Human papillomavirus type 16 E6 promotes retinoblastoma protein phosphorylation and cell cycle progression.
We show that E6 proteins from benign human papillomavirus type 1 (HPV1) and oncogenic HPV16 have the ability to alter the regulation of the G(1)/S transition of the cell cycle in primary human fibroblasts. Overexpression of both viral proteins induces cellular proliferation, retinoblastoma (pRb) phosphorylation, and accumulation of products of genes that are negatively regulated by pRb, such as p16(INK4a), CDC2, E2F-1, and cyclin A. Hyperphosphorylated forms of pRb are present in E6-expressing cells even in the presence of ectopic levels of p16(INK4a). The E6 proteins strongly increased the cyclin A/cyclin-dependent kinase 2 (CDK2) activity, which is involved in pRb phosphorylation. In addition, mRNA and protein levels of the CDK2 inhibitor p21(WAF1/CIP1) were strongly down-regulated in cells expressing E6 proteins. The down-regulation of the p21(WAF1/CIP1) gene appears to be independent of p53 inactivation, since HPV1 E6 and an HPV16 E6 mutant unable to target p53 were fully competent in decreasing p21(WAF1/CIP1) levels. E6 from HPV1 and HPV16 also enabled cells to overcome the G(1) arrest imposed by oncogenic ras. Immunofluorescence staining of cells coexpressing ras and E6 from either HPV16 or HPV1 revealed that antiproliferative (p16(INK4a)) and proliferative (Ki67) markers were coexpressed in the same cells. Together, these data underline a novel activity of E6 that is not mediated by inactivation of p53.
Malanchi
Ilaria
I
Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, 69372 Lyon cedex 08, France.
Accardi
Rosita
R
Diehl
Frank
F
Smet
Anouk
A
Androphy
Elliot
E
Hoheisel
Jörg
J
Tommasino
Massimo
M
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009061:Mouth Mucosa / Q000166:cytology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase
C068651:E6 protein, Human papillomavirus type 16; C466080:E6 protein, human papillomavirus type 1; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016160:Retinoblastoma Protein