title: The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation.
abstract: While the transactivation function of the tumor suppressor p53 is well understood, less is known about the transrepression functions of this protein. We have previously shown that p53 interacts with the corepressor protein mSin3a (hereafter designated Sin3) in vivo and that this interaction is critical for the ability of p53 to repress gene expression. In the present study, we demonstrate that expression of Sin3 results in posttranslational stabilization of both exogenous and endogenous p53, due to an inhibition of proteasome-mediated degradation of this protein. Stabilization of p53 by Sin3 requires the Sin3-binding domain, determined here to map to the proline-rich region of p53, from amino acids 61 to 75. The correlation between Sin3 binding and stabilization supports the hypothesis that this domain of p53 may normally be subject to a destabilizing influence. The finding that a synthetic mutant of p53 lacking the Sin3-binding domain has an increased half-life in cells, compared to wild-type p53, supports this premise. Interestingly, unlike retinoblastoma tumor suppressor protein, MDMX, and p14(ARF), Sin3 stabilizes p53 in an MDM2-independent manner. The ability of Sin3 to stabilize p53 is consistent with the model whereby these two proteins must exist on a promoter for extended periods, in order for repression to be an effective mechanism of gene regulation. This model is consistent with our data indicating that, unlike the p300-p53 complex, the p53-Sin3 complex is immunologically detectable for prolonged periods following exposure of cells to agents of DNA damage.
authors.affiliation: Department of Pharmacology, Fox Chase Cancer Center, Philadelphia Pennsylvania 19111, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Zilfou
authors.forename: W H
authors.initials: WH
authors.lastname: Hoffman
authors.forename: M
authors.initials: M
authors.lastname: Sank
authors.forename: D L
authors.initials: DL
authors.lastname: George
authors.forename: M
authors.initials: M
authors.lastname: Murphy
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004355:Drug Stability; D006801:Humans; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins; D017354:Point Mutation; D011392:Proline / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D016159:Tumor Suppressor Protein p53; D011392:Proline; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D056264:Sin3 Histone Deacetylase and Corepressor Complex