Jong-Sup Park^‡§, Eun-Joo Kim^‡§, Ho-Jeong Kwon^¶, Eun-Seong Hwang^∥, Sung-Eun Namkoong^‡ and Soo-Jong Um^¶**

From the ^‡Department of Obstetrics and Gynecology, Catholic University Medical College, Seoul, 137-040 Korea, the^¶Department of Bioscience and Biotechnology, Sejong University, Seoul, 143-747 Korea, and the ^∥Department of Life Science, University of Seoul, Seoul, 130-743 Korea

Abstract
In studying biological roles of interferon regulatory factor (IRF)-1 tumor suppressor in cervical carcinogenesis, we found that HPV E7 is functionally associated with IRF-1. Binding assays indicate a physical interaction between IRF-1 and HPV E7in vivo and in vitro. The carboxyl-terminal transactivation domain of IRF-1 was required for the interaction. Transient co-expression of E7 significantly inhibits the IRF-1-mediated activation of IFN-β promoter in NIH-3T3 cells. Co-transfection of E7 mutants reveals that the pRb-binding portion of E7 is necessary for the E7-mediated inactivation of IRF-1. It was next determined whether histone deacetylase (HDAC) is involved in the inactivation mechanism as recently suggested, where the carboxyl-terminal zinc finger domain of E7 associates with NURD complex containing HDAC. When trichostatin A, an inhibitor of HDAC, was treated, the repressing activity of E7 was released in a dose-dependent manner. Furthermore, the mutation of zinc finger abrogates such activity without effect on the interaction with IRF-1. These results suggest that HPV E7 interferes with the transactivation function of IRF-1 by recruiting HDAC to the promoter. The immune-promoting role of IRF-1 evokes the idea that our novel finding might be important for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer.

Footnotes
* This study was supported in part by a grant (1999?042-D00102) from the Korean Research Foundation and in part by a grant (1999?1-209?007-5) from KOSEF, Republic of Korea.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

** To whom correspondence should be addressed: Dept. of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul, 143-747, Republic of Korea. Fax: +82-2-595-8774.

Received October 21, 1999.
Revision received January 12, 2000.