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Abrogation of growth arrest signals by human papillomavirus type 16 E7 is mediated by sequences required for

G W Demers1, E Espling, J B Harry

  • 1Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98040, USA.

Journal of Virology
|October 1, 1996
PubMed

Insights

Human papillomavirus (HPV) E7 oncogenes disrupt cell cycle arrest signals, promoting cell proliferation and contributing to cancer. Mutated E7 proteins that bind retinoblastoma protein are key to this effect.

Area of Science:

  • Cell Biology
  • Virology
  • Molecular Biology

Background:

  • Cells normally arrest in G1/G0 phase due to negative growth signals.
  • Human papillomavirus (HPV) oncogenes may overcome these signals, contributing to neoplastic potential.
  • Understanding how viral proteins affect cell cycle regulation is crucial.

Purpose of the Study:

  • To investigate the ability of HPV oncogenes, specifically E7 and E6 proteins, to bypass distinct negative growth arrest signals in epithelial cells.
  • To determine the role of retinoblastoma protein binding in the function of HPV E7.
  • To compare the effects of high-risk (HPV-16) and low-risk (HPV-6) HPV proteins on cell cycle control.

Main Methods:

  • Assessing the ability of HPV-16 E7 and E6 proteins to abrogate specific cell cycle arrest signals (suprabasal quiescence, DNA damage-induced G1 arrest, TGF-β-induced arrest).
  • Utilizing mutated E7 proteins to identify critical functional domains, including retinoblastoma protein binding.
  • Comparing the effects of HPV-16 proteins with those of HPV-6 proteins.

Main Results:

  • HPV-16 E7 abrogated all three tested negative growth arrest signals.
  • Mutant E7 proteins unable to abrogate growth arrest, including those that did not bind retinoblastoma protein, were transformation deficient.
  • HPV-16 E6 only bypassed DNA damage-induced G1 arrest.
  • HPV-6 E6 and E7 proteins did not bypass any of the tested growth arrest signals.

Conclusions:

  • The E7 protein of high-risk HPV-16 plays a significant role in disrupting multiple cell cycle checkpoints, likely contributing to its oncogenic potential.
  • Retinoblastoma protein binding is essential for the ability of HPV-16 E7 to abrogate growth arrest signals.
  • Low-risk HPV-6 proteins lack the ability to significantly interfere with these cellular growth control mechanisms.

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