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Journal of Virology, September 1999, p. 7590-7598, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The E7 Oncoprotein of Human Papillomavirus Type 16 Stabilizes p53 through a Mechanism Independent of p19ARF

Scott E. Seavey, Marisa Holubar, Leslie J. Saucedo, and Mary Ellen Perry*

Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

Received 24 May 1999/Accepted 11 June 1999

High-risk human papillomaviruses are causally associated with cervical cancer. Two viral oncogenes, E6 and E7, are expressed in most cervical cancers, and these genes cause cancer when expressed in experimental animals. The E6 protein targets the p53 tumor suppressor for degradation, while the E7 protein inactivates the retinoblastoma susceptibility protein (pRb), in part by stimulating its degradation. In contrast, expression of E7 in the absence of E6 leads to stabilization of p53. Here we show that E7 stabilizes p53 in mouse embryo fibroblasts lacking p19ARF. The stable p53 is active as a transcriptional activator, as evidenced by the increased expression of the p53-responsive mdm2 gene. Normally, MDM2 protein inhibits p53 function in an autoregulatory loop. Regulation of p53 by MDM2 is required for murine development as well as for proliferation of cultured human fibroblasts. However, E7-expressing human fibroblasts continue to divide even though E7 abrogates the ability of MDM2 and p53 to bind. Furthermore, E7-expressing cells are not more sensitive to UV light, an agent that has been reported to induce apoptosis mediated by p53. These results indicate that in addition to inhibiting the ability of MDM2 to regulate p53, E7 must block signaling steps downstream of p53 to allow cell division.

* Corresponding author. Mailing address: 207A McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Ave., Madison, WI 53706. Phone: (608) 265-5537. Fax: (608) 262-2824. E-mail: perry{at}oncology.wisc.edu.

Journal of Virology, September 1999, p. 7590-7598, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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