Investigating the relationship between UbcH10 and the anaphase promoting complex/cyclosome

Foster, Jessica (2018). Investigating the relationship between UbcH10 and the anaphase promoting complex/cyclosome. University of Birmingham. Ph.D.

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UbcH10 functions as an E2-conjugating enzyme for the Anaphase-Promoting Complex/Cyclosome (APC/C) E3-ubiquitin ligase, and helps to facilitate the APC/C-dependent ubiquitylation of substrates during mitosis and G1. UbcH10 is also a proto-oncogene product that is overexpressed in a number of human cancers. Despite its ability to promote APC/C ubiquitin ligase activity, and initiate tumourigenesis, very little is known about the UbcH10 interactome. Here we used immunoprecipitations-coupled to mass spectrometry to identify the UbcH10 interactome in HeLa and RPE-1 cells. Of those proteins identified, Geminin and Cdt1 have been determined previously to be APC/C substrates.

Further studies confirmed that PDZ-RhoGEF was a novel UbcH10-interacting protein, and identified PDZ-RhoGEF as a novel APC/C substrate. PDZ-RhoGEF was shown to be degraded in early mitosis in a SAC-insensitive manner, whilst overexpression of wild-type (WT) UbcH10 was shown to induce the premature degradation of PDZ-RhoGEF. ASPP1 and ASPP2 were also shown to interact with UbcH10 and be targeted for degradation by the APC/C in a SAC-sensitive manner; over expression of WT UbcH10 induced the premature degradation of both ASPP1 and ASPP2. ASPP2 was shown to be a substrate for APC/C-targeted ubiquitylation, whilst an ASPP2 species lackinf APC/C degrons stimulated p53 transcriptional activity better than WT ASPP2.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer and Genomic Sciences
Funders: Medical Research Council
Subjects: Q Science > QR Microbiology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)


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