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J. Biol. Chem., Vol. 280, Issue 16, 15497-15502, April 22, 2005

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Phosphorylated Retinoblastoma Protein Complexes with pp32 and Inhibits pp32-mediated Apoptosis^*

Onikepe Adegbola and Gary R. Pasternack

From the Division of Molecular Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The retinoblastoma gene product (Rb) is a tumor suppressor that affects apoptosis paradoxically. Most sporadic cancers inactivate Rb by preferentially targeting the pathway that regulates Rb phosphorylation, resulting in resistance to apoptosis; this contrasts with Rb inactivation by mutation, which is associated with high rates of apoptosis. How phosphorylated Rb protects cells from apoptosis is not well understood, but there is evidence that Rb may sequester a pro-apoptotic nuclear factor. pp32 (ANP32A) is a pro-apoptotic nuclear phosphoprotein, the expression of which is commonly increased in cancer. We report that hyperphosphorylated Rb interacts with pp32 but not with the closely related proteins pp32r1 and pp32r2. We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation. These results suggest a mechanism whereby cancer cells gain both a proliferative and survival advantage when Rb is inactivated by hyperphosphorylation.

Received for publication, October 5, 2004 , and in revised form, February 3, 2005.

^* This work was supported in part by United States Army Medical Research and Materiel Command Prostate Cancer Research Program Grant W81XWH-04-1-0270 and a grant from the Merck/United Negro College Fund program (to O. A.). 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.

Supported by National Institutes of Health Training Grant T32CA67751.

To whom correspondence should be addressed: Dept. of Pathology, The Johns Hopkins University School of Medicine, 417 N. Caroline St., Rm. B300, Baltimore, MD 21231. Tel.: 410-955-7402; Fax: 410-502-5158; E-mail: gpastern{at}jhmi.edu.

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