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J. Biol. Chem., Vol. 278, Issue 47, 46482-46487, November 21, 2003

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SV40 Large T Antigen Promotes Dephosphorylation of p130^*

Jennifer Y. Lin and James A. DeCaprio¶

From the Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts 02115 and Harvard Medical School, Boston, Massachusetts 02115

SV40 large T antigen (Ag) binds to all members of the retinoblastoma (RB) tumor suppressor family including pRb, p107, and p130. Although the LXCXE motif of T Ag binds directly to the RB proteins, it is not sufficient to fully inactivate their function. The N-terminal DNA J domain of T Ag cooperates with the LXCXE motif to override RB-mediated repression of E2F-dependent transcription. In addition, T Ag can reduce the overall phosphorylation state of p107 and p130 that is dependent on an intact J domain and LXCXE motif. However, the mechanism of this activity has not been described. Here we describe the use of a cell-free system to characterize the effect of T Ag on p130 phosphorylation. When incubated in extracts prepared from S phase cells, p130 undergoes specific phosphorylation. Addition of T Ag to S phase extracts leads to a reduction of p130 phosphorylation in vitro. The ability of T Ag to reduce the phosphorylation of p130 in vitro is dependent on an intact DNA J domain and can be inhibited by okadaic acid and PP2A-specific inhibitors. These results suggest that T Ag recruits a phosphatase activity in a DNA J domain-dependent manner to reduce the phosphorylation of p130.

Received for publication, July 2, 2003 , and in revised form, September 5, 2003.

^* This work was supported in part by Grant CA063113 from the NCI, National Institutes of Health. 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: Dana-Farber Cancer Institute, Mayer 457, 44 Binney St., Boston, MA 02115. Tel.: 617-632-3825; Fax: 617-632-4760; E-mail: james_decaprio{at}dfci.harvard.edu.

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