Human papillomavirus type 11 and 16 E5 represses p21(WafI/SdiI/CipI) gene expression in fibroblasts and keratinocytes

Abstract

Here we report that the E5 proteins of human papillomavirus type 11 (HPV-11) and HPV-16 suppressed the expression of the p21 WafI/SdiI/CipI tumor suppressor gene in NIH 3T3 cells and immortalized human keratinocytes. The promoter activity of p21 was repressed by E5 of HPV-11 and-16, suggesting that p21 gene suppression by E5 was at the transcriptional level. Using an inducible system, we demonstrated that increased induction of HPV-11 E5 in NIH 3T3 cells and keratinocytes led to increased repression of p21 promoter activity. The repression of p21 promoter activity by a series of E5 mutants was somewhat correlated with their respective transforming activities. Previously, we and other investigators showed that the E5 proteins of HPV-11 and-16 can activate the expression of c-jun. The repression of p21 gene expression might be a mechanism of oncogene-mediated growth promotion, since the expression of c-jun also led to a reduction of the levels of p21 RNA and protein in keratinocytes. This is the first demonstration that E5 proteins of 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.

Modulation of apoptosis by human papillomavirus (HPV) oncoproteins

“…Indeed, prior to integration, when the HPV genome is episomal, the E5 mRNA is the most abundant viral transcript [74]. E5 has also been reported to inhibit the expression of the p21 tumor suppressor [88], which suggest that it may co-operate with E6 and E7 to transform keratinocytes. Interestingly, the E5 protein has been shown to protect HaCat keratinocytes from both Fas-and TRAIL-mediated apoptosis, albeit by different mechanisms [40].…”

HPV16/18 E5, a promising candidate for cervical cancer vaccines, affects SCPs, cell proliferation and cell cycle, and forms a potential network with E6 and E7

“…7). E5 might promote cell proliferation in this way (23). A previous study (24) indicated that intradermal injection of cottontail rabbit papillomavirus DNA, a virus with a natural history of infection similar to that of HPV-16 but with mutations in E7 of critical residues for the binding of pRb, can still induce papilloma formations in rabbits.…”

“…(e) E6 proteins increase the turnover of p53, which leads to abrogation of p21-mediated or P21 unrelated G1/S arrest in response to DNA-damaging agents (22). (f) The keratinocytes expressing E7 alone also fail to undergo a G1/S arrest, not directly via p21 suppression but through deregulation of E2F activity (23). Notably, all the details about E5, E6 and E7 can rescue G1 arrest and promote S phase entry in different ways, forming a potential network.…”

Effect of HCMV IE86 on the Expression of p21 in Malignant Glioma Cells

“…Early studies showed that HPV16 E5 can inhibit the activity of p21 gene promoter and downregulate its expression level. P21 is a key protein regulating cell cycle progression, and its downregulation eventually leads to accelerated cell growth and malignant proliferation [23]. However, studies on the effects of HCMV IE86 on p53 and its downstream gene p21 have been rarely reported.…”