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SUMMARY:Shedding light on Ubiquitin Modification in Cancer. - Vishva Dixit
 \, Genentech
DTSTART:20120612T151500Z
DTEND:20120612T170000Z
UID:TALK37938@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:COP1 (constitutively photometric 1) and DET (De-Etiolated) fun
 ction to repress plant photomorphogenesis\, the light mediated program of 
 plant development. Mutants of COP1 and DET are constitutively photomorphog
 enic\, and this has been attributed to their inability to negatively regul
 ate (degrade) the plant transcription factors LAF1 and HY5.\n\nThe role of
  COP1 and DET in mammalian cells is less well characterized. We previously
  found that COP1\, promotes ubiquitination and degradation of the proto-on
 cogenic 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).\n\nRecent studies suggest t
 hat the proto-oncogenes ETV1\, ETV4\, and ETV5 that belong to the PEA3 fam
 ily of ETS transcription factors are also substrates for the COP1 E-3 liga
 se complex. The critical role of ETS transcription factors in human malign
 ancy is underscored by the finding that they are commonly subject to chrom
 osomal rearrangements in prostate cancer. This rearrangement results in th
 eir dysregulated overexpression.  Little is known\, however\, about their 
 post-translational regulation.   We found that COP1\, together with its bi
 nding partner DET1\, ubiquitinated members of the PEA3 family\, resulting 
 in their proteasomal degradation.  Importantly\, we discovered that trunca
 tion by the cancer associated translocations removed the COP1 binding moti
 f (degron) and thereby enhanced stability.  Consistent with a critical rol
 e for COP1 in regulating PEA3 transcription factors\, COP1 deficiency in p
 rimary mouse prostate cells produced prostate intraepithelial neoplasia in
  vivo.  The relationship between COP1 and ETV1 was also evident in human p
 rostate cancer samples where loss of COP1 expression correlated with eleva
 ted ETV1 protein.\n\nIn closing I’ll discuss the importance of the COP/P
 EA3 axis in Ras driven colon cancer.
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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