HUMAN PAPILLOMAVIRUS TYPE-11 AND TYPE-16 E5 REPRESSES P(21WAFI SDII/CIPI) GENE-EXPRESSION IN FIBROBLASTS AND KERATINOCYTES/

Here we report that the E5 proteins of human papillomavirus type 11 (H PV-11) and HPV-16 suppressed the expression of the p21(WafI/SdiI/CipI) tumor suppressor gene in NIH 3T3 cells and immortalized human keratin ocytes. The promoter activity of p21 was repressed by E5 of HPV-11 and -16, suggesting that p21 gene suppression by E5 was at the transcript ional level. Using an inducible system, we demonstrated that increased induction of HPV-11 E5 in NIR 3T3 cells and keratinocytes led to incr eased repression of p21 promoter activity. The repression of p21 promo ter activity by a series of E5 mutants was somewhat correlated with th eir respective transforming activities. Previously, we and other inves tigators showed that the E5 proteins of HPV-11 and -16 can activate th e expression of c-jun, The repression of p21 gene expression might be a mechanism of oncogene-mediated growth promotion, since the expressio n of c-jun also led to a reduction of the levels of p21 RNA and protei n in keratinocytes. This is the first demonstration that E5 proteins o f HPV-11 and -16 repress p21 gene expression, and this might be one of the mechanisms by which E5 stimulates cell proliferation. In addition , this is also the first report of c-jun repression of p21.