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J. Biol. Chem., Vol. 282, Issue 36, 26381-26391, September 7, 2007

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RbAp48 Is a Critical Mediator Controlling the Transforming Activity of Human Papillomavirus Type 16 in Cervical Cancer^*

Li Kong, Xiu-Ping Yu^¶1, Xiao-Hui Bai, Wei-Fang Zhang, Yan Zhang, Wei-Ming Zhao, Ji-Hui Jia^¶, Wei Tang, Ya-Bin Zhou, and Chuan-ju Liu^||2

From the Department of Orthopaedic Surgery, New York University Medical Center, New York, New York 10003, the Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China, the ^¶Key Laboratory of Experimental Teratology, Chinese Ministry of Education, Jinan, Shandong 250012 China, and the ^||Department of Cell Biology, New York University School of Medicine, New York, New York 10016

Although human papillomavirus (HPV) infections are the primary cause of cervical cancer, the molecular mechanism by which HPV induces cervical cancer remains largely unclear. We used two-dimensional electrophoresis with mass spectrometry to study protein expression profiling between HPV16-positive cervical mucosa epithelial H8 cells and cervical cancer Caski cells to identify 18 differentially expressed proteins. Among them, retinoblastoma-binding protein 4 (RbAp48) was selected, and its differentiation expression was verified with both additional cervical cancer-derived cell lines and human tissues of cervical intraepithelial neoplasia and cervical cancer. Suppression of RbAp48 using small interfering RNA approach in H8 cells significantly stimulated cell proliferation and colony formation and inhibited senescence-like phenotype. Remarkably, H8 cells acquired transforming activity if RpAp48 was suppressed, because H8 cells stably transfected with RbAp48 small interfering RNA led to tumor formation in nude mice. In addition, overexpression of RbAp48 significantly inhibited cell growth and tumor formation. This RbAp48-mediated transformation of HPV16 is probably because of the regulation by RbAp48 of tumor suppressors retinoblastoma and p53, apoptosis-related enzymes caspase-3 and caspase-8, and oncogenic genes, including E6, E7, cyclin D1 (CCND1), and c-MYC. In brief, RbAp48, previously unknown in cervical carcinogenesis, was isolated in a global screen and identified as a critical mediator controlling the transforming activity of HPV16 in cervical cancer.

Received for publication, March 13, 2007 , and in revised form, June 29, 2007.

^* This work was supported by National Institutes of Health Research Grants AR052022 (to C. L.) and AR050620 (to C. L.), by the National Natural Science Foundation of China Grant 30370064 (to X. P. Y.), and the Higher Education Doctoral Degree Special Research Foundation Grant 20030422053 (to X. P. Y.). 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 Tables 1S and 2S.

¹ To whom correspondence may be addressed. Tel.: 86-531-88382579; E-mail: yuxp{at}sdu.edu.cn. ² To whom correspondence may be addressed: Dept. of Orthopaedic Surgery and Dept. of Cell Biology, New York University School of Medicine, 301 East 17th St., New York, NY 10003. Tel.: 212-598-6103; Fax: 212-598-6096; E-mail: chuanju.liu{at}med.nyu.edu.

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