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Analysis of the p53-mediated G1 growth arrest pathway in cells expressing the human papillomavirus type 16 E7

D L Jones1, K Münger

  • 1Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Journal of Virology
|April 1, 1997
PubMed

Insights

Human papillomavirus type 16 (HPV-16) E7 protein disrupts cell cycle regulation by reducing pRB and p107 protein stability. This mechanism allows HPV-16 E7-expressing cells to evade p53-mediated growth arrest.

Area of Science:

  • Molecular Biology
  • Virology
  • Cell Cycle Regulation

Background:

  • Human papillomavirus type 16 (HPV-16) oncoproteins E6 and E7 are known to disrupt cell cycle control.
  • Cells expressing HPV-16 E6 are resistant to p53-mediated G1 growth arrest.
  • The precise mechanism by which HPV-16 E7 contributes to cell cycle dysregulation requires further elucidation.

Purpose of the Study:

  • To investigate the p53-mediated DNA damage response pathway in cells expressing HPV-16 E7.
  • To determine how HPV-16 E7 expression leads to continued cell cycling despite DNA damage.
  • To identify the molecular targets of HPV-16 E7 involved in cell cycle progression.

Main Methods:

  • Comparison of G1/S-phase cyclin and cyclin-dependent kinase (Cdk) levels in E7-expressing cells versus parental RKO cells.
  • Assessment of Cdk2 kinase activity in response to DNA damage.
  • Analysis of pRB and p107 protein and mRNA levels and pRB protein half-life.
  • Infection of primary human foreskin keratinocytes with HPV-16 E7 expressing retroviruses.

Main Results:

  • HPV-16 E7-expressing cells showed no significant difference in G1/S-phase cyclin or Cdk levels compared to parental cells.
  • Cdk2 kinase activity was inhibited in both RKO and E7-expressing cells, but remained active in E6-expressing cells.
  • Steady-state levels of pRB and p107 proteins were significantly lower in E7-expressing cells, with a markedly shorter pRB half-life.
  • E7 expression in primary keratinocytes reduced pRB protein levels, independent of immortalization or transformation.

Conclusions:

  • HPV-16 E7 protein interferes with the stability of pRB and p107 proteins.
  • The reduction in pRB and p107 protein levels contributes to the ability of HPV-16 E7 to overcome p53-mediated G1 growth arrest.
  • These findings elucidate a key mechanism by which HPV-16 E7 promotes uncontrolled cell proliferation.

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