title: Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation.
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.
authors.affiliation: Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Zunamys I
authors.initials: ZI
authors.lastname: Carrero
authors.affiliation: Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS 39216, USA.|Cancer Institute, University of Mississippi, Jackson, MS 39216, USA.
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Kollareddy
authors.affiliation: Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS 39216, USA.|Cancer Institute, University of Mississippi, Jackson, MS 39216, USA.
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Chauhan
authors.affiliation: Department of Biochemistry, The University of Mississippi Medical Center, Jackson, MS 39216, USA.|Cancer Institute, University of Mississippi, Jackson, MS 39216, USA.
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Ramakrishnan
authors.affiliation: Department of Pathology and Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez
mesh_terms: D000072283:A549 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C482641:DET1 protein, human; C494069:ETS2 protein, human; D050787:Proto-Oncogene Protein c-ets-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: constitutive photomorphogenesis protein 1 (COP1); de-etiolated 1 (DET1); erythroblastosis virusE26 oncogene homologue 2 (ETS2); mutant p53; protein stability