Shedding light on Ubiquitin Modification in Cancer.

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• Vishva Dixit, Genentech
• Tuesday 12 June 2012, 16:15-18:00
• Max Perutz Lecture Theatre, Medical Research Council (MRC) (MRC Laboratory of Molecular Biol.

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COP1 (constitutively photometric 1) and DET (De-Etiolated) function to repress plant photomorphogenesis, the light mediated program of plant development. Mutants of COP1 and DET are constitutively photomorphogenic, and this has been attributed to their inability to negatively regulate (degrade) the plant transcription factors LAF1 and HY5 .

The role of COP1 and DET in mammalian cells is less well characterized. We previously found that COP1 , promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing human DET , DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A) and Regulator of Cullins-1 (ROC1).

Recent studies suggest that the proto-oncogenes ETV1 , ETV4, and ETV5 that belong to the PEA3 family of ETS transcription factors are also substrates for the COP1 E -3 ligase complex. The critical role of ETS transcription factors in human malignancy is underscored by the finding that they are commonly subject to chromosomal rearrangements in prostate cancer. This rearrangement results in their dysregulated overexpression. Little is known, however, about their post-translational regulation. We found that COP1 , together with its binding partner DET1 , ubiquitinated members of the PEA3 family, resulting in their proteasomal degradation. Importantly, we discovered that truncation by the cancer associated translocations removed the COP1 binding motif (degron) and thereby enhanced stability. Consistent with a critical role for COP1 in regulating PEA3 transcription factors, COP1 deficiency in primary mouse prostate cells produced prostate intraepithelial neoplasia in vivo. The relationship between COP1 and ETV1 was also evident in human prostate cancer samples where loss of COP1 expression correlated with elevated ETV1 protein.

In closing I’ll discuss the importance of the COP /PEA3 axis in Ras driven colon cancer.

This talk is part of the MRC LMB Seminar Series series.

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