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J. Biol. Chem., Vol. 280, Issue 9, 7654-7658, March 4, 2005

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The SV40 Large T Antigen Contains a Decoy Phosphodegron That Mediates Its Interactions with Fbw7/hCdc4^*

Markus Welcker and Bruce E. Clurman¶||

From the Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109 and the ^¶Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98104

Cell transformation by simian virus 40 (SV40) results mostly from the highly oncogenic activities of the large T antigen (LT), which corrupts the cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. The most prominent LT targets are the retinoblastoma protein (pRb) and p53. Here we report that LT binds directly to Fbw7, the substrate recognition component of the SCF^Fbw7 ubiquitin ligase and a human tumor suppressor. LT binding mislocalizes the nucleolar Fbw7 isoform to the nucleoplasm. Interestingly, the binding of LT to Fbw7 occurs via a decoy phospho-epitope within the C terminus of LT that closely mimics the consensus Cdc4 phospho-degron found within Fbw7 substrates. We demonstrate that, using this mode of interaction, LT can interfere with Fbw7-driven cyclin E turnover in vivo and causes increased cyclin E-associated kinase activity. Our data suggest that LT competes with cellular proteins for Fbw7 binding in a substrate-like fashion.

Received for publication, November 29, 2004

^* This work was supported by NCI (National Institutes of Health) Grants RO1CA84069 and RO1CA102742 (to B. E. C.) and by the Leukemia and Lymphoma Society (to M. W.). 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.

This article was selected as a Paper of the Week.

^|| A W. M. Keck Distinguished Young Investigator in Medical Research. To whom correspondence should be addressed: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109. Tel.: 206-667-4524; Fax: 206-667-5255; E-mail: bclurman{at}fhcrc.org.

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