EMBL Keynote Lecture - Ubiquitin mediated regulation of transcription factor stability, Vishva Dixit

Presenter: Vishva Dixit, Genentech, SA

From the EMBL–Wellcome Genome Campus Conference: Proteomics in Cell Biology and Disease Mechanisms
EMBL Advanced Training Centre Heidelberg, Germany
7 – 9 March 2019

Proto-oncogenes ETV1, ETV4, and ETV5 belong to the PEA3 family of ETS transcription factors and have been identified recently in prostate cancer chromosomal rearrangements that result in their overexpression. Little is known, however, about their post-translational regulation. We previously showed that ETV1, ETV4, and ETV5 interact with the ubiquitin ligase COP1. COP1 together with its binding partner DET1 ubiquitinates ETV1, resulting in its proteasomal degradation. Importantly, truncation of ETV1 by the TMPRSS2:ETV1 translocation found in prostate cancer removes its COP1 binding motif and thereby enhances its stability. Consistent with a critical role for COP1 in regulating PEA3 transcription factors,COP1 deficiency in primary mouse prostate cells produced prostate intraepithelial neoplasia invivo. The relationship between COP1 and ETV1 was also evident in human prostate cancer samples where loss of COP1 expression correlated with elevated ETV1 protein. I will discuss unpublished work that underscores the importance of COP1 as a tumor suppressor in melanoma.

References:
[1]. Wertz I, O’Rourke K, Zhang Z, Dornan D, Arnott D, Deshaies R, and Dixit VM (2004). Human De-Etiolated-1 Regulates c-Jun by Assembling a CUL4A Ubiquitin Ligase. Science 303: 1371-1374.
[2] Vitari AC, Leong KG, Newton K,Yee C, O’Rourke K, Liu J, Phu L, Vij R, Ferrando R, Couto SS, Mohan S, Pandita A, Hongo J-A, Arnott D, Gao W-Q, French DM, and Dixit V (2011) COP1 is a Tumor Suppressor that Causes Deregulation of Proto-oncogenic ETS Transcription Factors. Nature 474: 403-408.
[3] Suriben R, Kaihara KA, Reichelt M, Kummerfeld SK, Modrusan Z, Dugger DL, Newton K, Webster JD, Liu J, Hebrok M, Dixit VM (2015). β-cell insulin secretion requires the ubiquitin ligase COP1. Cell 163: 1457-1467.

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