The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation

While the transactivation function of the tumor suppressor p53 is well unde rstood, less is known about the transrepression functions of this protein. We have previously shown that p53 interacts with the corepressor protein mS in3a (hereafter designated Sin3) in vivo and that this interaction is criti cal for the ability of p53 to repress gene expression. In the present study , we demonstrate that expression of Sin3 results in posttranslational stabi lization of both exogenous and endogenous p53, due to an inhibition of prot easome-mediated degradation of this protein. Stabilization of p53 by Sin3 r equires 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 bin ding and stabilization supports the hypothesis that this domain of p53 may normally be subject to a destabilizing influence. The finding that a synthe tic mutant of p53 lacking the Sin3-binding domain has an increased half-lif e 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 stabil ize 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 effect ive mechanism of gene regulation. This model is consistent with our data in dicating that, unlike the p300-p53 complex, the p53-Sin3 complex is immunol ogically detectable for prolonged periods following exposure of cells to ag ents of DNA damage.