Human papillomavirus type 16 E6 promotes retinoblastoma protein phosphorylation and cell cycle progression

Ilaria Malanchi, Rosita Accardi, Frank Diehl, Anouk Smet, Elliot Androphy, Jörg Hoheisel, Massimo Tommasino

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

We show that E6 proteins from benign human papillomavirus type 1 (HPV1) and oncogenic HPV16 have the ability to alter the regulation of the G1/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 p16INK4a, CDC2, E2F-1, and cyclin A. Hyperphosphorylated forms of pRb are present in E6-expressing cells even in the presence of ectopic levels of p16INK4a. 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 p21WAF1/CIP1 were strongly down-regulated in cells expressing E6 proteins. The down-regulation of the p21WAF1/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 G1 arrest imposed by oncogenic ras. Immunofluorescence staining of cells coexpressing ras and E6 from either HPV16 or HPV1 revealed that antiproliferative (p16INK4a) 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.

Original languageEnglish (US)
Pages (from-to)13769-13778
Number of pages10
JournalJournal of virology
Volume78
Issue number24
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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