Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation

Zunamys I Carrero, Madhusudhan Kollareddy, Krishna M Chauhan, Gopalakrishnan Ramakrishnan, Luis A Martinez

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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.

Original languageEnglish
Pages (from-to)12554-67
Number of pages14
JournalOncotarget
Volume7
Issue number11
Early online date9 Feb 2016
DOIs
Publication statusPublished - 15 Mar 2016

Keywords

  • A549 Cells
  • Carrier Proteins/genetics
  • Gene Knockdown Techniques
  • Genes, p53
  • Humans
  • Mutation
  • Proto-Oncogene Protein c-ets-2/genetics
  • Transfection
  • Tumor Suppressor Protein p53/genetics
  • Ubiquitin-Protein Ligases/genetics

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    Carrero, Z. I., Kollareddy, M., Chauhan, K. M., Ramakrishnan, G., & Martinez, L. A. (2016). Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation. Oncotarget, 7(11), 12554-67. https://doi.org/10.18632/oncotarget.7275