The E7 oncoprotein of human papillomavirus type 16 stabilizes p53 through a mechanism independent of p19(ARF)

High-risk human papillomaviruses are causally associated,vith cervical cant er. Two viral oncogenes, E6 and E7, are expressed in most cervical cancers, and these genes cause cancer when expressed in experimental animals. The E 6 protein targets the p53 tumor suppressor for degradation, while the E7 pr otein inactivates the retinoblastoma susceptibility protein (pRb), in part by stimulating its degradation. In contrast, expression of E7 in the absenc e of E6 leads to stabilization of p53. Here we show that E7 stabilizes p53 in mouse embryo fibroblasts lacking p19(ARF) 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 a n autoregulatory loop. Regulation of p53 by MDM2 is required for murine dev elopment as well as for proliferation of cultured human fibroblasts. Howeve r, E7-expressing human fibroblasts continue to divide even though E7 abroga tes the ability of MDM2 and p53 to bind. Furthermore, E7-expressing cells a re not more sensitive to UV light, an agent that has been reported to induc e apoptosis mediated by p53. These results indicate that in addition to inh ibiting the ability of MDM2 to regulate p53, E7 must block signaling steps downstream of p53 to allow cell division.