+publisher:"Penn State University" +contributor:("Adam Bleier Glick, Committee Member")

Penn State University

1. Yang, Xiaoxu. Investigating the roles of primary cilium in Gli protein activation and Hedgehog signaling pathway using Sufu/Gli ciliary recruitment system.

Degree: 2017, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/14719xzy112

► The Hedgehog (Hh) signaling pathway is crucial for various developmental processes such as proliferation, differentiation and cell migration. Primary cilia are critical for Hh signaling… (more)

Subjects/Keywords: Hh signaling; Sufu; Gli2; primary cilia

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

APA (6^th Edition):

Yang, X. (2017). Investigating the roles of primary cilium in Gli protein activation and Hedgehog signaling pathway using Sufu/Gli ciliary recruitment system. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/14719xzy112

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, Xiaoxu. “Investigating the roles of primary cilium in Gli protein activation and Hedgehog signaling pathway using Sufu/Gli ciliary recruitment system.” 2017. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/14719xzy112.

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, Xiaoxu. “Investigating the roles of primary cilium in Gli protein activation and Hedgehog signaling pathway using Sufu/Gli ciliary recruitment system.” 2017. Web. 07 Mar 2021.

Vancouver:

Yang X. Investigating the roles of primary cilium in Gli protein activation and Hedgehog signaling pathway using Sufu/Gli ciliary recruitment system. [Internet] [Thesis]. Penn State University; 2017. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/14719xzy112.

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. Investigating the roles of primary cilium in Gli protein activation and Hedgehog signaling pathway using Sufu/Gli ciliary recruitment system. [Thesis]. Penn State University; 2017. Available from: https://submit-etda.libraries.psu.edu/catalog/14719xzy112

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

Penn State University

2. Su, Shengzhong. Transcriptional regulation of the human microsomal epoxide hydrolase gene (EPHX1) driven by a far upstream alternative promoter.

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/18909

► Microsomal epoxide hydrolase (mEH) is an important metabolizing enzyme that plays roles in both detoxification and bioactivation of xenobiotics. Human mEH gene expression is subjected… (more)

▼ Microsomal epoxide hydrolase (mEH) is an important metabolizing enzyme that plays roles in both detoxification and bioactivation of xenobiotics. Human mEH gene expression is subjected to the regulation of alternative promoter usage generating multiple transcripts, including the most prevalent, termed E1b and E1. These transcripts possess distinct untranslated first exons but encode identical mEH protein given that the second exon contains the translation initiation site. E1b is ubiquitously expressed at high levels in all tissues while E1 is selectively expressed in the liver. Although several liver-specific transcription factors were characterized previously as involved in the regulation of E1 transcription, little is known regarding the molecular mechanism regulating E1b expression. Study of those underlying processes is the principle focus of these investigations. Initially in these studies we sought to identify the key transcription factors responsible for controlling the constitutive expression of the E1b transcript. Sequence analysis of E1b proximal promoter revealed several potential Sp1/Sp3 binding sites. Site-directed mutagenesis of these motifs established their roles in regulating E1b promoter activities. Chromatin immunoprecipitation (ChIP) analyses demonstrated that both Sp1 and Sp3 are bound to the proximal promoter region of E1b. Silencing, or knockdown of Sp1 expression using siRNA had no detectable effect on the endogenous E1b transcriptional level. However, knockdown of Sp3 greatly diminished E1b expression in several different human cell lines. These results demonstrated that Sp3 in particular was involved in regulating the basal expression patterns of the mEH E1b variant transcript. Secondly, following analysis of DNase I hypersensitivity data available in the ENCODE project, we identified and characterized two intronic DNA elements in the mEH genomic region. This led to the discovery that the master oxidative stress regulator, Nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) functioned as a mediator of E1b upregulation in lung cancer-derived cells. Results obtained from both luciferase gene reporter and ChIP assays indicated that Nrf2 interacts with the 2nd intronic DNA element following its activation with the antioxidants, sulforaphane or tBHQ. DNA sequence analysis of the enhancer region together with electrophoretic mobility shift assays (EMSA) enabled the identification of a conserved antioxidant-response element within the enhancer that appeared to mediate these transcriptional responses. Finally in these studies, we sought to characterize differences in the transcriptional responses of the E1b and E1 promoters in hepatoma cell lines and human normal hepatocytes to chemical mediators. Nrf2 siRNA knockdown studies in hepatoma C3A cells were performed to identify the Nrf2 signaling pathway as functional in mediating the activation effects contributed by the monofunctional inducers, sulforaphane and tBHQ, to both of E1b and E1 promoters. Luciferase reporter assays… Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Chair/Co-Chair, Adam Bleier Glick, Committee Member, Kumble Sandeep Prabhu, Committee Member, John Patrick Vanden Heuvel, Committee Member, Joshua D Lambert, Committee Member.

Subjects/Keywords: Microsomal epoxide hydrolase; Nrf2; Xenobiotic metabolism; Bioactivation; Lung cancer; Sp1; Sp3; AhR

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

APA (6^th Edition):

Su, S. (2013). Transcriptional regulation of the human microsomal epoxide hydrolase gene (EPHX1) driven by a far upstream alternative promoter. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/18909

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):

Su, Shengzhong. “Transcriptional regulation of the human microsomal epoxide hydrolase gene (EPHX1) driven by a far upstream alternative promoter.” 2013. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/18909.

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

MLA Handbook (7^th Edition):

Su, Shengzhong. “Transcriptional regulation of the human microsomal epoxide hydrolase gene (EPHX1) driven by a far upstream alternative promoter.” 2013. Web. 07 Mar 2021.

Vancouver:

Su S. Transcriptional regulation of the human microsomal epoxide hydrolase gene (EPHX1) driven by a far upstream alternative promoter. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/18909.

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

Council of Science Editors:

Su S. Transcriptional regulation of the human microsomal epoxide hydrolase gene (EPHX1) driven by a far upstream alternative promoter. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/18909

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

Penn State University

3. Zhu, Bokai. Modulation Of Skin Cancer By Peroxisome Proliferator-activated Receptor Beta/delta.

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/15143

► Ligand activation of peroxisome proliferator–activated receptor-β/δ (PPARβ/δ) inhibits chemically-induced skin tumorigenesis and Pparβ/δ-null mice exhibit enhanced chemically-induced skin tumorigenesis compared to wild-type mice. Since over… (more)

▼ Ligand activation of peroxisome proliferator–activated receptor-β/δ (PPARβ/δ) inhibits chemically-induced skin tumorigenesis and Pparβ/δ-null mice exhibit enhanced chemically-induced skin tumorigenesis compared to wild-type mice. Since over 90% of chemically-induced tumors contain Hras mutations, this suggests that PPARβ/δ could inhibit chemically-induced skin tumorigenesis by modulating Hras signaling, which was examined in this study. In addition, ligand activation of PPARβ/δ and inhibition of cyclooxygenase-2 (COX2) activity by nonsteroidal anti-inflammatory drugs (NSAID) can both attenuate skin tumorigenesis. The hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX2 activity will increase the efficacy of chemoprevention of chemically induced skin tumorigenesis over that observed with either approach alone is also examined in this study. Ligand activation of PPARβ/δ caused a negative selection against cells expressing higher levels of HRAS by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparβ/δ-null keratinocytes as compared to HRAS-expressing wild-type keratinocytes. Ligand activated PPARβ/δ repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation, and increasing promoter recruitment of p130/p107. In addition, co-treatment with a PPARβ/δ ligand and various mitosis inhibitors increases the efficacy of increasing G2/M arrest. Moreover, PPARβ/δ suppresses tumorigenesis by promoting HRAS-induced senescence. PPARβ/δ transcriptionally regulates Rasgrp1 and Ilk causing increased p-ERK and decreased p-AKT that promote HRAS-induced senescence. PPARβ/δ also promotes senescence through attenuation of HRAS-induced ER stress and ER stress-associated UPR by repressing p-AKT-mTOR signaling. Further, these studies demonstrate a novel positive feedback loop between p-AKT, ER stress and UPR. An acute increase of ER stress is sufficient to establish the positive loop, maintaining higher UPR and p-AKT activity, collectively causing evasion of senescence and malignant conversion. Moreover, increased PPARβ/δ expression and decreased ER stress correlated with increased senescence in both mouse and human tumors. Ligand activation of PPARβ/δ with GW0742 caused a PPARβ/δ-dependent delay in the onset of tumor formation. Nimesulide also delayed the onset of tumor formation and caused inhibition of tumor multiplicity in wild-type mice but not in Pparβ/δ-null mice. Combining ligand activation of PPARβ/δ with dietary nimesulide resulted in a further decrease of tumor multiplicity in wild-type mice but not in Pparβ/δ-null mice. Biochemical and molecular analysis of skin and tumor samples show that these effects were due to the modulation of terminal differentiation, attenuation of inflammatory signaling, and induction of apoptosis through both PPARβ/δ-dependent and PPARβ/δ-independent mechanisms. Increased levels and activity of PPARβ/δ by nimesulide were also observed. These… Advisors/Committee Members: Jeffrey Maurice Peters, Dissertation Advisor/Co-Advisor, Jeffrey Maurice Peters, Committee Chair/Co-Chair, Yanming Wang, Committee Member, Gary H Perdew, Committee Member, Adam Bleier Glick, Committee Member, Wendy Hanna Rose, Committee Member.

Subjects/Keywords: PPARb/d; HRAS; Mitosis; Senescence; ER stress

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

APA (6^th Edition):

Zhu, B. (2012). Modulation Of Skin Cancer By Peroxisome Proliferator-activated Receptor Beta/delta. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/15143

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):

Zhu, Bokai. “Modulation Of Skin Cancer By Peroxisome Proliferator-activated Receptor Beta/delta.” 2012. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/15143.

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

MLA Handbook (7^th Edition):

Zhu, Bokai. “Modulation Of Skin Cancer By Peroxisome Proliferator-activated Receptor Beta/delta.” 2012. Web. 07 Mar 2021.

Vancouver:

Zhu B. Modulation Of Skin Cancer By Peroxisome Proliferator-activated Receptor Beta/delta. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/15143.

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

Council of Science Editors:

Zhu B. Modulation Of Skin Cancer By Peroxisome Proliferator-activated Receptor Beta/delta. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/15143

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

Penn State University

4. De Keyser, Joshua Gordon. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9350

► The human constitutive androstane receptor (CAR) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene utilizes multiple alternative splicing… (more)

▼ The human constitutive androstane receptor (CAR) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene utilizes multiple alternative splicing events during pre-mRNA processing, thereby increasing the CAR transcriptome. The work presented in this dissertation focuses on the functional analysis of a prominent human CAR variant, CAR2 that possesses a 4- amino acid insertion in the ligand binding domain. Previous investigations led us to hypothesize that the CAR2 variant is a ligand-activated receptor and possesses a unique ligand binding profile giving rise to novel biological function. We now demonstrate that CAR2 constitutes approximately one-third and one-half of the total CAR transcriptome in human hepatocytes and small intestine, respectively. Further, we identify the common plasticizers, di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP) as highly potent and uniquely selective agonists of CAR2. Results from reporter transactivation assays reveal that DEHP and DiNP activate CAR2 at low nanomolar concentrations. In addition, comparative genomic analysis show that the typical mouse, rat and marmoset models of toxicity can not accurately profile potential human toxicity due to these species inability to generate a CAR2-like transcript. It is also demonstrated that CAR2 possesses an altered ligand pocket that allows for the highly potent and specific activation of the variant by DEHP and DiNP. Further studies show that CAR1 and CAR3 share similar ligand activation profiles; whereas CAR2 responds to most CAR1 and CAR3 ligands as well as a unique subset of chemicals. Finally, it is now shown that meclizine, a human CAR1 inverse-agonist, is a specific agonist of CAR2. A meclizine derived pharmacophore was utilized in a ligand-based virtual screening and identified two novel CAR2 agonists from the NCI chemical database. The results of this dissertation will aid in the development of better models of human CAR activation, give a more complete understanding of the interaction of CAR with xenobiotics, yield novel insight into potential mechanisms of phthalate toxicity and provide the foundation for future studies into the physiologic functions of alternatively spliced variants of CAR. Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Chair/Co-Chair, Reka Z Albert, Committee Member, Adam Bleier Glick, Committee Member, John Patrick Vanden Heuvel, Committee Member.

Subjects/Keywords: phthalates; alternative splicing; constitutive androstane receptor; drug and xenobiotic metabolism; meclizine; nuclear receptors; gene induction

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

APA (6^th Edition):

De Keyser, J. G. (2009). ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9350

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):

De Keyser, Joshua Gordon. “ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .” 2009. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/9350.

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

MLA Handbook (7^th Edition):

De Keyser, Joshua Gordon. “ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY .” 2009. Web. 07 Mar 2021.

Vancouver:

De Keyser JG. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/9350.

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

Council of Science Editors:

De Keyser JG. ALTERNATIVE SPLICING OF THE HUMAN CONSTITUTIVE ANDROSTANE RECEPTOR GENE CREATES RECEPTORS WITH UNIQUE FUNCTION AND LIGAND SPECIFICITY . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9350

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

Penn State University

5. Shuman, Laurie Ann. Interaction of Metastatic Breast Cancer Cells with Osteoblasts .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9358

► A majority of cancer deaths (90%) are a result of the dissemination of tumor cells from the primary site to a secondary site, not due… (more)

▼ A majority of cancer deaths (90%) are a result of the dissemination of tumor cells from the primary site to a secondary site, not due to the primary tumor itself. Therefore, it is necessary to investigate mechanisms utilized by tumor cells to promote growth in and destruction of the secondary sites. Advances in microarray technology allow for rapid screening and identification of potential genetic targets involved in host response to cancers, however there is a need for high-throughput screening of the identified targets to determine their efficacy. In vitro systems that more accurately represent in vivo microenvironments would be a useful tool to screen potential genetic targets as treatment of diseases. Here we examined the interaction of breast cancer cells with osteoblasts in a specialized culture device (bioreactor). Breast cancer preferentially metastasizes to the bone resulting in the formation of osteolytic lesions. While administration of osteoclast-inhibiting drugs, such as bisphosphonates, slow further lesion formation, existing lesions do not heal. Therefore, osteoblasts appear functionally disabled in the presence of metastatic breast cancer cells. Previous studies in this laboratory have shown that breast cancer cells alter osteoblast adhesion and morphology, increase osteoblast apoptosis, and decrease the expression of osteoblast differentiation genes when exposed to metastatic breast cancer cell conditioned medium for extended periods (5 – 35 days). In order to examine the interaction of metastatic breast cancer cells with osteoblasts apart from osteoclasts, a specialized bioreactor culture system was utilized. In this culture device, osteoblasts grew and differentiated into a multiple-cell-layer, three-dimensional mineralizing tissue. Co-culture of metastatic breast cancer cells with osteoblasts in a bioreactor were compared to co-culture in conventional cell culture. The breast cancer cells not only attached and grew on the osteoblast tissue in the bioreactor culture system, but also formed distinct colonies that aligned in the same axis as the osteoblasts, similar to “Indian filing” seen in authentic pathological tissue. Moreover, in this culture system, the breast cancer cells penetrated the osteoblast tissue, a phenomenon not apparent with conventional cell culture methods. Metastatic breast cancer cells also interfered with the differentiation of osteoblasts as evidenced by a decrease in production of proteins, such as osteocalcin and collagen. In addition, co-culture of the metastatic breast cancer cells with osteoblasts resulted in increased production of the inflammatory cytokine, IL-6, a known activator of osteoclasts. The bioreactor culture system is advantageous over conventional cell culture systems in emulating the bone microenvironment and for studying the interaction of metastatic breast cancer cells with osteoblasts. Additionally, in this report, transcription factor targets within MC3T3-E1 cells treated with MDA-MB-231 human metastatic breast cancer cell conditioned… Advisors/Committee Members: Andrea Marie Mastro, Dissertation Advisor/Co-Advisor, Andrea Marie Mastro, Committee Chair/Co-Chair, Adam Bleier Glick, Committee Member, Rosalyn Bryson Irby, Committee Member, Robert Paulson, Committee Member, Danny Welch, Committee Member.

Subjects/Keywords: transcription factor; cytokine; metastasis; osteoblast; Breast cancer

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

APA (6^th Edition):

Shuman, L. A. (2009). Interaction of Metastatic Breast Cancer Cells with Osteoblasts . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9358

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):

Shuman, Laurie Ann. “Interaction of Metastatic Breast Cancer Cells with Osteoblasts .” 2009. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/9358.

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

MLA Handbook (7^th Edition):

Shuman, Laurie Ann. “Interaction of Metastatic Breast Cancer Cells with Osteoblasts .” 2009. Web. 07 Mar 2021.

Vancouver:

Shuman LA. Interaction of Metastatic Breast Cancer Cells with Osteoblasts . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/9358.

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

Council of Science Editors:

Shuman LA. Interaction of Metastatic Breast Cancer Cells with Osteoblasts . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9358

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

Penn State University

6. Bility, Moses Turkle. MODULATION OF SKIN CANCER BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BETA/DELTA .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9430

► Pparb/d-null mice exhibit enhanced tumorigenesis in a two-stage carcinogenesis bioassay model when compared to wild-type mice, which is likely due in part to enhanced epidermal… (more)

▼ Pparb/d-null mice exhibit enhanced tumorigenesis in a two-stage carcinogenesis bioassay model when compared to wild-type mice, which is likely due in part to enhanced epidermal hyperplasia and decreased apoptosis following treatment with phorbol ester. Previous work also showed that ligand activation of PPARb/d induces terminal differentiation and inhibits proliferation in primary keratinocytes. In the present studies, the effect of ligand activation of PPARb/d on skin carcinogenesis was examined using both in vivo and ex vivo skin carcinogenesis models. Inhibition of chemically-induced skin tumorigenesis was observed in wild-type mice administered the synthetic PPARb/d ligand GW0742, and this effect was likely the result of PPARb/d activation induced terminal differentiation. These effects were not found in similarly treated Pparb/d-null mice. Ligand activation of PPARb/d also inhibited cell proliferation and induced terminal differentiation in neoplastic keratinocyte lines that represent different stages of skin carcinogenesis. The initiation stage of the chemically-induced skin cancer model can be replaced by introduction of the ras oncogene. Mutation of the Ha-ras allele by an initiator is a critical event in the initiation stage of the chemically-induced skin cancer model. To further characterize the molecular mechanisms by which PPARb/d inhibited skin carcinogenesis, a ras oncogene-induced neoplastic keratinocyte model was utilized. v-rasHa-induced neoplastic/ malignant transformation was exacerbated in Pparb/d-null keratinocytes when compared to wild-type keratinocytes, and this effect was likely the result of PPARb/d mediated induction of senescence and terminal differentiation and concomitant inhibition of cell proliferation. PPARb/d can also inhibit cell proliferation by modulating the mitogen activated protein kinase (MAPK) signaling cascade, which is induced in the oncogenic ras model. Members of the MAPK signaling cascade are critical downstream effectors of Ras signaling. v-rasHa-induced neoplastic transformation of primary keratinocytes resulted in an enhanced activation of MAPK proteins in Pparb/d-null keratinocytes when compared to wild-type keratinocytes. Oncogenic ras exerts its tumorigenic effects via several different downstream effectors. A major downstream effector of oncogenic ras signaling is COX2. To further characterize the chemotherapeutic efficacy of PPARb/d activation on skin carcinogenesis, the effect of PPARb/d ligand coupled with COX2 inhibitor on skin carcinogenesis was examined using both in vivo and ex vivo skin carcinogenesis models. Results from these studies suggest that combining PPARb/d ligands with other chemotherapeutic agents such as COX2 inhibitors could serve as powerful chemopreventive and/or chemotherapeutic tools against skin cancer. Overall, this dissertation provides evidence that targeting ligand activation of PPARb/d could improve the efficacy of current chemopreventive/ chemotherapeutic strategies for skin cancer. Advisors/Committee Members: Jeffrey Maurice Peters, Dissertation Advisor/Co-Advisor, Andrea Marie Mastro, Committee Member, Curtis John Omiecinski, Committee Member, Gary H Perdew, Committee Member, Adam Bleier Glick, Committee Member, Jeffrey Maurice Peters, Committee Chair/Co-Chair, Peter John Hudson, Committee Member.

Subjects/Keywords: PPARb/d; nuclear receptors; v-rasHa-induced skin carcinogenesis; chemically-induced skin carcinogenesis; skin carcinogenesis; PPARs

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

APA (6^th Edition):

Bility, M. T. (2009). MODULATION OF SKIN CANCER BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BETA/DELTA . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9430

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):

Bility, Moses Turkle. “MODULATION OF SKIN CANCER BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BETA/DELTA .” 2009. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/9430.

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

MLA Handbook (7^th Edition):

Bility, Moses Turkle. “MODULATION OF SKIN CANCER BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BETA/DELTA .” 2009. Web. 07 Mar 2021.

Vancouver:

Bility MT. MODULATION OF SKIN CANCER BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BETA/DELTA . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/9430.

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

Council of Science Editors:

Bility MT. MODULATION OF SKIN CANCER BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BETA/DELTA . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9430

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

Penn State University

7. 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 07, 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. 07 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 07]. 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

8. Sharda, Daniel Richard. INDUCTION OF MACROPHAGE ARGINASE I EXPRESSION BY RON AND THE IMPLICATIONS FOR PROMOTING SYNGENEIC TUMOR GROWTH .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10502

► In the innate immune response, macrophages play a role as the first line of defense against microbial infection through phagocytosis and secretion of inflammatory mediators… (more)

▼ In the innate immune response, macrophages play a role as the first line of defense against microbial infection through phagocytosis and secretion of inflammatory mediators such as nitric oxide (NO) and reactive oxygen species (ROS). The adaptive immune response is primed through antigen presentation by macrophages, which then respond to T cell cytokines that further aid in the clearance of pathogenic insult. Following clearance of pathogens, macrophages downregulate the inflammatory response of both the innate and adaptive branches of immunity, and this is coupled with the upregulation of genes that promote resolution of inflammation. Macrophage regulation of inducible nitric oxide synthase and arginase I expression have long been studied as prototypic markers of classical (inflammatory) versus alternative (anti-inflammatory) macrophage activation. Dampening of classical activation by the Ron receptor tyrosine kinase in macrophages has been well characterized in the murine model of septic shock where Ron-/- mice produce elevated levels of IFNã and succumb to death while wild-type animals survive. Conversely, it has been demonstrated that the Ron receptor tips the balance of macrophage activation away from the classically activated phenotype and promotes hallmarks of alternative macrophage activation, including arginase I expression. In this dissertation, we first set out to determine the mechanism by which arginase I is regulated by Ron. We demonstrate that, while IL-4 and the ligand for the Ron receptor, MSP, both enhance arginase I expression in macrophages, MSP induction of the arginase I promoter occurs at sites independent from those induced by IL-4. MSP, but not IL-4, induces potent MAPK activation in primary macrophages and, through systematic mutagenesis, we demonstrate that induction of the arginase I promoter in response to MSP is mediated by an AP-1 binding site located 433bp upstream of the transcription start site (TSS). In contrast, IL-4 induces arginase I expression through a Stat6 site located ~2.9kb upstream of the TSS. The role of these sites in vivo in primary macrophages is supported by results from ChIP analysis demonstrating enhanced binding of Fos to the AP-1 site following MSP, but not IL-4 stimulation, and the enhanced binding of Stat6 primarily by IL-4 or to a lesser extent by MSP. These data suggest that MSP and IL-4 induce arginase I expression in macrophages by both shared and divergent mechanisms. While alternative macrophage activation of arginase I is important in altering the inflammatory response to pathogens and in promoting wound healing, tumor development hijacks elevated expression of arginase I in macrophages as a means of enhancing tumor growth. Because Ron alters the balance between classically and alternatively activated macrophages, we hypothesized that activation of Ron on macrophages would promote tumor growth by enhancing arginase I expression. Here, we find that growth of the syngeneic tumors 3LL, B16-F10, and EG.7 is reduced in Ron-/- mice. Concurrently,… Advisors/Committee Members: Pamela Hankey Giblin, Dissertation Advisor/Co-Advisor, Pamela Hankey Giblin, Committee Chair/Co-Chair, Robert Paulson, Committee Member, Adam Bleier Glick, Committee Member, K Sandeep Praubu, Committee Member, Yanming Wang, Committee Member.

Subjects/Keywords: macrophage activation; tumorigenesis; arginase; RTK; Ron; MSP; IL-4

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

APA (6^th Edition):

Sharda, D. R. (2010). INDUCTION OF MACROPHAGE ARGINASE I EXPRESSION BY RON AND THE IMPLICATIONS FOR PROMOTING SYNGENEIC TUMOR GROWTH . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10502

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):

Sharda, Daniel Richard. “INDUCTION OF MACROPHAGE ARGINASE I EXPRESSION BY RON AND THE IMPLICATIONS FOR PROMOTING SYNGENEIC TUMOR GROWTH .” 2010. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/10502.

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

MLA Handbook (7^th Edition):

Sharda, Daniel Richard. “INDUCTION OF MACROPHAGE ARGINASE I EXPRESSION BY RON AND THE IMPLICATIONS FOR PROMOTING SYNGENEIC TUMOR GROWTH .” 2010. Web. 07 Mar 2021.

Vancouver:

Sharda DR. INDUCTION OF MACROPHAGE ARGINASE I EXPRESSION BY RON AND THE IMPLICATIONS FOR PROMOTING SYNGENEIC TUMOR GROWTH . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/10502.

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

Council of Science Editors:

Sharda DR. INDUCTION OF MACROPHAGE ARGINASE I EXPRESSION BY RON AND THE IMPLICATIONS FOR PROMOTING SYNGENEIC TUMOR GROWTH . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/10502

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

Penn State University

9. Coleman, Jeffrey David. Roles of Peroxisome Proliferator-Activated Receptor-beta/delta and B-cell Lymphoma-6 in Pancreatic Cancer .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11405

► The Peroxisome proliferator-activated receptors are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPARs are implicated in the regulation of various cellular… (more)

▼ The Peroxisome proliferator-activated receptors are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPARs are implicated in the regulation of various cellular processes, including glucose and lipid homeostasis, fatty acid oxidation, inflammation and cell proliferation and invasion. Of the three subtypes − PPARα, PPARβ/δ and PPARγ − PPARβ/δ is the least well understood in terms of its endogenous ligands and biological role(s). The PPARβ/δ null mouse is more susceptible to hepatotoxicity than the wild-type mouse following challenge with Arsenic or CCl4, compounds known to induce toxicity via increased reactive oxygen intermediates. Recently, PPARβ/δ has generated much interest in its ability to regulate the inflammatory response in coordination with the transcriptional repressor, B-cell lymphoma-6 (BCL-6). This dissertation will examine the hypothesis that modulation of oxidative stress underlies the protective role of PPARβ/δ in the mouse liver, and that the regulation of inflammation and cell invasion by PPARβ/δ and BCL-6 is a significant role for the receptor in human pancreatic cancer cells. Oxidized very-low density lipoprotein (oxVLDL) and its constituents, including 13-S- hydroxyoctadeca-dienoic acid (13-S-HODE) and 4-hydroxynonenal (4-HNE), are endogenous PPARβ/δ activators in PPRE-dependent reporter assays. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype. Other oxidative stress mediators, including 4-hyroxy-hexenal (4-HHE), 4-oxo-2-nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal, did not activate this receptor in these experiments. Gene expression assays using both wild-type and PPARβ/δ-/- cells demonstrated that 4-HNE induced gene expression in a PPARβ/δ-dependent manner. Furthermore, wild-type cells were more resistant to 4-HNE-induced toxicity (EC50 68μM) compared with PPARβ/δ-/- cells (EC50 5μM). Consistent with this observation, addition of a synthetic PPARβ/δ activator protected cells from 4-HNE-induced toxicity, while treatment with a PPARβ/δ antagonist reversed this observation. Microarray analyses using both wild-type and PPARβ/δ-/- cells indicated several anti-oxidant genes known to be involved in 4-HNE metabolism that were increased at the transcript level in a PPARβ/δ-dependent manner. Molecular modeling, using the coordinates of PPARβ/δ bound to another endogenous ligand, eicosapentadienoic acid (EPA), indicated that 4-HNE forms a putative hydrogen bonding interaction with His413 in the PPARβ/δ ligand-binding pocket. Thus, 4-HNE binding activates the PPARβ/δ subtype, increasing transcription of anti-oxidant and detoxification genes in a PPARβ/δ-dependent fashion, and this observation may account for the protective role of the… Advisors/Committee Members: Dr Jack Vanden Heuvel, Dissertation Advisor/Co-Advisor, John Patrick Vanden Heuvel, Committee Chair/Co-Chair, Kumble Sandeep Prabhu, Committee Member, Adam Bleier Glick, Committee Member, Karam E El Bayoumy, Committee Member.

Subjects/Keywords: B-cell lymphoma-6; pancreatic cancer; PPARbeta/delta

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

APA (6^th Edition):

Coleman, J. D. (2010). Roles of Peroxisome Proliferator-Activated Receptor-beta/delta and B-cell Lymphoma-6 in Pancreatic Cancer . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11405

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):

Coleman, Jeffrey David. “Roles of Peroxisome Proliferator-Activated Receptor-beta/delta and B-cell Lymphoma-6 in Pancreatic Cancer .” 2010. Thesis, Penn State University. Accessed March 07, 2021. https://submit-etda.libraries.psu.edu/catalog/11405.

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

MLA Handbook (7^th Edition):

Coleman, Jeffrey David. “Roles of Peroxisome Proliferator-Activated Receptor-beta/delta and B-cell Lymphoma-6 in Pancreatic Cancer .” 2010. Web. 07 Mar 2021.

Vancouver:

Coleman JD. Roles of Peroxisome Proliferator-Activated Receptor-beta/delta and B-cell Lymphoma-6 in Pancreatic Cancer . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 07]. Available from: https://submit-etda.libraries.psu.edu/catalog/11405.

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

Council of Science Editors:

Coleman JD. Roles of Peroxisome Proliferator-Activated Receptor-beta/delta and B-cell Lymphoma-6 in Pancreatic Cancer . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11405

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

Open Access Theses and Dissertations