Examination of the pRb-dependent and pRb-independent functions of E7 in vivo

Scott Balsitis, Fred Dick, Denis Lee, Linda Farrell, Ricia K Hyde, Anne E. Griep, Nicholas Dyson, Paul F. Lambert

Research output: Contribution to journalArticle

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Abstract

High-risk human papillomaviruses encode two oncogenes, E6 and E7, expressed in nearly all cervical cancers. Although E7 protein is best known for its ability to inactivate the retinoblastoma tumor suppressor protein, pRb, many other activities for E7 have been proposed in in vitro studies. Herein, we describe studies that allowed us to define unambiguously the pRb-dependent and -independent activities of E7 for the first time in vivo. In these studies, we crossed mice transgenic for human papillomavirus 16 E7 to knock-in mice genetically engineered to express a mutant form of pRb (pRb ΔLXCXE) that is selectively defective for binding E7. pRb inactivation was necessary for E7 to induce DNA synthesis and to overcome differentiation-dependent cell cycle withdrawal and DNA damage-induced cell cycle arrest. While most of E7's effects on epidermal differentiation were found to require pRb inactivation, a modest delay in terminal differentiation with resulting hyperplasia was observed in E7 mice on the RbΔLXCXE mutant background. E7-induced p21 upregulation was also pRb dependent, and genetic Rb inactivation was sufficient to reproduce this effect. While E7-mediated p21 induction was partially p53 dependent, neither p53 nor p21 induction by E7 required p19ARF. These data show that E7 upregulates the expression of p53 and p21 via pRb-dependent mechanisms distinct from the proposed p19-Mdm2 pathway. These results extend our appreciation of the importance of pRb as a relevant target for high-risk E7 oncoproteins.

Original languageEnglish (US)
Pages (from-to)11392-11402
Number of pages11
JournalJournal of virology
Volume79
Issue number17
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

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inactivation
Up-Regulation
Tumor Suppressor Proteins
Retinoblastoma Protein
Human papillomavirus 16
Oncogene Proteins
mice
Cell Cycle Checkpoints
Oncogenes
Uterine Cervical Neoplasms
Transgenic Mice
DNA Damage
Hyperplasia
mutants
Cell Cycle
uterine cervical neoplasms
Papillomaviridae
oncogenes
hyperplasia
in vitro studies

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Balsitis, S., Dick, F., Lee, D., Farrell, L., Hyde, R. K., Griep, A. E., ... Lambert, P. F. (2005). Examination of the pRb-dependent and pRb-independent functions of E7 in vivo. Journal of virology, 79(17), 11392-11402. https://doi.org/10.1128/JVI.79.17.11392-11402.2005

Examination of the pRb-dependent and pRb-independent functions of E7 in vivo. / Balsitis, Scott; Dick, Fred; Lee, Denis; Farrell, Linda; Hyde, Ricia K; Griep, Anne E.; Dyson, Nicholas; Lambert, Paul F.

In: Journal of virology, Vol. 79, No. 17, 01.09.2005, p. 11392-11402.

Research output: Contribution to journalArticle

Balsitis, S, Dick, F, Lee, D, Farrell, L, Hyde, RK, Griep, AE, Dyson, N & Lambert, PF 2005, 'Examination of the pRb-dependent and pRb-independent functions of E7 in vivo', Journal of virology, vol. 79, no. 17, pp. 11392-11402. https://doi.org/10.1128/JVI.79.17.11392-11402.2005
Balsitis, Scott ; Dick, Fred ; Lee, Denis ; Farrell, Linda ; Hyde, Ricia K ; Griep, Anne E. ; Dyson, Nicholas ; Lambert, Paul F. / Examination of the pRb-dependent and pRb-independent functions of E7 in vivo. In: Journal of virology. 2005 ; Vol. 79, No. 17. pp. 11392-11402.
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