Research Papers:
Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation
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Abstract
Zunamys I. Carrero1, Madhusudhan Kollareddy1,2, Krishna M. Chauhan1,2, Gopalakrishnan Ramakrishnan1,2, Luis A. Martinez3
1Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS 39216, USA
2Cancer Institute, University of Mississippi, Jackson, MS 39216, USA
3Department of Pathology and Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
Correspondence to:
Luis A. Martinez, e-mail: [email protected]
Keywords: erythroblastosis virusE26 oncogene homologue 2 (ETS2), mutant p53, constitutive photomorphogenesis protein 1 (COP1), de-etiolated 1 (DET1), protein stability
Received: August 24, 2015 Accepted: January 22, 2016 Published: February 09, 2016
ABSTRACT
Mutations in the tumor suppressor gene TP53 contribute to the development of approximately half of all human cancers. One mechanism by which mutant p53 (mtp53) acts is through interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with the erythroblastosis virus E26 oncogene homologue 2 (ETS2), an ETS transcription factor, and increases its protein stability. To study the mechanism underlying ETS2 degradation, we knocked down ubiquitin ligases known to interact with ETS2. We observed that knockdown of the constitutive photomorphogenesis protein 1 (COP1) and its binding partner De-etiolated 1 (DET1) significantly increased ETS2 stability, and conversely, their ectopic expression led to increased ETS2 ubiquitination and degradation. Surprisingly, we observed that DET1 binds to ETS2 independently of COP1, and we demonstrated that mutation of multiple sites required for ETS2 degradation abrogated the interaction between DET1 and ETS2. Furthermore, we demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Mechanistically, we show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. Our study reveals a hitherto unknown function in which DET1 mediates the interaction with the substrates of its cognate ubiquitin ligase complex and provides an explanation for the ability of mtp53 to protect ETS2.
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PII: 7275