1; Second harmonic generation
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APA (6th Edition):
Frei, J. N. (2020). Characterisation of the conformational landscape of the β1-adrenergic receptor and development of a strategy towards NMR studies of the protease-activated receptor 1. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/303160
Chicago Manual of Style (16th Edition):
Frei, Jan Niclas. “Characterisation of the conformational landscape of the β1-adrenergic receptor and development of a strategy towards NMR studies of the protease-activated receptor 1.” 2020. Doctoral Dissertation, University of Cambridge. Accessed January 22, 2021.
https://www.repository.cam.ac.uk/handle/1810/303160.
MLA Handbook (7th Edition):
Frei, Jan Niclas. “Characterisation of the conformational landscape of the β1-adrenergic receptor and development of a strategy towards NMR studies of the protease-activated receptor 1.” 2020. Web. 22 Jan 2021.
Vancouver:
Frei JN. Characterisation of the conformational landscape of the β1-adrenergic receptor and development of a strategy towards NMR studies of the protease-activated receptor 1. [Internet] [Doctoral dissertation]. University of Cambridge; 2020. [cited 2021 Jan 22].
Available from: https://www.repository.cam.ac.uk/handle/1810/303160.
Council of Science Editors:
Frei JN. Characterisation of the conformational landscape of the β1-adrenergic receptor and development of a strategy towards NMR studies of the protease-activated receptor 1. [Doctoral Dissertation]. University of Cambridge; 2020. Available from: https://www.repository.cam.ac.uk/handle/1810/303160
University of Southern California
28.
Shen, Howard Chung-Hao.
Functional analyses of androgen receptor structure
pertaining to prostate cancer.
Degree: PhD, Molecular Epidemiology, 2007, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/477600/rec/2936
► Various peptide regions of the human androgen receptor (AR) were characterized for their potential role in mediating the androgenic signaling response that is integrally linked…
(more)
▼ Various peptide regions of the human androgen
receptor
(AR) were characterized for their potential role in mediating the
androgenic signaling response that is integrally linked to prostate
cancer development and resistance to treatment. A series of
site-directed mutant AR constructs was created that targeted
putative signaling motifs within the molecule, and was utilized in
functional assays to determine how deviations from the wild-type AR
sequence at these sites impacted
receptor activity. It was shown
that the AR amino-terminal transactivation domain (NTD) possesses
great compensatory ability, as independent disruption of several
sites had little impact on
receptor function in prostate-cancer
derived cell lines. Size modulations of the glycine trinucleotide
repeat in the NTD had a direct effect on
receptor signaling,
suggestive of this region having important influence on NTD
structure. It was determined that a motif located in the proximal
region of the NTD contributes greatly to overall
receptor function
through mediating ligand-dependent interactions between the AR NTD
and ligand-binding domains (LBD). In addition, it was revealed that
one mechanism by which the p160
nuclear receptor coactivators
enhance AR function is through enhancement of this inter-domain
communication. In related studies it was shown that the AR Hinge
domain imparts a pivotal contribution to normal AR signaling
through mediating communication between AR and the 26S proteasome.
Dual roles of the proteasome in AR signaling were characterized
based on observations that separate signaling motifs within the AR
Hinge control a balance between the apo-
receptor and holo-
receptor
responses to proteasome influence.; These findings yield insight
into how specific structural components of the AR cooperatively
function within the entirety of the actively signaling
receptor,
and will contribute to new strategies for therapeutically targeting
the AR molecule in the context of the aberrant androgen signaling
axis that is evident in prostate cancer.
Advisors/Committee Members: Coetzee, Gerhard A. (Committee Chair), Ingles, Sue A. (Committee Member), Stallcup, Michael R. (Committee Member).
Subjects/Keywords: androgen receptor; steroid receptor; nuclear receptor; prostate cancer
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Manager
APA (6th Edition):
Shen, H. C. (2007). Functional analyses of androgen receptor structure
pertaining to prostate cancer. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/477600/rec/2936
Chicago Manual of Style (16th Edition):
Shen, Howard Chung-Hao. “Functional analyses of androgen receptor structure
pertaining to prostate cancer.” 2007. Doctoral Dissertation, University of Southern California. Accessed January 22, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/477600/rec/2936.
MLA Handbook (7th Edition):
Shen, Howard Chung-Hao. “Functional analyses of androgen receptor structure
pertaining to prostate cancer.” 2007. Web. 22 Jan 2021.
Vancouver:
Shen HC. Functional analyses of androgen receptor structure
pertaining to prostate cancer. [Internet] [Doctoral dissertation]. University of Southern California; 2007. [cited 2021 Jan 22].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/477600/rec/2936.
Council of Science Editors:
Shen HC. Functional analyses of androgen receptor structure
pertaining to prostate cancer. [Doctoral Dissertation]. University of Southern California; 2007. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/477600/rec/2936
Brunel University
29.
Hassan Ahmed, Mai.
Discovery and restoration of aberrant nuclear structure and genome behaviour in breast cancer cells.
Degree: PhD, 2013, Brunel University
URL: http://bura.brunel.ac.uk/handle/2438/8847
;
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607528
► The eukaryotic interphase nucleus is well organised and the genome positioned non-randomly. Nuclear structure is an important regulator of genome behaviour and function. Genome organisation…
(more)
▼ The eukaryotic interphase nucleus is well organised and the genome positioned non-randomly. Nuclear structure is an important regulator of genome behaviour and function. Genome organisation and nuclear structure are compromised in diseases such as cancer and laminopathies. This study was to find out and to determine if there is any functional relationship between nuclear structure and genome mis-organisation in cancer cells. I have assessed the presence and distribution of specific nuclear structural proteins (A-type, B-type lamins and its receptor LBR, many of their binding proteins such as MAN1, LAP2α, LAP2, and Emerin and other nuclear proteins (PML, Nucleolin, and Ki67) using indirect immunofluorescence. From this study, it is found that the nuclear structure of breast cancer cells is often altered. The most severely affected proteins are the nuclear lamins B1 and B2 and they found as large foci within the nucleoplasm with little LBR expression to localise the lamin B. I also assessed the chromosome positioning (HSA 7, 10, 11, 14 and 17) and gene positioning (AKT1, CCND1, HSP90AA1, EGFR, ERRBB2/HER2 and PTEN) in breast cancer cell lines (T-47D, GI-101, Sk-Br-3 and BT-474) and in normal breast cell lines (MCF-10A) using 2D-FISH technique. I also assessed the position of the genes in nuclei and correlated with gene expression using qRT-PCR. Breast cell lines have treated with a drug named lovastatin and it was found that the cells have restored LBR expression and localisation of lamin B, leading to altered gene positioning and changed expression of breast cancer genes. Since the drug (lovastatin, 12 μM/48 hours) affects the prenylation as a post-translation modification process and lamins B biosythensis, it is found that B-type lamins and its receptor expression and distribution were improved and increased in expression by 2-fold in expression levels in the most affected cells (T-47D, and BT-474) compared to the normal cells (MCF-10A) and these cells also showed abnormal nuclei and dead cells. When analysing the nuclear positioning of the genes (AKT1, HSP90AA1 and ERRBB2/HER2), it is found that AKT1 was positioned periphery in BT-474 and T-47D cells and interiorly in the normal cells (MCF-10A) before treatment whereas the same gene was positioned periphery in T-47D and MCF-10A cells and interiorly in BT-474 after treatment with lovastatin. It is also found that HSP90AA1 was positioned periphery in MCF-10A and T-47D cells and interiorly in BT-474 cells before and after treatment (no change). Moreover, ERRBB2/HER2 gene was positioned periphery in T-47D and BT-474 cells and interiorly in MCF-10A cells before treatment whereas the same gene was positioned periphery in MCF-10A and T-47D cells and interiorly in BT-474 after treatment with the same drug. Regarding LMNB1, LMNB2, and LBR genes, the study focussed only on their expression levels and no work has done on their chromosome positioning as well as gene position before and after treatment. These three genes were over expressed when assessed by measuring the…
Subjects/Keywords: 616.99; Breast cancer; Nuclear lamins; Lamin B receptor; Nuclear structure; Genome organisation
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APA ·
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APA (6th Edition):
Hassan Ahmed, M. (2013). Discovery and restoration of aberrant nuclear structure and genome behaviour in breast cancer cells. (Doctoral Dissertation). Brunel University. Retrieved from http://bura.brunel.ac.uk/handle/2438/8847 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607528
Chicago Manual of Style (16th Edition):
Hassan Ahmed, Mai. “Discovery and restoration of aberrant nuclear structure and genome behaviour in breast cancer cells.” 2013. Doctoral Dissertation, Brunel University. Accessed January 22, 2021.
http://bura.brunel.ac.uk/handle/2438/8847 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607528.
MLA Handbook (7th Edition):
Hassan Ahmed, Mai. “Discovery and restoration of aberrant nuclear structure and genome behaviour in breast cancer cells.” 2013. Web. 22 Jan 2021.
Vancouver:
Hassan Ahmed M. Discovery and restoration of aberrant nuclear structure and genome behaviour in breast cancer cells. [Internet] [Doctoral dissertation]. Brunel University; 2013. [cited 2021 Jan 22].
Available from: http://bura.brunel.ac.uk/handle/2438/8847 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607528.
Council of Science Editors:
Hassan Ahmed M. Discovery and restoration of aberrant nuclear structure and genome behaviour in breast cancer cells. [Doctoral Dissertation]. Brunel University; 2013. Available from: http://bura.brunel.ac.uk/handle/2438/8847 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607528
Universiteit Utrecht
30.
Hollman, D.A.A.
Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors.
Degree: 2011, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/208274
► Farnesoid X Receptor (FXR) is an important player in the upregulation of genes (transactivation) in bile acid homeostasis and fat and glucose metabolism. Recently, it…
(more)
▼ Farnesoid X
Receptor (FXR) is an important player in the upregulation of genes (transactivation) in bile acid homeostasis and fat and glucose metabolism. Recently, it has become clear that an additional important role for FXR consists of downregulating genes (transrepression) in inflammation. Because of this dual role of FXR, full agonists will likely have serious side effects, which would be similar to what is known for other members of the
Nuclear Receptor (NR) family. Therefore selective modulators of FXR should be developed. However, the molecular mechanisms deciding between transactivation and transrepression in FXR are currently unknown. For the NR family, cases of SUMOylation and phosphorylation have been reported to be distinctive between transactivation and transrepression. SUMOylation can either diminish transactivation selectively or increase transrepression. Phosphorylation was observed to prime for SUMOylation, thereby also selectively augmenting transrepression. Here, we review the state of current knowledge about FXR transactivation and transrepression and compare this to what is known in other members of the NR family. Ultimately, increased knowledge on the differential mechanisms of transactivation and transrepression will lead to the development of more specific drugs with less serious side effects.
Advisors/Committee Members: Mil, S.W.C. van.
Subjects/Keywords: Nuclear Receptors; Farnesoid X Receptor; Transactivation; Transrepression; Post-translational modifications
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APA (6th Edition):
Hollman, D. A. A. (2011). Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors. (Masters Thesis). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/208274
Chicago Manual of Style (16th Edition):
Hollman, D A A. “Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors.” 2011. Masters Thesis, Universiteit Utrecht. Accessed January 22, 2021.
http://dspace.library.uu.nl:8080/handle/1874/208274.
MLA Handbook (7th Edition):
Hollman, D A A. “Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors.” 2011. Web. 22 Jan 2021.
Vancouver:
Hollman DAA. Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors. [Internet] [Masters thesis]. Universiteit Utrecht; 2011. [cited 2021 Jan 22].
Available from: http://dspace.library.uu.nl:8080/handle/1874/208274.
Council of Science Editors:
Hollman DAA. Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors. [Masters Thesis]. Universiteit Utrecht; 2011. Available from: http://dspace.library.uu.nl:8080/handle/1874/208274
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