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J. Biol. Chem., Vol. 280, Issue 39, 33165-33177, September 30, 2005

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BRCA1 Interaction with Human Papillomavirus Oncoproteins^*

Yiyu Zhang, Saijun Fan, Qinghui Meng, Yongxian Ma, Pragati Katiyar, Richard Schlegel, and Eliot M. Rosen1

From the Departments of Oncology and Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C. 20057-1469

Previously, we reported that BRCA1 strongly represses the transcriptional activity of estrogen receptor- (ER-) in human breast and prostate cancer cells but only weakly inhibits ER- in cervical cancer cells. We now report that introduction of the human papillomavirus E7 or E6 oncogenes into human papillomavirus-negative cells rescues the BRCA1 repression of ER- activity and that the E7 and E6 oncoproteins interact directly with BRCA1 in vitro and associate with BRCA1 in vivo in cultured cells. This interaction involves at least two contact points on BRCA1, one within an N-terminal site shown previously to interact with ER- and the other in a C-terminal region of BRCA1 containing the first BRCA1 C-terminal domain. Point mutations within the zinc finger domains of E7 and E6 inactivated the binding to the N terminus of BRCA1 and reduced their ability to rescue BRCA1 inhibition of ER-. E6 and E7 also antagonized the ability of BRCA1 to inhibit c-Myc E-box-mediated transactivation and human telomerase reverse transcriptase promoter activity, in a manner dependent upon the zinc finger domains. Finally, the ability of E6 and E7 to antagonize BRCA1 did not involve proteolytic degradation of BRCA1. These findings suggest functional interactions of BRCA1 with E7 and E6. The potential significance of these findings is discussed.

Received for publication, May 10, 2005 , and in revised form, June 22, 2005.

^* This work was supported in part by United States Public Health Service Grants R01-CA80000, R01-CA82599, and R01-ES09169 and by Research Grants BASIC99–003255 and BCTR0201295 from the Susan G. Komen Breast Cancer Foundation (to E. M. R.). 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: Dept. of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Preclinical Sciences Bldg., Rm. GM12B, 3970 Reservoir Rd., NW, Box 571469, Washington D. C. 20057. Tel.: 202-687-7695; Fax: 202-787-7256; E-mail: emr36{at}georgetown.edu.

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