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J. Biol. Chem., Vol. 278, Issue 44, 43163-43168, October 31, 2003

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Activation of c-Myc Contributes to Bovine Papillomavirus Type 1 E7-induced Cell Proliferation^*

Xueli Fan, Yun Liu, and Jason J. Chen¶

From the Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605-2324

Inactivation of the tumor suppressor pRB by the human papillomavirus (HPV) oncoprotein E7 is a mechanism by which HPV promotes cell growth. The bovine papillomavirus type 1 (BPV-1) E7 does not bind pRB efficiently yet is required for full transformation of murine cells by BPV-1. In the present study, we investigated the mechanism of BPV-1 E7-induced cell proliferation. Our studies indicate that expression of BPV-1 E7 induces DNA synthesis and stimulates cells to enter S phase in quiescent cells. The induction of cell proliferation by BPV-1 E7 can occur in the retinoblastoma gene (Rb)-null cells, suggesting an Rb-independent mechanism. Consistent with this observation, BPV-1 E7 does not efficiently activate the transcription of the E2F family of transcription factors (E2F)-responsive promoters. Notably, c-Myc is able to induce cells to enter S phase in quiescent cells through an Rb/E2F-independent pathway. Significantly, c-Myc levels are increased in BPV-1 E7-expressing cells. Moreover, expression of a dominant negative c-Myc mutant inhibited BPV-1 E7-induced DNA synthesis. Consistent with the notion that c-Myc could down-regulate p27 and activate Cdk2, p27 level is decreased while both cyclin A and cyclin E-associated kinase activities are up-regulated in BPV-1 E7-expressing cells. These studies indicate an important role for c-Myc in BPV-1 E7-induced cell proliferation.

Received for publication, June 9, 2003 , and in revised form, July 29, 2003.

^* This research was supported in part by National Institutes of Health Grant F32 (to Y. L.), the Massachusetts Breast Cancer research grant, and Dermatology Foundation research grant (to J. J. C.). 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.

Present Address: Dept. of Dermatology, Xijing Hospital, The Fourth Military Medical University, 15 West Changle Rd., Xian 710032, China.

Present Address: Dept. of Comparative Genomics, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406.

^¶ To whom correspondence should be addressed: Dept. of Medicine, University of Massachusetts Medical School, NRB Rm. 323, 364 Plantation St., Worcester, MA 01605-2324. Tel.: 508-856-1857; Fax: 508-856-6797; E-mail: jason.chen{at}umassmed.edu.

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