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J. Biol. Chem., Vol. 283, Issue 1, 66-75, January 4, 2008

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SCF^βTrCP1 Activates and Ubiquitylates TAp63^*

Jayme R. Gallegos¹, Joel Litersky, Hunjoo Lee, Yi Sun, Keiichi Nakayama^¶||, Keiko Nakayama^¶**, and Hua Lu²

From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239, the Department of Biochemistry and Molecular Biology, University of Indiana, Indianapolis, Indiana 46202, the Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, the ^¶Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan, ^||CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan, and the ^**Department of Developmental Biology, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan

p63 is a member of the p53 tumor suppressor family that is critical for epithelial differentiation and also has an important role in cancer progression. Currently, the molecular mechanisms governing regulation of p63 function remain largely unclear. This study identifies a unique E3 ubiquitin ligase for p63, SCF^βTrCP1. SCF^βTrCP1 is able to bind p63 isoforms, with a higher affinity for the TAp63 isoform. Strikingly, co-expression of TAp63 and βTrCP1 leads to the stabilization of TAp63. This stabilization of TAp63 leads to up-regulation of p21 at the mRNA and protein level by increased binding of TAp63 at the p21 promoter. The up-regulation of p21 causes a subsequent increase in G₁ phase cell cycle arrest. Last, SCF^βTrCP1 is able to ubiquitylate TAp63, and this ubiquitylation, as well as the increased activity of TAp63, is ablated with the expression of a ubiquitin-deficient mutant of βTrCP1 (FβTrCP1). Therefore, our study reveals that SCF^βTrCP1 is an E3 ligase that activates p63 through ubiquitylation.

Received for publication, June 7, 2007 , and in revised form, October 26, 2007.

^* This work is supported in part by NCI, National Institutes of Health Grants CA 93614, CA 095441, and CA 079721 (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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Recipient of funding from an Oregon Health and Science University Department of Dermatology predoctoral fellowship (National Institutes of Health) and an Oregon Health and Science University Ophthalmology and Immunology predoctoral research fellowship (National Institutes of Health).

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Indiana, 635 Barnhill Dr., MS 4053, Indianapolis, IN 46202. Tel.: 317-278-0920; E-mail: hualu{at}iupui.edu.

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