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Degradation of Tob1 Mediated by SCF^Skp2-Dependent Ubiquitination

¹ Second Department of Surgery and ² Department of Biochemistry 1, Hamamatsu University School of Medicine, Hamamatsu, Japan; ³ Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; ⁴ Department of Molecular Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and ⁵ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Requests for reprints: Masatoshi Kitagawa, Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Phone: 81-53-435-2322; Fax: 81-53-435-2322; E-mail: kitamasa{at}hama-med.ac.jp.

Tob1, a member of the Tob/BTG family, is involved in the control of G₁-S progression by suppressing cyclin D1 expression and acts as a tumor suppressor gene. Tob1 was reported to have a quick turnover through the ubiquitin-proteasome pathway, but proteins involved in this process are still unknown. We showed that Skp2, a substrate-targeting subunit of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex, was involved in ubiquitin-dependent degradation of Tob1. Skp2 interacted with Tob1 and facilitated ubiquitination of Tob1 in intact cells as well as in vitro. Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1. Tob1 was stabilized in both Skp2^–/– mouse fibroblasts and Skp2 knockdown HeLa cells. Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells. These data suggest that Tob1 is a novel target for degradation by the SCF-Skp2 ubiquitin ligase. (Cancer Res 2006; 66(17): 8477-83)

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