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J. Biol. Chem., Vol. 279, Issue 19, 20035-20043, May 7, 2004

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MDM2 Mediates p300/CREB-binding Protein-associated Factor Ubiquitination and Degradation^*

Yetao Jin, Shelya X. Zeng, Hunjoo Lee, and Hua Lu

From the Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239

We recently reported that MDM2, a negative feedback regulator of the tumor suppressor p53, inhibits p300/CREB-binding protein-associated factor (PCAF)-mediated p53 acetylation. Our further study showed that MDM2 also regulates the stability of PCAF. MDM2 ubiquitinated PCAF in vitro and in cells. PCAF ubiquitination occurred at the N terminus and in the nucleus, as the nuclear localization signal sequence-deletion mutant of MDM2, which localized in the cytoplasm and degraded p53, was unable to degrade nuclear PCAF. Restriction of PCAF in the nucleus by leptomycin B did not affect MDM2-mediated PCAF degradation. Consistently, overexpression of MDM2 in p53 null cells caused the reduction of the protein level of PCAF, but not the mRNA level. Conversely, PCAF levels were higher in MDM2-deficient mouse p53^-/-/mdm2^-/- embryonic fibroblast (MEF) cells than that in MDM2-containing MEF cells. Furthermore, MDM2 reduced the half-life of PCAF by 50%. These results demonstrate that MDM2 regulates the stability of PCAF by ubiquitinating and degrading this protein.

Received for publication, September 8, 2003 , and in revised form, February 7, 2004.

^* This work was supported by National Institutes of Health Grants CA95441, CA079721, and CA93614 (to H. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-7414; Fax: 503-494-8393; E-mail: luh{at}ohsu.edu.

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