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WTX is a novel regulator of ubiquitination in the Wnt/beta-catenin and KEAP1/NRF2 pathways

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dc.contributor.advisor Moon, Randall T en_US Camp, Nathan en_US 2012-08-10T17:37:54Z 2012-08-10T17:37:54Z 2012-08-10 2012 en_US
dc.identifier.other Camp_washington_0250E_10063.pdf en_US
dc.description Thesis (Ph.D.)--University of Washington, 2012 en_US
dc.description.abstract Ubiquitination of proteins and subsequent proteosome-mediated degradation is one mechanism cells use to regulate protein steady-state levels. This essential process permits cells to rapidly respond to extracellular cues or cytotoxic insult, through selective modulation of intracellular signaling cascades. For example, the Wnt/beta-catenin pathway is controlled by ubuitination. In the absence of a WNT ligand, the transcription factor beta-catenin is directed to the SCFBTRC E3 ubiquitin ligase complex where it is poly-ubiqutinated. Poly-ubiquitinated beta-catenin is then recognized and rapidly degraded by the proteosome. WNT ligand binding to its cognate receptor prevents beta-catenin ubiquitination, allowing it to circumvent proteasome degradation, accumulate in the nucleus and drive transcription of genes required for proliferation and differentiation. My research investigated the functional roles of a novel regulator of the Wnt/beta-catenin pathway, Wilms Tumor gene on the X-chromosome (WTX). My study revealed that WTX interacts with two E3 ubiquitin ligase adaptors, BTRC and KEAP1. The WTX/BTRC complex promoted -catenin ubiquitination, while the WTX/KEAP1 complex inhibited ubiquitination of the stress response transcription factor NRF2). Mutations in WTX have been proposed to the cause of Wilms tumor, the most common form of pediatric kidney cancer. Therefore, the results of my thesis provide a mechanism explaining how mutations in WTX cause disease, and provide potential solutions to treating this disorder. en_US
dc.format.mimetype application/pdf en_US
dc.language.iso en_US en_US
dc.rights Copyright is held by the individual authors. en_US
dc.subject en_US
dc.subject.other Molecular biology en_US
dc.subject.other Pharmacology en_US
dc.title WTX is a novel regulator of ubiquitination in the Wnt/beta-catenin and KEAP1/NRF2 pathways en_US
dc.type Thesis en_US
dc.embargo.terms No embargo en_US

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