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Regulation of the versican gene : implications for vascular health and disease Rahmani, Maziar

Abstract

Versican, a chondroitin sulfate proteoglycan, is one of the main components of the extracellular matrix and hence plays a central role in tissue morphogenesis and a number of pathologic processes. My main goal has been to investigate the mechanisms of versican gene regulation, focusing on the signal transduction pathways, promoter regions, cis-acting elements, and trans- factors. This thesis puts forth new knowledge regarding transcriptional regulation of the human versican gene. In chapter III, I present the cloning of a 752-bp fragment of the human versican promoter (- 634/+118 bp) and nine stepwise 5' deletion fragments in the PGL3-luciferase reporter plasmid. Furthermore, I identify three potential enhancer and two repressor regions in this promoter. I also demonstrate that both cAMP and C/EBPβ enhanced and repressed versican transcription in HeLa cells and rat aortic smooth muscle cells (SMC), respectively, suggesting that versican transcription is differentially regulated by the respective mediator and transcription factor in epithelial cells and SMC. In chapter IV, I reveal the role of PI3K/PKB/GSK-3β signaling pathway in regulating versican promoter activity and transcription. Furthermore, I identify that the β-catenin/TCF-4 transcription factor complex, one of the downstream targets of GSK-3β, mediates versican promoter activity and transcription. In chapter V, I identify that variations in C-terminal regions of TCF family members determine their repressor or enhancer properties on Wnt target genes. Furthermore, I show that curcumin is a strong inhibitor of the β-catenin/TCF-p300 mediated gene expression. In chapter VI, I demonstrate that the androgen receptor trans-activates versican transcription in prostate cancer cells. Furthermore, I show cross-talk between the androgen receptor and β-catenin in regulating versican transcription in prostate stromal fibroblasts. Overall, this study charts previously uncharacterized promoter elements, transcription factors, and signal transduction pathways involved in regulation of the versican gene.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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