The Human papillomavirus-16 E6 Oncoprotein Decreases the Vigilance of Mitotic Checkpoints

Oncogene. 1997 Dec 18;15(25):3025-35. doi: 10.1038/sj.onc.1201495.

Abstract

The E6 and E7 proteins of the high risk human papillomaviruses (HPVs) are consistently expressed in HPV-positive cervical carcinomas. We investigated the ability of HPV-16 E6 and E7 to disrupt mitotic checkpoints in normal diploid human cells. Acute expression of HPV-16 E6, but not HPV-16 E7, decreased the fidelity of multiple checkpoints controlling entry into and exit from mitosis. After irradiation, nearly 50% of cells containing HPV-16 E6 readily entered mitosis as opposed to less than 10% of control cells. Consistent with this, asynchronous populations of cells expressing HPV-16 E6 had increased cdc2-associated histone H1 kinase activity relative to control populations. In addition, HPV-16 E6 increased sensitivity to chemically-induced S-phase premature mitosis and decreased mitotic spindle assembly checkpoint function relative to control populations. HPV-16 E6 mutants with a reduced ability to target p53 for degradation were unable to abrogate mitotic checkpoints, suggesting a possible mechanism by which HPV-16 E6 disrupts mitotic checkpoints. Expression of a mutant p53 gene yielded an intermediate phenotype relative to HPV-16 E6, generating moderate increases in sensitivity to chemically-induced S-phase PCC and mitotic spindle disruption and a heightened propensity to enter mitosis after irradiation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CDC2 Protein Kinase / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Cycle / radiation effects
  • Fibroblasts / metabolism
  • G2 Phase / drug effects
  • G2 Phase / physiology
  • G2 Phase / radiation effects
  • Humans
  • Keratinocytes / metabolism
  • Lung / cytology
  • Mitosis / drug effects
  • Mitosis / physiology*
  • Mitosis / radiation effects
  • Oncogene Proteins, Viral / physiology*
  • Papillomavirus E7 Proteins
  • Protein Kinases / metabolism
  • Repressor Proteins*
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / physiology
  • Spindle Apparatus / radiation effects

Substances

  • E6 protein, Human papillomavirus type 16
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • oncogene protein E7, Human papillomavirus type 16
  • Protein Kinases
  • histone H1 kinase
  • CDC2 Protein Kinase