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" The Regulation of Epithelial-Mesenchymal Transition by the Ubiquitin-Proteasome System "
Garcia, Daniel Abraham
Chang, John T
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Latin Dissertation
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English
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| Record Number
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898115
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TL7jh563pn
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| Main Entry
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Walkington, Lori M.
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| Title & Author
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The Regulation of Epithelial-Mesenchymal Transition by the Ubiquitin-Proteasome System\ Garcia, Daniel AbrahamChang, John T
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| Date
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2018
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2018
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| Abstract
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Epithelial-mesenchymal transition (EMT) is a conserved cellular plasticity program that is reactivated in carcinoma cells and drives metastasis. EMT is well studied, but its regulatory mechanisms remain unclear. In this dissertation, we explore two ways in which the ubiquitin-proteasome system regulates EMT. First, we investigate the role of the 26S proteasome in regulating EMT. In Chapters 1-2, we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy. Second, we explore potential novel regulators of EMT within the ubiquitin-proteasome system pathway. In Chapters 3-4, we uncover novel regulators of EMT by mining previously published microarray data and found a group of deubiquitinases (DUBs) upregulated in cells that have undergone EMT. Here, we show that one DUB in particular, Ubiquitin specific peptidase 11 (USP11), enhances TGF-β-induced EMT and self-renewal in immortalized human mammary epithelial cells. Furthermore, modulating USP11 expression in human breast cancer cell lines altered migratory capacity in vitro and metastasis in vivo. Moreover, we found that high USP11 expression in human breast cancer patient clinical samples correlated with decreased survival. Mechanistically, modulating USP11 expression altered the stability of TGF-β receptor type 2 (TGFBR2) and TGF-β downstream signaling in human breast cancer cell lines. Together, these data suggest that deubiquitination of TGFBR2 by USP11, effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis and suggest USP11 as a potential therapeutic target for breast cancer.
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Garcia, Daniel Abraham
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UC San Diego
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