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J. Biol. Chem., Vol. 280, Issue 50, 41553-41561, December 16, 2005

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Human Kruppel-like Factor 5 Is a Target of the E3 Ubiquitin Ligase WWP1 for Proteolysis in Epithelial Cells^*

Ceshi Chen, Xiaodong Sun, Peng Guo, Xue-Yuan Dong, Pooja Sethi, Xiaohong Cheng, Jun Zhou, Junxiu Ling, Jonathan W. Simons, Jerry B. Lingrel¶, and Jin-Tang Dong||1

From the Winship Cancer Institute and Department of Hematology and Oncology and the ^||Department of Urology and Program in Genetics and Molecular Biology, Emory University School of Medicine, Atlanta, Georgia 30322, the Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 300071 Tianjin, China, and the ^¶Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45221

The transcription factor KLF5 plays an important role in human carcinogenesis. In epithelial cells, the KLF5 protein is tightly regulated by the ubiquitin-proteasome pathway. To better understand the mechanisms for the regulation of KLF5 protein, we identified and characterized an E3 ubiquitin ligase for KLF5, i.e. WWP1. We found that WWP1 formed a protein complex with KLF5 in vivo and in vitro. Furthermore, WWP1 mediated the ubiquitination and degradation of KLF5, and the catalytic cysteine residue of WWP1 is essential for its function. A PY motif in a transactivation domain of KLF5 is necessary for its interaction with WWP1. Finally, WWP1 was amplified and overexpressed in some cancer cell lines from the prostate and breast, which negatively regulated the function of KLF5 in gene regulation. These findings not only established WWP1 as an E3 ubiquitin ligase for KLF5, they also further implicated the KLF5 pathway in human carcinogenesis.

Received for publication, June 7, 2005 , and in revised form, September 28, 2005.

^* This work was supported in part by the American Foundation for Urologic Disease (AFUD)/American Urological Association (AUA) Research Scholar Program, by Grant CA87921 from the NCI, National Institutes of Health, by Grant DAMD17-03-2-0033 from the Department of Defense Prostate Cancer Research Program, by the Georgia Cancer Coalition, and by the Susan G. Komen Breast Cancer Foundation. 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.

¹ To whom correspondence should be addressed. E-mail: jin-tang.dong{at}emory.edu.

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