+publisher:"Penn State University" +contributor:("Jeffrey Maurice Peters, Committee Member")

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Penn State University

1. Wang, Li. The Effects Of Monounsaturated Fatty Acid-enriched Diets With And Without Avocados On Cardio-metabolic Risk Factors.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/25111

► Dietary guidance recommends a healthy dietary pattern that is low in saturated fat (SFA) to lower low-density lipoprotein cholesterol (LDL-C), a primary target for cardiovascular… (more)

▼ Dietary guidance recommends a healthy dietary pattern that is low in saturated fat (SFA) to lower low-density lipoprotein cholesterol (LDL-C), a primary target for cardiovascular disease (CVD) risk reduction. Using either carbohydrates (CHO) or unsaturated fat to replace saturated fat in an average American diet may achieve a similar reduction in LDL-C, but a high intake of dietary CHO may increase triglycerides (TG), lower high density lipoprotein cholesterol (HDL-C), and increase small, dense LDL, along with promoting insulin resistance thereby increasing the risk of metabolic syndrome and type 2 diabetes. These cardio-metabolic risk factors also are targets for dietary intervention to achieve a greater CVD risk reduction. When SFA is replaced with unsaturated fat, the predominant fatty acid class is monounsaturated fatty acids (MUFA) because the recommended intake of polyunsaturated fatty acids (PUFA) is less than 10% of energy. Overall, the substitution of MUFA instead of CHO (especially refine grains and added sugar) for SFA calories may favorably affect other lipid risk factors of CVD. The oxidative modification of LDL particles is a key factor in the initial process of atherosclerosis. Dietary antioxidant vitamins, polyphenols, and other bioactive compounds from foods (e.g., fruits and vegetables) have been a focus of nutrition because of their role in improving antioxidant status and lowering LDL oxidation. Identifying foods that can beneficially improve multiple cardio-metabolic risk factors is needed for the primary prevention of CVD. Avocados are a nutrient-dense source of MUFA, rich in vitamins, minerals, fiber, phytosterols and polyphenols. It is unclear whether avocados affect cardio-metabolic risk factors beyond their fatty acid profile. This dissertation investigated the effects of a MUFA enriched moderate fat diets including one avocado per day on established and novel cardio-metabolic risk factors. A randomized, cross-over, controlled feeding trial was conducted with 45 healthy overweight/obese participants with baseline LDL-C levels in the 25-90th percentile. After a 2 week run-in average American diet (34% fat, 13% SFA, 11% MUFA, 51% carbohydrate, 16% protein) at baseline, three cholesterol-lowering diets (6-7% SFA) were fed (5 weeks each) with a random sequence: a lower-fat diet (LF: 24% fat, 7% SFA, 11% MUFA, 9% PUFA, 59% carbohydrate, 16-17% protein); and two moderate fat diets matched for macronutrients and fatty acids (34% fat, 6% SFA, 17% MUFA, 9% PUFA, 49% carbohydrate, 16-17% protein): the avocado diet included one fresh Hass avocado (136 g) per day, and the moderate fat diet provided mostly the same foods (as the avocado diet) but used high oleic acid oils and low fat dairy products to match the fatty acid profile of one avocado. All three cholesterol-lowering diets met current dietary recommendations on macronutrient percentage range and the serving amount for each food group. Specifically, the grain product in the lower fat diet contained more than half whole grains,… Advisors/Committee Members: Penny Margaret Kris Etherton, Dissertation Advisor/Co-Advisor, Penny Margaret Kris Etherton, Committee Chair/Co-Chair, Joshua D Lambert, Committee Member, Jeffrey Maurice Peters, Committee Member, Michael Thomas Green, Committee Member, Mosuk Chow, Committee Member.

Subjects/Keywords: avocado; antioxidant; CVD; LDL-C; lipid; lipoprotein; metabolic syndrome; MUFA; nutrition; oxidation; small dense LDL.

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APA (6^th Edition):

Wang, L. (2015). The Effects Of Monounsaturated Fatty Acid-enriched Diets With And Without Avocados On Cardio-metabolic Risk Factors. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/25111

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Wang, Li. “The Effects Of Monounsaturated Fatty Acid-enriched Diets With And Without Avocados On Cardio-metabolic Risk Factors.” 2015. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/25111.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Wang, Li. “The Effects Of Monounsaturated Fatty Acid-enriched Diets With And Without Avocados On Cardio-metabolic Risk Factors.” 2015. Web. 05 Mar 2021.

Vancouver:

Wang L. The Effects Of Monounsaturated Fatty Acid-enriched Diets With And Without Avocados On Cardio-metabolic Risk Factors. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/25111.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wang L. The Effects Of Monounsaturated Fatty Acid-enriched Diets With And Without Avocados On Cardio-metabolic Risk Factors. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/25111

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

2. DiNatale, Brett C. The role of the aryl hydrocarbon receptor in tumor cell phenotype.

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11597

► The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely associated with its function in xenobiotic metabolism and its ability to bind environmental pollutants… (more)

▼ The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely associated with its function in xenobiotic metabolism and its ability to bind environmental pollutants in the polycyclic aromatic hydrocarbon family such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Upon ligand binding, the AHR translocates to the nucleus, exchanges its chaperone complex for its heterodimerization partner, the aryl hydrocarbon receptor nuclear translocator, and binds to dioxin response elements (DREs) in the promoter of target genes, driving transcription. However, researchers have tied the AHR to a variety of cellular processes in addition to xenobiotic metabolism, not all of which occur through DRE binding and direct transcriptional activation. The studies presented here build upon the finding that combinatorial treatment with exogenous AHR ligands and IL1B leads to synergistic IL6 expression in some typically non-responsive tumor cell lines. The overall hypothesis was that the AHR plays a molecular role in IL6 transcription and represents a viable point of treatment to mediate tumor cell signaling. Analysis of the mechanism by which these two signals mediate IL6 induction revealed that the liganded AHR binds to DREs far upstream from the IL6 promoter, yet plays a role in the de-repression of the chromatin of the proximal promoter through dismissal of co-repressor complexes. Following this, IL1B-induced NFkB activity is able to positively affect transcription of the IL6 gene. Subsequently, the role played by the AHR in the relatively high basal and readily inducible cytokine expression of head and neck squamous cell carcinoma (HNSCC) cell lines was assessed. Multiple HNSCC cell lines derived from various loco-regional tumors showed a similar state of IL6 de-repression with AHR occupancy of the promoter in the absence of exogenous ligand. This promoter configuration could be reversed and transcription repressed through treatment of cells with an AHR antagonist and the resultant decrease in receptor occupancy of the IL6 promoter. Next, the hypothesis was tested that basal AHR occupancy of the IL6 promoter in HNSCC cell lines is indicative of a constitutive level of receptor activity, and that the role of the AHR in various cellular processes that enhance tumor cell phenotype were similarly occurring. Treatment of HNSCC cell lines with AHR antagonists decreased tumor cell proliferation, migration, invasive ability, and prevented the increase of an integral protein for a chemotherapy efflux pump. The significance of the results presented in these studies reflects on both the field of AHR biology and the potential for AHR-targeted treatment in cancer, including HNSCC. Uncovering a mechanism whereby AHR activation is one of two signals required for gene regulation opens a new field of research into combinatorial effects of the receptor and points to previously undocumented genes as being AHR targets with or without DREs in the proximal promoter. Finally, AHR antagonist treatment is a viable… Advisors/Committee Members: Gary H Perdew, Dissertation Advisor/Co-Advisor, Gary H Perdew, Committee Chair/Co-Chair, Jeffrey Maurice Peters, Committee Member, Craig Richard Baumrucker, Committee Member, Andrea Marie Mastro, Committee Member, Kumble Sandeep Prabhu, Committee Member.

Subjects/Keywords: ahr; aryl hydrocarbon receptor; cancer

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APA (6^th Edition):

DiNatale, B. C. (2011). The role of the aryl hydrocarbon receptor in tumor cell phenotype. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11597

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

DiNatale, Brett C. “The role of the aryl hydrocarbon receptor in tumor cell phenotype.” 2011. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/11597.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

DiNatale, Brett C. “The role of the aryl hydrocarbon receptor in tumor cell phenotype.” 2011. Web. 05 Mar 2021.

Vancouver:

DiNatale BC. The role of the aryl hydrocarbon receptor in tumor cell phenotype. [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/11597.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

DiNatale BC. The role of the aryl hydrocarbon receptor in tumor cell phenotype. [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/11597

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. Tanos , Rachel. Novel regulation of lipid homeostasis by the Ah receptor.

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/15460

► The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor. Activation of AHR has been associated with toxicity through its binding to dioxin response… (more)

▼ The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor. Activation of AHR has been associated with toxicity through its binding to dioxin response element (DRE) sequences in its target genes (e.g. CYP1A1). Evolutionary conservation of the receptor and the phenotype of mice lacking the AHR suggest an endogenous role for the receptor beyond responding to xenobiotic exposure. Based on previous work in our lab showing the ability of the receptor to alter gene expression independent of DRE sequences, we set out to explore a possible involvement of the receptor in key cellular pathways. We performed a microarray analysis on liver isolated from ligand-treated transgenic mice expressing a wild-type Ahr or a DRE-binding mutant Ahr (A78D). The results revealed that AHR ligand treatment suppressed cholesterol synthesis but did not require DRE binding. In order to confirm this finding in humans, primary human hepatocytes were administered an AHR ligand and subsequent analysis of mRNA levels revealed a significant trend of repression in fatty acid and cholesterol synthesis genes. Our lab has also established the ability of the ligand SGA360 to activate AHR without inducing DRE-mediated activity. Since toxicity associated with hyperactivation of the AHR is a DRE-mediated event and our microarray data revealed that DRE-binding is not essential for the regulation of our genes of interest, we tested the effect of SGA360 in primary human hepatocytes. Selective activation of the receptor showed a significant attenuation in the expression of our target genes and the ability of the receptor to inhibit the compensatory mechanism of statins on cholesterol synthesis gene expression. In addition, SGA360 exhibited a higher degree of repression of fatty acid and cholesterol biosynthesis gene expression than the AHR agonist BNF. Mirroring our gene expression results, a significant repression of fatty acid and cholesterol secretion was observed in human cells. In an effort to elucidate the mechanism of this regulation by AHR, we investigated the activity of AHR on the sterol element binding proteins (SREBPs), the key regulators of both pathways. Our results indicated the targeted proteosomal degradation of the cleaved active form of those transcription factors when AHR is activated causing the attenuation of their transcriptional signaling. The discovery of AHR as a regulator of fatty acid and cholesterol biosynthesis pathways independently of its DRE-binding and the ability to selectively activate the receptor for this purpose suggests that AHR may be a previously unrecognized therapeutic target. Advisors/Committee Members: Gary H Perdew, Dissertation Advisor/Co-Advisor, Jeffrey Maurice Peters, Committee Member, Richard John Frisque, Committee Member, Ross Cameron Hardison, Committee Member, Joshua D Lambert, Committee Member.

Subjects/Keywords: Ah receptor; AHR; cholesterol; Fatty acid; lipid; SREBP

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APA (6^th Edition):

Tanos , R. (2012). Novel regulation of lipid homeostasis by the Ah receptor. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/15460

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tanos , Rachel. “Novel regulation of lipid homeostasis by the Ah receptor.” 2012. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/15460.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tanos , Rachel. “Novel regulation of lipid homeostasis by the Ah receptor.” 2012. Web. 05 Mar 2021.

Vancouver:

Tanos R. Novel regulation of lipid homeostasis by the Ah receptor. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/15460.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tanos R. Novel regulation of lipid homeostasis by the Ah receptor. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/15460

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

4. Roy, Aditi. Blood lead levels, dietary intake, and oxidative stress in lead-exposed Uruguayan children.

Degree: 2014, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/21775

► Lead exposure poses threats to health of millions of children worldwide. Weight of the evidence from experimental and epidemiological studies suggests that low-level lead exposure,… (more)

▼ Lead exposure poses threats to health of millions of children worldwide. Weight of the evidence from experimental and epidemiological studies suggests that low-level lead exposure, a condition currently observed in general population, is associated with various adverse health outcomes in spite of the null findings in some studies. Although, we have a knowledge-base of the health consequences of exposure to lead in children, important questions particularly on the mechanisms of its toxicity, as well as prevention and treatment of lead exposure remain unanswered. Understanding the association between socio-demographic and dietary factors that could affect children’s lead exposure and the relation between lead and oxidative stress, a proposed common mechanism for many lead-induced toxicities, could potentially help in finding effective preventive strategies for exposure and toxicities of low-level lead. This cross-sectional study in 211 children (5-8 years old) from Montevideo, Uruguay identified the potential sociodemographic and household risk factors that can predict children’s blood lead levels (BLLs), a biomarker of lead exposure. The study also examined the relation between dietary intakes of nutrients and BLL, and investigated the association between BLL and two oxidative stress markers (measured as F2- 8α isoprostane or isoprostane, a lipid oxidation marker and 8- hydroxy-2- deoxy Guanosine or 8-OH-dG, a DNA oxidation marker), and tested whether intakes of antioxidants act as effect modifiers. The mean BLL of the study children was 4.7 ± 2.2 μg/dL and 30.2% children had elevated BLL [≥ 5 μg/dL, the current reference level set by Centre for Disease Control for identification and monitoring of children who are exposed to more lead than most children; CDC, 2012]. The most salient socio-demographic and household risk factors for BLL in the study were: father’s smoking, father’s employment in jobs with potential for metal exposure (such as construction, factories, and print shops, and as mechanics or drivers), and the number of young child (< 5 years old) in a household. Among dietary factors, carbohydrate (both as absolute amount and as percentage of energy intake) and fat (as % energy)—were positively associated with children’s BLL. On the other hand, calcium intake was inversely associated with children’s BLL. Majority of the study children did not meet the recommended intake for calcium(800 mg/day). Other nutrients were not associated with BLL and no interactions between pairs of nutrients (iron-zinc, iron-vitamin C or iron-calcium) on BLL were observed. Finally, a weak positive association was found between BLL and the urinary concentrations of isoprostane in the study children, but not between children’s BLL and the concentration of urinary 8-OH-dG. The interactive effects of antioxidants (vitamin C or zinc) with BLL on oxidative stress markers were not statistically significant. This study provides evidence that Uruguayan children continue to be exposed to lead years after the withdrawal of lead from gasoline.… Advisors/Committee Members: Katarzyna Kordas, Dissertation Advisor/Co-Advisor, Katarzyna Kordas, Committee Chair/Co-Chair, Shannon Leanne Kelleher, Committee Member, Laura E Murray Kolb, Committee Member, Jeffrey Maurice Peters, Committee Member.

Subjects/Keywords: Lead exposure; blood lead level; children; Uruguay; dietary intake; oxidative stress

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Roy, A. (2014). Blood lead levels, dietary intake, and oxidative stress in lead-exposed Uruguayan children. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/21775

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Roy, Aditi. “Blood lead levels, dietary intake, and oxidative stress in lead-exposed Uruguayan children.” 2014. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/21775.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Roy, Aditi. “Blood lead levels, dietary intake, and oxidative stress in lead-exposed Uruguayan children.” 2014. Web. 05 Mar 2021.

Vancouver:

Roy A. Blood lead levels, dietary intake, and oxidative stress in lead-exposed Uruguayan children. [Internet] [Thesis]. Penn State University; 2014. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/21775.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Roy A. Blood lead levels, dietary intake, and oxidative stress in lead-exposed Uruguayan children. [Thesis]. Penn State University; 2014. Available from: https://submit-etda.libraries.psu.edu/catalog/21775

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

5. Shen, Qiuying. INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12127

► Major depressive disorder (MDD) exhibits extensive comorbidity with anxiety and poorly predictable responsiveness to different types of antidepressant drugs. In particular, melancholic MDD shows great… (more)

▼ Major depressive disorder (MDD) exhibits extensive comorbidity with anxiety and poorly predictable responsiveness to different types of antidepressant drugs. In particular, melancholic MDD shows great reductions in GABA, aberrant function of the hypothalamic-pituitary-adrenal (HPA) axis as well as characteristics of anxious depression. Mice that are heterozygous for the γ2 subunit gene of GABAARs (γ2+/−) exhibit a modest functional deficit in GABAARs, yet they have been shown to recapitulate behavioral, pharmacological, and cognitive alterations reminiscent of anxiety disorders. In addition, this phenotype of γ2+/− mice includes increased behavioral passivity under stressful conditions, as expected of an animal model of mood disorders. Conditional knockdown of the γ2 subunit in the embryonic telencephalon was shown to result in anxious-depressive behavior similar to that of γ2+/- mice that carry the mutation in the germ line. By contrast, a comparable forebrain-specific γ2 subunit deficit that was delayed to the fourth postnatal week and limited to mature neurons was without anxiety- or depressive-like consequences. These findings are consistent with evidence that the vulnerability for anxiety and mood disorders is established early in life, and that they represent developmental disorders. In this thesis I embarked on further analyzing the brain substrate of anxious depression. In particular, I investigated putative HPA axis deficits and the behavioral and endocrine responsiveness of γ2+/− mice to treatment with serotonin (5-HT)- and norepinephrine (NE)-selective reuptake inhibitors. In addition, I investigated the critical developmental periods responsible for anxious depressive like behavior of γ2+/− mice in adulthood We found that the baseline corticosterone concentration of adult γ2-deficient mice was elevated independent of whether the genetic lesion was induced during embryogenesis or delayed to adolescence. However, the manifestation of anxious-depressive behavior in different γ2-deficient mouse lines was correlated with early onset HPA axis hyperactivity during postnatal development. Chronic but not subchronic treatment of γ2+/- mice with fluoxetine or desipramine normalized the anxiety-like phenotype in the novelty suppressed feeding test. Moreover, desipramine had antidepressant-like effects in that it normalized HPA axis function and depression-related behavior of γ2+/- mice in the forced swim, tail suspension, and sucrose consumption tests. By contrast, fluoxetine was ineffective as an antidepressant and failed to normalize HPA axis function. Collectively, these data indicate that developmental deficits in GABAergic inhibition may cause behavioral and endocrine abnormalities and selective antidepressant drug responsiveness indicative of anxious-depressive disorders such as melancholic depression, which are frequently characterized by HPA axis hyperactivity and greater efficacy of desipramine versus fluoxetine. … Advisors/Committee Members: Bernhard Luscher, Dissertation Advisor/Co-Advisor, Bernhard Luscher, Committee Chair/Co-Chair, Douglas Cavener, Committee Member, Wendy Hanna Rose, Committee Member, Debashis Ghosh, Committee Member, Jeffrey Maurice Peters, Committee Member, Robert Paulson, Committee Member.

Subjects/Keywords: HPA axis; GABA; anxious depression; critical period

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Shen, Q. (2011). INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12127

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Shen, Qiuying. “INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION .” 2011. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/12127.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Shen, Qiuying. “INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION .” 2011. Web. 05 Mar 2021.

Vancouver:

Shen Q. INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/12127.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Shen Q. INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12127

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

6. Gopinathan, Lakshmi. Regulation of Peroxisome Proliferator-Activated Receptor alpha by Ribosomal Protein L11, Murine Double Minute 2, and E6-Associated Protein.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9217

► The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and glucose metabolism, adipocyte differentiation, fatty acid oxidation, and inflammation. Regulation of these diverse responses… (more)

▼ The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and glucose metabolism, adipocyte differentiation, fatty acid oxidation, and inflammation. Regulation of these diverse responses requires a series of highly coordinated cellular events that include binding of ligand, association with a heterodimeric partner, recruitment of transcriptional machinery, and multiple protein-protein interactions. This thesis will examine a subset of these protein-protein interactions and detail the effects of the association on PPAR-alpha transcription activity. The ribosomal protein L11 (rpL11) is a PPAR alpha-interacting protein that inhibits receptor transcriptional activity. Ablation of rpL11 expression by RNAi resulted in increased ligand-induced mRNA levels of PPAR-alpha target genes, and increased PPAR-alpha transactivation in PPRE-dependent reporter assays. Growth inhibitory conditions such as serum deprivation and treatment with low concentrations of Actinomycin D facilitate increases in the level of non-ribosomal L11; these conditions decreased transcriptional activity of PPAR-alpha. Ribosomal protein L11 also acts as a negative regulator of murine double minute 2 (MDM2), mediating p53 stabilization. Whether interactions with rpL11 resulted in a convergence of PPAR-alpha and p53 pathways in response to peroxisome proliferators (PPs) was examined. Although treatment of Hepa-1 cells with the PPAR-alpha ligand Wy-14,643 decreased transcriptional activity of p53, this effect could not be attributed to rpL11. Increased p53 activity mediated by rpL11 remained unaffected by Wy-14,643 or coexpression of PPAR-alpha. Thus, rpL11 regulates both p53 and PPAR-alpha pathways, although the effects of peroxisome proliferators on p53 activity cannot be attributed to rpL11 associating with PPAR-alpha. The identification of rpL11 as an MDM2-interacting protein and regulator of the MDM2/p53 pathway prompted further studies investigating the role of MDM2 in regulation of PPAR-alpha. MDM2 interacted with the A/B domain of PPAR-alpha and regulated the transcriptional activity of the receptor. Knockdown of MDM2 by siRNA in FaO hepatoma cells decreased ligand-induced mRNA levels of several PPAR-alpha target genes involved in lipid metabolism, indicating that MDM2 enhances the transcriptional activity of PPAR-alpha. MDM2 associated with PPAR-alpha on target gene promoters, and this association increased in the presence of Wy-14,643. Interestingly, treatment of mice with clofibrate resulted in decreased protein expression of MDM2 in wildtype, but not PPAR-alpha null mice, suggesting that PPAR-alpha controls MDM2 through a negative feedback mechanism. MDM2 coexpression increased ubiquitination of PPAR-alpha; the E3 ubiquitin ligase activity of MDM2 regulated PPAR-alpha protein expression and transcriptional activity. PPAR-alpha protein expression was decreased in FaO cells transfected with MDM2 siRNA indicating that MDM2 stabilized PPAR-alpha protein levels. In support, MDM2 null mouse embryonic fibroblasts (MEFs)… Advisors/Committee Members: John Patrick Vanden Heuvel, Committee Chair/Co-Chair, Gary H Perdew, Committee Member, Jeffrey Maurice Peters, Committee Member, Kumble Sandeep Prabhu, Committee Member.

Subjects/Keywords: PPAR; ribosomal protein L11; MDM2; E6-AP; ubiquitin ligase; nuclear receptor

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APA (6^th Edition):

Gopinathan, L. (2008). Regulation of Peroxisome Proliferator-Activated Receptor alpha by Ribosomal Protein L11, Murine Double Minute 2, and E6-Associated Protein. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9217

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gopinathan, Lakshmi. “Regulation of Peroxisome Proliferator-Activated Receptor alpha by Ribosomal Protein L11, Murine Double Minute 2, and E6-Associated Protein.” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/9217.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gopinathan, Lakshmi. “Regulation of Peroxisome Proliferator-Activated Receptor alpha by Ribosomal Protein L11, Murine Double Minute 2, and E6-Associated Protein.” 2008. Web. 05 Mar 2021.

Vancouver:

Gopinathan L. Regulation of Peroxisome Proliferator-Activated Receptor alpha by Ribosomal Protein L11, Murine Double Minute 2, and E6-Associated Protein. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/9217.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gopinathan L. Regulation of Peroxisome Proliferator-Activated Receptor alpha by Ribosomal Protein L11, Murine Double Minute 2, and E6-Associated Protein. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/9217

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

7. Ramadoss, Preeti. DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6785

► The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the transcription of several genes in reponse to binding ligand. AhR ligands include… (more)

▼ The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the transcription of several genes in reponse to binding ligand. AhR ligands include a structurally diverse group of chemicals, and some of these are major environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to these chemicals results in a variety of toxic responses, and the AhR is thought to mediate most, if not all of these adverse reactions. There are a number of intra- and inter-species differences in terms of the relative sensitivity to the toxic effects of AhR ligands, and there is also considerable variation in the AhR’s amino acid sequence between species. It is likely that the differences in the AhR are partly responsible for the differences in sensitivity to TCDD between species. Mouse models are most commonly used in toxicological studies to evaluate the risk upon exposure to AhR ligands and the data is extrapolated to estimate risk to humans. If there are substantial differences between the mouse AhR (mAhR) and human AhR (hAhR) that lead to variation in response to ligand exposure, there may be a need to develop a more suitable model to estimate toxicological risk to humans. This work characterized some of the biochemical differences between mAhR and hAhR and found that there were a number of differences between mAhR and hAhR. This variation could contribute to differences in response to ligand at the molecular level. hAhR exhibits nucleo-cytoplasmic shuttling properties that are different from mAhR, and hAhR is not influenced in the same way as mAhR by the chaperone protein XAP2. hAhR also has a 10-fold lower apparent ligand affinity than mAhR. Some of these differences appear to be due to the sequence variation in the poorly conserved transactivation domain of the receptor. This study also attempted to identify novel AhR target genes through the use of chromatin immunoprecipitation coupled with microarrays, and this method can eventually be adapted to perform in vivo chromatin immunoprecpitations from tissue. In summary, these studies will help provide a better understanding of the molecular mechanisms through which the AhR mediates a toxic response upon exposure to ligands. Advisors/Committee Members: Gary H Perdew, Committee Chair/Co-Chair, Jeffrey Maurice Peters, Committee Member, Richard John Frisque, Committee Member, Avery August, Committee Member, David John Vandenbergh, Committee Member.

Subjects/Keywords: Aryl Hydrocarbon Receptor; TCDD; XAP2; Relative Ligand Affinity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ramadoss, P. (2008). DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6785

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ramadoss, Preeti. “DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS .” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/6785.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ramadoss, Preeti. “DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS .” 2008. Web. 05 Mar 2021.

Vancouver:

Ramadoss P. DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/6785.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ramadoss P. DIVERGENT PROPERTIES OF MOUSE AND HUMAN ARYL HYDROCARBON RECEPTORS . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6785

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

8. Hollingshead, Brett David. In vitro and in vivo analysis of aryl hydrocarbon receptor regulation by the hepatitis B virus X-associated protein 2 .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7318

► The aryl hydrocarbon receptor (AHR) is a soluble ligand-activated transcription factor that regulates the expression of a battery of metabolically important genes. Sustained activation of… (more)

▼ The aryl hydrocarbon receptor (AHR) is a soluble ligand-activated transcription factor that regulates the expression of a battery of metabolically important genes. Sustained activation of the AHR resulting from exposure to the high affinity and metabolically resistant environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a myriad of deleterious responses in humans and rodents. The AHR is also physiologically involved in liver development and immune system homeostasis. Therefore, obtaining a full mechanistic appreciation of AHR properties is imperative to understand how the AHR exerts its physiologic properties. In its inactive form the AHR resides in the cytoplasm as a multi-protein complex consisting of one AHR molecule and a dimer of the 90 kDa heat shock protein (HSP90). Additionally, the co-chaperone proteins p23 and the hepatitis B virus X-associated protein 2 (XAP2) can be found in the unliganded receptor complex. The research presented in this thesis investigates the regulation of AHR activity by XAP2 in cell culture as well as in transgenic mouse models. Through studies in cell culture utilizing a point mutant form of the AHR that is unable to functionally interact with XAP2 it is demonstrated that XAP2 acts as a repressor of AHR transcriptional activity. The absence of endogenous XAP2 binding to the mutant receptor results in higher transcriptional activity than the non-mutant AHR. Therefore, it is concluded that XAP2 modulates AHR activity, but its presence in the mature unliganded AHR complex is not essential for the formation of a transcriptionally competent receptor. XAP2 protein levels are low in liver compared to many other tissues. This led to the hypothesis that XAP2 levels in the liver are not sufficient to maximally regulate AHR transcriptional activity. Two lines of transgenic mice were generated that exhibited high, hepatocyte-specific expression of XAP2. Gene expression experiments were performed in mice using a broad dose range of the AHR agonist beta- naphthoflavone. Surprisingly, little difference in gene expression was observed between wild type and transgenic mouse lines. It was determined that although the liver expression of XAP2 was much higher in transgenic as compared to wild type mice, no significant stoichiometric increase in XAP2 binding within the unliganded AHR complex occurred. Consequently, it is concluded that the seemingly “low” levels of expressed XAP2 in liver are sufficient to maximally associate with AHR-HSP90 complexes and regulate AHR transcriptional activation. Finally, preliminary experiments demonstrate that the carcinogenic diol epoxide forms of select polycyclic aromatic hydrocarbons are capable of interacting with the AHR. They may utilize the AHR binding pocket to gain access to the nuclear DNA by way of receptor nucleocytoplasmic shuttling, whereby they can form potentially cancer-inducing DNA adducts. These introductory experiments set a foundation for future analysis of the AHR’s contribution to DNA damage resulting from… Advisors/Committee Members: Gary H Perdew, Committee Chair/Co-Chair, Jeffrey Maurice Peters, Committee Member, Ross Cameron Hardison, Committee Member, Ming Tien, Committee Member, Scott Trent Feldman, Committee Member.

Subjects/Keywords: aryl hydrocarbon receptor; XAP2; HSP90; gene regulation; chaperone proteins; AIP

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hollingshead, B. D. (2008). In vitro and in vivo analysis of aryl hydrocarbon receptor regulation by the hepatitis B virus X-associated protein 2 . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7318

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hollingshead, Brett David. “In vitro and in vivo analysis of aryl hydrocarbon receptor regulation by the hepatitis B virus X-associated protein 2 .” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/7318.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hollingshead, Brett David. “In vitro and in vivo analysis of aryl hydrocarbon receptor regulation by the hepatitis B virus X-associated protein 2 .” 2008. Web. 05 Mar 2021.

Vancouver:

Hollingshead BD. In vitro and in vivo analysis of aryl hydrocarbon receptor regulation by the hepatitis B virus X-associated protein 2 . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/7318.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hollingshead BD. In vitro and in vivo analysis of aryl hydrocarbon receptor regulation by the hepatitis B virus X-associated protein 2 . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7318

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

9. Moon, Mi Sun. IN VITRO AND IN VIVO SYSTEMS FOR EVALUATING THE EFFECTS OF ELEVATED IRON ON ACUTE AND CHRONIC LIVER INJURY .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11373

► Liver diseases are responsible for more than 42,000 deaths each year in the U.S. Liver cancer is the third most deadly cancer worldwide. Patients with… (more)

▼ Liver diseases are responsible for more than 42,000 deaths each year in the U.S. Liver cancer is the third most deadly cancer worldwide. Patients with cirrhosis and chronic liver disease developed approximately 70-90% of all detected hepatocellular carcinoma incidence. Patients with hereditary hemochromatosis have an increased risk of developing hepatocellular carcinoma. Dietary iron overload in individuals in Africa has also been associated with an increased risk of hepatocellular carcinoma. These findings indicate that hepatic iron may play a role in development of liver cancer. Iron has been proposed as a promoter leading to cancer indirectly or directly. The mechanisms by which excess hepatic iron may contribute to the development of hepatocellular carcinoma are not fully understood. However, iron is known to generate reactive oxygen species such as hydroxyl radicals, which can attack macromolecules nonselectively. Moreover, iron may impair the tumoricidal activity of macrophages. The aim of this dissertation was to investigate the role of hepatic iron on acute and chronic liver toxicity. Four systems were utilized to achieve three specific aims; 1) to investigate the role of iron on acetaminophen (APAP)-induced hepatotoxicity in vitro, 2) to determine the effects of iron overload on APAP toxicity in vivo in a mouse model, 3) to establish an appropriate human cell culture model system to study the interaction between iron overload and hepatitis C virus (HCV). To induce acute liver toxicity, APAP was used because it has been used as a representative toxicant to study drug-induced liver toxicity. Long-term cultured primary mouse hepatocytes were established in dimethyl sulfoxide and iron overloaded by 3,5,5-trimethyl-hexanoyl ferrocene (TMHF) treatment. APAP toxicity, when evaluated in long-term cultured primary mouse hepatocytes by using a cell viability assay, induced cytotoxicity in a dose- and time-dependent manner. The reduction of glutathione upon APAP treatment indicates that APAP is metabolized in this cell culture system and glutathione is reduced by APAP metabolites. Special emphasis was placed on oxidative stress produced by APAP toxicity in Aim 1 of this dissertation project. When cells were exposed to APAP, the production of reactive oxygen species and mitochondrial permeability transition occurred and progressed with time. Furthermore, when cells were treated with either TMHF or desferoxamine to regulate intracellular iron levels along with APAP treatment, the generation of reactive oxygen species and mitochondrial permeability transition was accelerated in the presence of excess iron, and delayed when iron was depleted. These results indicated that iron plays a role in APAP toxicity and in APAP induced reactive oxygen species and mitochondrial dysfunction. The effects of excess hepatic iron on acute liver toxicity were also studied in mouse hepatocytes in vivo in the intact liver. An iron overload mouse model generated by feeding a TMHF diet was used. Iron deposits were… Advisors/Committee Members: Harriet C Isom, Dissertation Advisor/Co-Advisor, Harriet C Isom, Committee Chair/Co-Chair, Craig Matthew Meyers, Committee Member, Jeffrey Maurice Peters, Committee Member, Jianming Hu, Committee Member.

Subjects/Keywords: Mitochondrial Dysfunction; Oxidative Stress; Liver; Acetaminophen; Hepatic iron; Hepatitis C virus; Iron-overload

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Moon, M. S. (2010). IN VITRO AND IN VIVO SYSTEMS FOR EVALUATING THE EFFECTS OF ELEVATED IRON ON ACUTE AND CHRONIC LIVER INJURY . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11373

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Moon, Mi Sun. “IN VITRO AND IN VIVO SYSTEMS FOR EVALUATING THE EFFECTS OF ELEVATED IRON ON ACUTE AND CHRONIC LIVER INJURY .” 2010. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/11373.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Moon, Mi Sun. “IN VITRO AND IN VIVO SYSTEMS FOR EVALUATING THE EFFECTS OF ELEVATED IRON ON ACUTE AND CHRONIC LIVER INJURY .” 2010. Web. 05 Mar 2021.

Vancouver:

Moon MS. IN VITRO AND IN VIVO SYSTEMS FOR EVALUATING THE EFFECTS OF ELEVATED IRON ON ACUTE AND CHRONIC LIVER INJURY . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/11373.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Moon MS. IN VITRO AND IN VIVO SYSTEMS FOR EVALUATING THE EFFECTS OF ELEVATED IRON ON ACUTE AND CHRONIC LIVER INJURY . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11373

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

10. Murosky, Thomas P. Regulation of Peroxisome Proliferator-Activated Receptor-Mediated Transcription by LXXLL Motif-Containing Co-Activators and the FOXO Subclass of Forkhead Box Proteins .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7975

► Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors containing three isoforms (a, b/d, g) belonging to the nuclear hormone receptor superfamily. PPARa is a specific… (more)

▼ Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors containing three isoforms (a, b/d, g) belonging to the nuclear hormone receptor superfamily. PPARa is a specific pharmacological target for dyslipidemia in humans, but prolonged administration of PPAR agonists causes peroxisome proliferation and hepatocarcinogenesis in rodents. Proliferation and cancer is not observed in humans suggesting divergence between mouse and human PPAR activation. The central hypothesis of this work is that PPARa is differentially regulated by LXXLL motif-containing coactivators and the forkhead box O subclass of proteins. The interaction of LXXLL motifs and PPARs was assessed utilizing fusion proteins containing the core motif in a mammalian expression vector. These experiments demonstrated the ability of fusion proteins to differentially block transcriptional activation of mouse PPAR isotypes and the human PPARa. Species specific PPARa activation was also caused by co-activators. Real time RT-PCR analysis of target genes with PPARa-null, human PPARa transgenic, and wild type mice suggested that these receptors differentially regulate target genes. Thus, PPARa activation can be traced to inherent species differences in the receptor dependent on both LXXLL motif recruitment and specific ligand activation. The forkhead box protein subclass O (FOXO) is a transcription factor implicated in crosstalk with nuclear receptors. FOX proteins are transcription factors containing a conserved 100 amino acid DNA binding domain that interacts with the insulin responsive sequence as a monomer. FOXO1A is potentially involved in crosstalk with PPARs due to the regulation of gluconeogenesis, and the present set of experiments examines this crosstalk. PPARs and FOXO1A were co-expressed revealing mutual co-repression of PPARs and FOXO1A in a reporter system. One-hybrid analysis of FOXO and PPARa or RXR revealed that the FOXO1A-mediated repression of PPARa is independent of heterodimerization. Immunoprecipitation of FOXO1A and PPARa failed to demonstrate direct interaction between these proteins. Repression of PPARa mRNA message cells was able to prevent PPARa ligand treatment from repressing endogenous FOXO activation of a specific target gene. These two nutritionally-regulated pathways are involved in crosstalk suggesting the activation of one pathway may repress the transcriptional activation of the other. In conclusion, mouse and human PPARa functionally differ. Advisors/Committee Members: Gary H Perdew, Committee Chair/Co-Chair, Jeffrey Maurice Peters, Committee Member, Curtis John Omiecinski, Committee Member, Donna Hope Korzick, Committee Member, Peter John Hudson, Committee Member.

Subjects/Keywords: Co-Activators; LXXLL; FOXO; PPAR

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Murosky, T. P. (2008). Regulation of Peroxisome Proliferator-Activated Receptor-Mediated Transcription by LXXLL Motif-Containing Co-Activators and the FOXO Subclass of Forkhead Box Proteins . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7975

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Murosky, Thomas P. “Regulation of Peroxisome Proliferator-Activated Receptor-Mediated Transcription by LXXLL Motif-Containing Co-Activators and the FOXO Subclass of Forkhead Box Proteins .” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/7975.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Murosky TP. Regulation of Peroxisome Proliferator-Activated Receptor-Mediated Transcription by LXXLL Motif-Containing Co-Activators and the FOXO Subclass of Forkhead Box Proteins . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/7975.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Murosky TP. Regulation of Peroxisome Proliferator-Activated Receptor-Mediated Transcription by LXXLL Motif-Containing Co-Activators and the FOXO Subclass of Forkhead Box Proteins . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7975

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

11. Shan, Weiwei. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR beta ATTENUATES CHEMICALLY-INDUCED LIVER TOXICITY .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7935

► In the past decade, heated discussions have been focusing on the physiological roles of peroxisome proliferaotor-activated receptor betaƒn(PPARbeta). Emerging evidence has implicated PPARbeta in the… (more)

▼ In the past decade, heated discussions have been focusing on the physiological roles of peroxisome proliferaotor-activated receptor betaƒn(PPARbeta). Emerging evidence has implicated PPARbeta in the regulation of cholesterol and glucose homeostasis, fatty acid oxidation in skeletal muscle and heart, epithelial differentiation, skin and colon carcinogenesis. However, functional roles of the receptor in the liver remain elusive. Recent studies suggested that PPARbeta can potentiate liver toxicity by inducing hepatic stellate cell proliferation and fibrogenesis. On the other hand, it has been reported that PPARbeta attenuates liver toxicity induced by methionine-and-choline-deficient-diet and could also prevent hepatocarcinogenesis by inhibiting hepatic oval cell proliferation. Combined, the role of PPARbeta in liver toxicity remains to be thoroughly evaluated. Preliminary results on colon carcinogenesis from our laboratory identified a potential role of PPARbeta in attenuating azoxymethane (AOM)-induced liver toxicity, suggested by the formation of preneoplasic lesions in AOM-treated PPARbeta-null mouse livers but not in the wild-type. The current study examines the hypothesis that PPARbeta ameliorates chemically-induced hepatotoxicity in mice. When wild-type and PPARbeta-null mice were treated with the liver-specific toxicant carbon tetrachloride (CCl4), exacerbated liver toxicity as indicated by more pathological lesions, elevated serum ALT, hepatic TNFalpha and SMAalpha expression was found in PPARbeta-null mice by comparison to similarly-treated wild-type, suggesting that the receptor is protective against chemically-induced liver toxicity. cDNA microarray analysis identified a large number of pro-inflammatory genes to be more induced by CCl4 in PPARbeta-null livers as compared to the wild-type. In addition, NF-kappaB activation was markedly augmented in response to CCl4 in the absence of PPARbeta, as measured by p65 immunohistochemical staining and NF-kappaB gel shift assay. These findings suggest that PPARbeta attenuates CCl4-induced liver toxicity by interfering with pro-inflammatory gene signaling, particularly NF-kappaB. Subsequently, the effect of ligand activation of PPARbeta on CCl4-induced liver toxicity was examined. Ligand activation of the receptor by a high-affinity ligand, GW0742 caused a significant down-regulation of serum ALT, hepatic TNFalpha and a few of NF-kappaB target genes in CCl4-treated wild-type mice but not in PPARbeta-null mice, suggesting that ligand activation of PPARbeta provides further protection against CCl4-induced hepatotoxicity. To better understand PPARbeta-mediated attenuation of liver toxicity on the cellular level, primary hepatocytes were isolated from wild-type and PPARbeta-null mouse livers, cultured with IL-1beta coupled with different concentrations of GW0742. The expression of mRNA encoding TNFalpha was considerably higher in PPARbeta-null primary hepatocytes as compared to the wild-type in response to IL-1beta, but was not influenced by GW0742 treatments.… Advisors/Committee Members: Jeffrey Maurice Peters, Committee Member, Gary H Perdew, Committee Chair/Co-Chair, Pamela Hankey Giblin, Committee Member, Kumble Sandeep Prabhu, Committee Member, Harriet C Isom, Committee Member.

Subjects/Keywords: liver toxicity; inflammation; peroxisome proliferator-activated receptor beta; NF-kappaB signaling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Shan, W. (2008). PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR beta ATTENUATES CHEMICALLY-INDUCED LIVER TOXICITY . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7935

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Shan, Weiwei. “PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR beta ATTENUATES CHEMICALLY-INDUCED LIVER TOXICITY .” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/7935.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Shan, Weiwei. “PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR beta ATTENUATES CHEMICALLY-INDUCED LIVER TOXICITY .” 2008. Web. 05 Mar 2021.

Vancouver:

Shan W. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR beta ATTENUATES CHEMICALLY-INDUCED LIVER TOXICITY . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/7935.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Shan W. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR beta ATTENUATES CHEMICALLY-INDUCED LIVER TOXICITY . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7935

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

12. Morales, Jose Luis. REGULATION OF THE ARYL HYDROCARBON RECEPTOR PROTEIN LEVELS AND SIGNAL TRANSDUCTION PATHWAYS.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8289

► The aryl hydrocarbon receptor is a ligand-activated transcription factor that mediates most of the toxic effects of numerous halogenated and non-halogenated polycyclic aromatic hydrocarbons (e.g.,… (more)

▼ The aryl hydrocarbon receptor is a ligand-activated transcription factor that mediates most of the toxic effects of numerous halogenated and non-halogenated polycyclic aromatic hydrocarbons (e.g., chlorinated dibenzo-p-dioxins). In its ligandbound state, the AhR rapidly accumulates in the nucleus where it dissociates from the hsp90/XAP2 complex and heterodimerizes with ARNT primarily to upregulate genes encoding metabolic enzymes implicated in the carcinogenic activation or detoxification of endogenous and exogenous substances. Interestingly, the AhR protein levels are rapidly depleted after its activation by full agonists in an ubiquitin and proteasomedependent manner. Given the potential role of the AhR in normal vascular, liver, and immune system development and/or regulation, as well as in mediating the toxicity of numerous HPAH and PAHs, the study of AhR protein level regulation and activation in the cell may be essential to our understanding of the mechanisms of toxicity elicited by persistent AhR activators (e.g., TCDD). The first project in this thesis explored the question of whether the carboxyl-terminus of hsc70 interacting-protein (CHIP) was involved in the regulation of the ligand-mediated degradation of the AhR in an ubiquitin and proteasome-dependent process. CHIP associates with chaperones such as hsp90 and hsc70 and negatively regulates their ability to function as protein folding complexes, causing client proteins (e.g., estrogen receptor) to be degraded through the proteasome. Immunoprecipitates of the AhR revealed that CHIP could also associate with the AhR protein complex at cellular levels and the transient expression of CHIP in cell cultures resulted in AhR protein turnover. Through the use of in vitro reconstitution assays, iv sucrose gradient fractionation, and RNA silencing methods we established that the E3 ubiquitin ligase CHIP can mediate ubiquitination of the AhR and hsp90. However, CHIP did not seem to regulate the steady-state protein levels of the AhR nor the ligandmediated degradation of the AhR. Rather, it appears that CHIP is capable of directly mediating ubiquitination of the hsp90 and, perhaps through this mechanism, it may affect the ability of the hsp90 chaperone to protect the AhR from ubiquitination and degradation through the proteasome. A second question explored whether the benzoimidazole-derived anti-asthmatic drugs termed M50354 and M50367 mediated their AhR-dependent therapeutic roles as partial agonists for the AhR and in a non-dioxin responsive element (DRE)-driven process. Previous published work suggested that these substances could not mediate classical DRE-driven gene activation of CYP1A1 to the same degree as established high-affinity AhR ligands. Presumably, these two drugs were also capable of mediating AhR-dependent immunomodulatory functions not entirely elicited by other established AhR ligands, possibly through a non-genomic role of the AhR. However, in contrast to previous observations, we demonstrated that both substances are full but transient AhR… Advisors/Committee Members: Craig Richard Baumrucker, Committee Member, Gary H Perdew, Committee Chair/Co-Chair, Avery August, Committee Member, Richard John Frisque, Committee Member, Jeffrey Maurice Peters, Committee Member.

Subjects/Keywords: AhR; hsp90; CHIP; Ubiquitin; Immunity; NF-kB

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Morales, J. L. (2008). REGULATION OF THE ARYL HYDROCARBON RECEPTOR PROTEIN LEVELS AND SIGNAL TRANSDUCTION PATHWAYS. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8289

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Morales, Jose Luis. “REGULATION OF THE ARYL HYDROCARBON RECEPTOR PROTEIN LEVELS AND SIGNAL TRANSDUCTION PATHWAYS.” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/8289.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Morales, Jose Luis. “REGULATION OF THE ARYL HYDROCARBON RECEPTOR PROTEIN LEVELS AND SIGNAL TRANSDUCTION PATHWAYS.” 2008. Web. 05 Mar 2021.

Vancouver:

Morales JL. REGULATION OF THE ARYL HYDROCARBON RECEPTOR PROTEIN LEVELS AND SIGNAL TRANSDUCTION PATHWAYS. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/8289.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Morales JL. REGULATION OF THE ARYL HYDROCARBON RECEPTOR PROTEIN LEVELS AND SIGNAL TRANSDUCTION PATHWAYS. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8289

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

13. Nelson, Amanda Marie. Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7530

► Nearly 40-50 million people of all races and ages in the United States have acne, making it the most common skin disease. Although acne is… (more)

▼ Nearly 40-50 million people of all races and ages in the United States have acne, making it the most common skin disease. Although acne is not a serious health threat, severe acne can lead to disfiguring, permanent scarring; increased anxiety; and depression. Isotretinoin (13-cis Retinoic Acid) is the most potent agent that affects each of the pathogenic features of acne: 1) follicular hyperkeratinization, 2) the activity of Propionibacterium acnes, 3) inflammation and 4) increased sebum production. Isotretinoin has been on the market since 1982 and even though it has been prescribed for 25 years, extensive studies into its molecular mechanism of action in human skin and sebaceous glands have not been done. Since isotretinoin is a teratogen, there is a clear need for safe and effective alternative therapeutic agents. The studies undertaken in this thesis were designed to increase our understanding of the effects of 13-cis RA on the sebaceous gland and its mechanism of action in sebum suppression. It is well established that isotretinoin drastically reduces the size and lipid secretion of sebaceous glands. We hypothesized that isotretinoin decreases the size of the sebaceous gland by inducing cell cycle arrest and/or apoptosis and that sebum suppression is most likely an indirect result of the reduced size of the sebaceous gland. Our studies show that 13-cis RA, unlike 9-cis RA or ATRA, induces cell cycle arrest and apoptosis in SEB-1 sebocytes. Its ability to induce apoptosis is not inhibited in the presence of functional retinoic acid receptor (RAR) pan antagonist AGN 193198, suggesting an RAR-independent mechanism of apoptosis. Gene expression analysis was performed in cultured SEB-1 sebocytes that were treated with 13-cis RA and in biopsies of skin taken from patients that were treated for one week with isotretinoin. These data indicate that 13-cis RA increases expression of neutrophil gelatinase associated lipocalin (NGAL) and Tumor Necrosis Factor related apoptosis inducing ligand (TRAIL). In turn, we report that both NGAL and TRAIL induce apoptosis within SEB-1 sebocytes and, as such, are potential mediators of 13-cis RA induced apoptosis in human sebocytes. These studies into the mechanism of action of 13-cis RA in sebaceous glands suggest that 13-cis RA mediates its sebosuppressive effect through preferential induction of apoptosis in sebaceous glands. Furthermore, these data provide a rationale for drug discovery of alternative agents that are capable of selectively inducing apoptosis in sebaceous glands as a treatment for severe acne. Advisors/Committee Members: Diane M Thiboutot, Committee Chair/Co-Chair, Gary Alan Clawson, Committee Member, Mark Kester, Ph D, Committee Member, Jeffrey Maurice Peters, Committee Member, Jong Kak Yun, Committee Member.

Subjects/Keywords: skin; retinoin; acne

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nelson, A. M. (2008). Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7530

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nelson, Amanda Marie. “Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function .” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/7530.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nelson, Amanda Marie. “Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function .” 2008. Web. 05 Mar 2021.

Vancouver:

Nelson AM. Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/7530.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nelson AM. Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7530

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

14. Burns, Katherine Anne. REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3 .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7598

► Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor involved in the maintenance of fatty acid homeostasis and is important for mediating the adaptive… (more)

▼ Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor involved in the maintenance of fatty acid homeostasis and is important for mediating the adaptive response to fasting. PPAR alpha is phosphorylated by multiple kinases which differentially regulate its activity. Computational analysis of PPAR alpha revealed 5 potential glycogen synthase kinase 3 (GSK3) phosphorylation sites. GSK3 is a key enzyme involved in glycogen metabolism, and is important for signaling by insulin, growth factors, and nutrients. It was hypothesized that PPAR alpha is a substrate for GSK3 phosphorylation and this association is involved in fasting mediated homeostasis. PPAR alpha is phosphorylated by GSK3 beta, primarily at serine-73 in the A/B domain of rat PPAR alpha. This residue is conserved across PPAR alpha species including humans. The regulation of PPAR alpha target gene expression was affected by manipulating GSK3 activity via chemical inhibitors and specific RNA inhibitors (RNAis). We also demonstrated an increased turnover and ubiquitination of PPAR alpha with the over-expression of GSK3 beta, presumably the result of increased PPAR alpha phosphorylation. In addition to GSK3 affecting PPAR alpha activity, it has been noted that ligands for this nuclear receptor, the peroxisome proliferators, influence GSK3 alpha and GSK3 beta expression and activity. The adaptive response in the liver to fasting involves both PPAR alpha and GSK3. Thus, mice subjected to fasting represents an ideal, physiologically-relevant model system to explore PPAR alpha and GSK3 activity and their confluence. Fatty acid metabolism genes, such as Acyl CoA Oxidase (ACO), the bifunctional enzyme (BIEN), and 3-ketoacyl-CoA thiolase (thiolase) were increased during fasting in wild-type (PPAR alpha +/+) but not in PPAR alpha knockout (PPAR alpha -/-) mice. GSK3 alpha was increased at the mRNA and protein level, while GSK3 beta was decreased at the phosphospecific level by fasting in wild-type mice. Two potential mechanistic links between PPAR alpha activation upon fasting and GSK3 expression and activity were examined, Tribbles 3 (TRB3) and Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). TRB3 is a fasting inducible inhibitor of the serine-threonine kinase AKT/PKB and PGC-1 alpha is a ligand inducible coactivator for PPAR alpha involved in the control of cellular energy metabolic pathways. In contrast to previously published results, TRB3 was not differentially regulated by fasting in wild-type or PPAR alpha -/- mice at the mRNA or protein level. However, PGC-1 alpha mRNA levels were increased upon fasting, and unexpectedly, the levels were increased in a PPAR alpha-dependent manner. This establishes a novel regulation of PGC-1 alpha that is dependent on the expression of PPAR alpha during fasting. This thesis has demonstrated that PPAR alpha is a substrate for GSK3 beta phosphorylation that causes increased ubiquitination and turnover of PPAR alpha, and that PPAR alpha, GSK3 alpha/beta, and PGC-1 alpha… Advisors/Committee Members: John Patrick Vanden Heuvel, Committee Chair/Co-Chair, Pamela Hankey Giblin, Committee Member, Donna Hope Korzick, Committee Member, Gary H Perdew, Committee Member, Jeffrey Maurice Peters, Committee Member.

Subjects/Keywords: fasting; phosphorylation; GSK3; PPARalpha

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Burns, K. A. (2008). REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3 . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7598

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Burns, Katherine Anne. “REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3 .” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/7598.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Burns, Katherine Anne. “REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3 .” 2008. Web. 05 Mar 2021.

Vancouver:

Burns KA. REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3 . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/7598.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Burns KA. REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3 . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7598

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

15. Patel, Rushang Dilipkumar. REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8497

► Adaptation in response to changes in internal as well as external environment is imperative to sustenance of life. Modulation of gene expression is a critical… (more)

▼ Adaptation in response to changes in internal as well as external environment is imperative to sustenance of life. Modulation of gene expression is a critical component of this adaptive response and is mediated by activation of various transcription factors. Individual signaling pathways have been well characterized for many transcription factor systems. Aryl hydrocarbon receptor (AHR) is a transcription factor that is activated by a variety of structurally diverse ligands, including the environmental contaminant dioxin, the cigarette smoke constituent benzo[a]pyrene and the therapeutically prescribed drug omeprazole. Prior to activation, AHR is primarily located in a cytoplasmic complex with chaperone and co-chaperone proteins. Ligand-binding is believed to initiate a conformational change that leads to nuclear translocation, dissociation from the chaperones and heterodimerization with AHR-nuclear translocator (ARNT). AHR-ARNT heterodimer recognizes and binds to a consensus DNA sequence (TNGCGTG), commonly referred to as a dioxin response element (DRE), to drive transcription of target genes. Phase I and II xenobiotic metabolism enzymes have been the well-characterized targets of AHR-mediated transactivation. This sequence of coordinate events has been described as the classical pathway of AHR activity. Different lines of evidence suggest that AHR serves physiologically relevant functions, though the details have not been elucidated. The goal of this research project was to identify previously uncharacterized targets of AHR-mediated gene regulation and to investigate the hypothesis that AHR functions through mechanisms that are independent of DNA-binding. The advances in performing genome-wide transcriptional profiling at the time of commencement of this project, encouraged the use of DNA-microarray technology for identifying new target genes. Epiregulin, a potent mitogen belonging to the epidermal growth factor family, was discovered to be regulated by AHR in immortalized murine hepatocytes. The fact that a number of AHR ligands have been associated with carcinogenesis signifies that the induction of growth factors like epiregulin might be a potential mechanism for AHR-mediated tumor enhancement. The next phase of this project led to the identification of the constitutive androstane receptor (CAR), another receptor involved in drug metabolism, as an in vivo target of AHR activation. This association between AHR-CAR highlights the possibility of crosstalk between AHR and other pathways. Exposure to divergent stimuli leads to simultaneous activation of multiple signaling pathways. This suggests that it is essential to study the networking of various pathways to be able to predict the biological outcomes. The third phase of this project focuses on the ability of AHR to modulate the inflammatory pathway and on the involved mechanism. AHR activation can repress the acute-phase response (APR) gene expression, implicated in disorders like septic shock and Alzheimer’s, partly by antagonizing NF-êB mediated gene regulation… Advisors/Committee Members: Gary H Perdew, Committee Chair/Co-Chair, Curtis John Omiecinski, Committee Member, Jeffrey Maurice Peters, Committee Member, Robert Bruce Mitchell, Committee Member, Naomi S Altman, Committee Member, Peter John Hudson, Committee Member.

Subjects/Keywords: Aryl hydrocarbon receptor; Dioxin; Inflammation; Toxicology; Nuclear receptor; Gene regulation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Patel, R. D. (2008). REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8497

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Patel, Rushang Dilipkumar. “REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION.” 2008. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/8497.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Patel, Rushang Dilipkumar. “REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION.” 2008. Web. 05 Mar 2021.

Vancouver:

Patel RD. REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/8497.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Patel RD. REGULATION OF GENE TRANSCRIPTION BY THE ARYL HYDROCARBON RECEPTOR –NEW TARGETS AND MECHANISMS OF REGULATION. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8497

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

16. Yang, Xi. Human Microsomal Epoxide Hydrolase (EPHX1): Genetic Polymorphism And Regulation By Chemopreventive Agents .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9828

► Microsomal epoxide hydrolase (EPHX1) is a critical catalytic determinant in the formation of the highly reactive electrophilic, and ultimately carcinogenic, epoxide metabolites of the polyaromatic… (more)

▼ Microsomal epoxide hydrolase (EPHX1) is a critical catalytic determinant in the formation of the highly reactive electrophilic, and ultimately carcinogenic, epoxide metabolites of the polyaromatic hydrocarbons. A central hypothesis of our research is that genetic variability and differential regulation of EPHX1 in human tissue are likely important determinants of interindividual responsiveness, resulting toxicities, and carcinogenicity outcomes related to chemical exposures. Our laboratory has demonstrated that the expression of the human EPHX1 gene is driven by the use of alternative promoters. An alternative promoter region, termed the E1-b promoter, is localized ~ 18.5 kb 5’-upstream from the structural region of the EPHX1 gene. The E1-b promoter is used exclusively to drive expression of EPHX1 mRNA transcripts in most tissues, along with a more proximal and highly liver-specific E1 promoter. Results of quantitative Real Time-PCR analyses demonstrated that the E1-b variant transcript is preferentially and broadly expressed in most tissues, such that it accounts for the majority of total EPHX1 transcript in vivo. In the studies conducted within this thesis research, detailed analysis of the E1-b promoter region demonstrated that this upstream EPHX1 promoter is replete with transposable elements. Further, we identified that two specific Alu elements are polymorphic (i.e. some chromosomes carry the two Alu insertions, whereas other do not) in the genome structure of different individuals. Results of luciferase gene reporter assays conducted in several human cell lines with E1-b promoter constructs demonstrated that the inclusion of the Alu (+/+) insertion significantly decreases basal transcriptional activities. Although we identified a putative aryl hydrocarbon receptor (AhR) binding motif within the Alu element structure, expression of human EPHX1 in an in vitro system was only modestly responsive to AhR ligands and we conclude that AhR regulation does not associate with the presence/absence of Alu elements. Two non-synonomous genetic polymorphisms that alter the EPHX1 amino acid structure were identified in our laboratory’s previous research efforts and several epidemiologic investigations have now implicated these EPHX1 coding region polymorphisms as a risk factor for lung cancer. In this study, using haplotype block analyses, we determined that the E1-b polymorphic promoter region was not in linkage disequilibrium with two previously identified non-synonomous SNPs in the coding region or with functional SNPs previously identified in the proximal promoter region of the gene. Modulation of xenobiotic-metabolizing enzymes by chemopreventive agents is a promising strategy offering protection against toxicity mediated by certain chemical carcinogens. In this research, we discovered that in human cells, EPHX1 mRNA and protein expression were regulated tissue-specificaly by the potent chemopreventive agent, sulforaphane. Subsequent mechanistic studies revealed that Nrf2/ARE pathway plays a central role in… Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Member, Robert Paulson, Committee Chair/Co-Chair, Jeffrey Maurice Peters, Committee Member, Adam Bleier Glick, Committee Member, Joshua D Lambert, Committee Member.

Subjects/Keywords: chemopreventive; Microsomal epoxide hydrolase; polymorphism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yang, X. (2009). Human Microsomal Epoxide Hydrolase (EPHX1): Genetic Polymorphism And Regulation By Chemopreventive Agents . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9828

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Yang, Xi. “Human Microsomal Epoxide Hydrolase (EPHX1): Genetic Polymorphism And Regulation By Chemopreventive Agents .” 2009. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/9828.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Yang, Xi. “Human Microsomal Epoxide Hydrolase (EPHX1): Genetic Polymorphism And Regulation By Chemopreventive Agents .” 2009. Web. 05 Mar 2021.

Vancouver:

Yang X. Human Microsomal Epoxide Hydrolase (EPHX1): Genetic Polymorphism And Regulation By Chemopreventive Agents . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/9828.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Yang X. Human Microsomal Epoxide Hydrolase (EPHX1): Genetic Polymorphism And Regulation By Chemopreventive Agents . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9828

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

17. Flaveny, Colin Ashton. MOLECULAR AND SPECIES-SPECIFIC DETERMINANTS OF ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL ACTIVITY.

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10449

► The aryl hydrocarbon receptor (AHR) is a transcription factor that modulates gene expression in response to ligand binding. AHR ligands include a structurally diverse group… (more)

▼ The aryl hydrocarbon receptor (AHR) is a transcription factor that modulates gene expression in response to ligand binding. AHR ligands include a structurally diverse group of planar hydrophobic polycyclic organic compounds, which include dietary flavinoids such as 2-(3,4dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (quercetin), as well as endogenous compounds like bilirubin and the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The AHR mediates most if not all of the adverse affects of TCDD exposure. Rodent models have been traditionally used in studies aimed at investigating TCDD-mediated toxicity and carcinogenesis and in the assessment of human risk. In order to enhance the accuracy of rodent-based toxicological data it is important to understand the molecular differences between human and rodent AHRs. We proposed that the hAHR would be functionally distinct from the mAHR. Therefore we attempted to identify biochemical and molecular factors that may influence interspecies differences between the mouse and human AHR. At a cellular level the hAHR also has contrasting nucleo-cytoplasmic shuttling properties compared to the mouse AHR (mAHR). This led to the hypothesis that identifying the underlying molecular mechanisms responsible for the ligand-independent nucleo-cytoplasmic shuttling of the AHR would shed light on this interspecies difference. Firstly we investigated the ability of the AHR to modulate gene expression in the absence of heterodimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT). Through the use of an ARNT-binding deficient AHR mutant in cell culture based luciferase-reporter assays it was demonstrated that the AHR is unable to activate dioxin responsive element (DRE)-driven gene activity or repress estrogen receptor activity in the absence of interaction with ARNT. Compared to the mAHR the hAHR also interacts less stably with heat shock protein 90 (HSP90). The co-chaperone p23 is a component of the unliganded AHR complex that was presumed to be important to stable interaction between AHR and HSP90. In the third chapter a p23 knockout mouse was used to investigate the importance of p23 expression to AHR ligand-binding and transcriptional activity in vivo. Gene expression and ligand binding analysis revealed that p23 expression was dispensable for AHR ligand binding and AHR-regulated gene induction. Amino acid sequence identity differences exist for the AHR between and within species that is in part responsible for the contrasting inter-species and intra-species sensitivity to TCDD exposure. We show in the fourth chapter that the amino acid sequence dissimilarity in the C-terminal domains of the mAHR and hAHR may actually result in differential recruitment of LXXLL-coactivator binding motif proteins which suggests that each receptor may differentially recruit coactivators. Compared to the human AHR (hAHR) the Ahrb allele, the most commonly used allele in TCDD toxicity and carcinogenesis studies, has a 10-fold higher affinity for typical AHR ligands… Advisors/Committee Members: Gary H Perdew, Dissertation Advisor/Co-Advisor, Craig Richard Baumrucker, Committee Member, Curtis John Omiecinski, Committee Member, Jeffrey Maurice Peters, Committee Member, Gary H Perdew, Committee Chair/Co-Chair.

Subjects/Keywords: TCDD.; ligand binding; gene regulation; Aryl hydrocarbon receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Flaveny, C. A. (2010). MOLECULAR AND SPECIES-SPECIFIC DETERMINANTS OF ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL ACTIVITY. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10449

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Flaveny, Colin Ashton. “MOLECULAR AND SPECIES-SPECIFIC DETERMINANTS OF ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL ACTIVITY.” 2010. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/10449.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Flaveny, Colin Ashton. “MOLECULAR AND SPECIES-SPECIFIC DETERMINANTS OF ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL ACTIVITY.” 2010. Web. 05 Mar 2021.

Vancouver:

Flaveny CA. MOLECULAR AND SPECIES-SPECIFIC DETERMINANTS OF ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL ACTIVITY. [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/10449.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Flaveny CA. MOLECULAR AND SPECIES-SPECIFIC DETERMINANTS OF ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL ACTIVITY. [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/10449

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

18. Markell, Lauren Mordasky. PHARMACOLOGICAL INHIBITION OF THE TGF-BETA TYPE I RECEPTOR REVEALS A DUAL ROLE OF TGF-BETA IN CARCINOGENESIS .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11358

► Transforming growth factor-beta 1 (TGF-beta 1) is a member of a large family of regulatory molecules that play both positive and negative roles in epithelial… (more)

▼ Transforming growth factor-beta 1 (TGF-beta 1) is a member of a large family of regulatory molecules that play both positive and negative roles in epithelial cancer. Pharmacological inhibitors of the Transforming Growth Factor-beta (TGF-beta) type I receptor (ALK5) have shown promise in blocking growth of xenotransplanted cancer cell lines but the effect on a multistage cancer model is not known. In the present studies, the role of the ALK5 inhibitor SB431542 (SB) was investigated in a two-stage skin chemical carcinogenesis assay in order to determine the effect on tumor formation and progression. In this model, nearly all tumors have activating mutations in codon 61 of the HRas gene. We show that topical SB significantly reduced the total number, incidence and size of papillomas compared to 12-O-tetradecanoylphorbol 13-acetate (TPA) promotion alone, and this was linked to increased epidermal apoptosis, decreased proliferation and decreased cutaneous inflammation during promotion. In contrast, the frequency of conversion to squamous cell carcinoma (SCC) was two-fold higher in papillomas treated with SB. While there was no difference in tumor cell proliferation in early premalignant lesions, those that formed after SB treatment exhibited reduced squamous differentiation and an altered inflammatory microenvironment similar to SCC. In an inducible epidermal HRAS transgenic model, treatment with SB enhanced proliferation and cutaneous inflammation in skin, but decreased expression of keratin 1 and increased expression of simple epithelial keratin 18, markers of premalignant progression. In agreement with increased frequency of progression in the multistage model, SB treatment resulted in increased tumor formation with a more malignant phenotype following long-term HRAS induction. To further characterize the altered squamous differentiation associated with reduced tumor formation and increased malignant progression by ALK5 inhibition, an HRAS oncogene-induced model of preneoplastic keratinocytes was utilized. SB significantly enhanced HRAS-induced cornification which correlated with the increased expression of terminal differentiation genes transglutaminase 1 (TGM1) and 3 (TGM3) and small proline-rich protein 1A (SPR1A) and 2H (SPR2H) which cross-link structural proteins that make up the cornified envelope. There was a similar increase in cornified layers and TGM and SPR gene expression following SB treatment of mice expressing inducible epidermal HRAS. Alternatively, treatment of HRAS-expressing keratinocytes with TGF-beta 1 or overexpression of TGF-beta 1 and HRAS in an inducible epidermal transgenic model resulted in reduced expression of TGM1 and TGM3 and cornification in vitro. Papilloma (SP1) and squamous cell carcinoma (PAM2.12) cell lines were less responsive to TGF-beta 1 suppression of markers and marker induction by SB. Interestingly, a subpopulation of HRAS-expressing keratinocytes were resistant to induction of terminal differentiation by ALK5 inhibition. These cells were also resistant to senescence and… Advisors/Committee Members: Adam Bleier Glick, Dissertation Advisor/Co-Advisor, Adam Bleier Glick, Committee Chair/Co-Chair, John Patrick Vanden Heuvel, Committee Member, Gary H Perdew, Committee Member, Zhi Chun Lai, Committee Member, Jeffrey Maurice Peters, Committee Member.

Subjects/Keywords: skin; skin carcinogenesis; TGF-beta; chemically-induced carcinogenesis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Markell, L. M. (2010). PHARMACOLOGICAL INHIBITION OF THE TGF-BETA TYPE I RECEPTOR REVEALS A DUAL ROLE OF TGF-BETA IN CARCINOGENESIS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11358

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Markell, Lauren Mordasky. “PHARMACOLOGICAL INHIBITION OF THE TGF-BETA TYPE I RECEPTOR REVEALS A DUAL ROLE OF TGF-BETA IN CARCINOGENESIS .” 2010. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/11358.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Markell, Lauren Mordasky. “PHARMACOLOGICAL INHIBITION OF THE TGF-BETA TYPE I RECEPTOR REVEALS A DUAL ROLE OF TGF-BETA IN CARCINOGENESIS .” 2010. Web. 05 Mar 2021.

Vancouver:

Markell LM. PHARMACOLOGICAL INHIBITION OF THE TGF-BETA TYPE I RECEPTOR REVEALS A DUAL ROLE OF TGF-BETA IN CARCINOGENESIS . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/11358.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Markell LM. PHARMACOLOGICAL INHIBITION OF THE TGF-BETA TYPE I RECEPTOR REVEALS A DUAL ROLE OF TGF-BETA IN CARCINOGENESIS . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11358

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

19. Facompre, Nicole Danielle. Organoselenium-mediated alteration of prostate cancer cell signaling pathways .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11123

► Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer related death in men in the United States. The lack of… (more)

▼ Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer related death in men in the United States. The lack of treatment for “worried well” patients with prostatic intraepithelial neoplasia (a premalignant condition) combined with issues of recurrence and hormone resistance present significant obstacles to prostate cancer survivorship. The long latency of prostate cancer provides opportunity to intervene with mechanistically-based agents at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor, PI3K/Akt, and mammalian target of rapamycin (mTOR) signaling pathways. Crosstalk between the androgen receptor and Akt pathways is thought to contribute to progression and hormone refractory disease. Studies have also implicated the mammalian target of rapamycin (mTOR) signaling pathway in the progression of prostate cancer and its transition to androgen independence, suggesting mTOR as a potential target for new therapies. Selenium, an essential nutrient and known antioxidant, has been shown in epidemiologic and preclinical studies to be protective against prostate cancer. However, clinical intervention trials with selenium have thus far had contradictory outcomes and the anti-cancer mechanisms of selenium compounds are not well understood. Studies consistently show that dose and form are critical factors in the actions of selenium compounds. In the present investigation we compare the effects of two structurally distinct organoselenium compounds naturally occurring selenomethionine (SM) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on cell growth, apoptosis, and signaling in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. We have found that, in contrast to SM, p-XSC dose-dependently inhibits viability, induces apoptosis, and modulates critical signaling molecules in both AR and AI cells. p-XSC effectively inhibits androgen receptor expression and transcriptional activity, Akt phosphorylation, and Akt-specific phosphorylation of the androgen receptor. We also show that p-XSC preferentially inhibits mTOR complex 2 (mTORC2) signaling in AI cells, a novel potential target for selenium in prostate cancer. Based on these findings, we hypothesized that the combination of p-XSC with rapamycin, which primarily targets mTOR complex 1 (mTORC1), may be a superior approach to inhibit prostate cancer cell growth than either agent alone. Drug combination strategies can offer a number of advantages to single-agent therapies including the enhancement of efficacy, the reduction of dose and toxicity, and the management of drug resistance. Our data show that inhibition of AI cell viability and mTOR signaling is significantly enhanced by combining p-XSC and rapamycin, compared with each agent individually. We propose that these agents achieve this effect, in part, by targeting the two distinct arms of the… Advisors/Committee Members: Karam E El Bayoumy, Dissertation Advisor/Co-Advisor, Karam E El Bayoumy, Committee Chair/Co-Chair, Raghu Sinha, Committee Member, Jeffrey Maurice Peters, Committee Member, Thomas E Spratt, Committee Member, Sergei A Grigoryev, Committee Member.

Subjects/Keywords: androgen receptor; selenium; prostate cancer; Akt

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APA (6^th Edition):

Facompre, N. D. (2010). Organoselenium-mediated alteration of prostate cancer cell signaling pathways . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11123

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Facompre, Nicole Danielle. “Organoselenium-mediated alteration of prostate cancer cell signaling pathways .” 2010. Thesis, Penn State University. Accessed March 05, 2021. https://submit-etda.libraries.psu.edu/catalog/11123.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Facompre, Nicole Danielle. “Organoselenium-mediated alteration of prostate cancer cell signaling pathways .” 2010. Web. 05 Mar 2021.

Vancouver:

Facompre ND. Organoselenium-mediated alteration of prostate cancer cell signaling pathways . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 05]. Available from: https://submit-etda.libraries.psu.edu/catalog/11123.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Facompre ND. Organoselenium-mediated alteration of prostate cancer cell signaling pathways . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11123

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Open Access Theses and Dissertations