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Molecular and Cellular Biology, June 2001, p. 3974-3985, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.3974-3985.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Corepressor mSin3a Interacts with the Proline-Rich Domain of p53 and Protects p53 from Proteasome-Mediated Degradation

Jack T. Zilfou,1 William H. Hoffman,1 Michael Sank,2 Donna L. George,2 and Maureen Murphy1,*

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia Pennsylvania 19111,1 and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042

Received 2 November 2000/Returned for modification 22 December 2000/Accepted 19 March 2001

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 p14ARF, 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.

* Corresponding author. Mailing address: Department of Pharmacology, Fox Chase Cancer Center,7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-5684. Fax: (215) 728-4333. E-mail: ME_Murphy{at}FCCC.edu.

Molecular and Cellular Biology, June 2001, p. 3974-3985, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.3974-3985.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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