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Insights into the molecular mechanism of p53 inhibition by HTLV type 1 Tax

C A Pise-Masison1, R Mahieux, M Radonovich

  • 1Basic Research Laboratory, Virus Tumor Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

AIDS Research and Human Retroviruses
|November 18, 2000
PubMed

Insights

The HTLV-1 Tax protein inactivates the tumor suppressor p53 in cancer cells, not by direct binding, but by inducing specific phosphorylation events linked to NF-kappaB activation. This mechanism highlights a novel pathway for p53 dysfunction in HTLV-1-associated cancers.

Area of Science:

  • Molecular Biology
  • Virology
  • Cancer Research

Background:

  • The p53 protein is a critical tumor suppressor that regulates cell cycle arrest and apoptosis in response to genotoxic stress.
  • While p53 mutations are common in many cancers, HTLV-1-transformed cells often harbor wild-type but functionally inactive p53.
  • The HTLV-1 Tax protein is known to interfere with cellular processes, including p53 function.

Purpose of the Study:

  • To elucidate the mechanism by which the HTLV-1 Tax protein inhibits p53 activity in transformed cells.
  • To investigate the role of specific p53 phosphorylation sites and NF-kappaB signaling in Tax-mediated p53 inhibition.

Main Methods:

  • Analysis of Tax mutants in lymphocytes and mouse embryo fibroblasts (MEFs).
  • Utilized phosphospecific antibodies to detect p53 phosphorylation at Ser-15 and Ser-392.
  • Employed p65 knockout (KO) MEFs to assess the necessity of NF-kappaB activation.
  • Created p53 mutants with alanine substitutions at Ser-15 and Ser-392.

Main Results:

  • Tax inhibits p53 trans-activation function through constitutive phosphorylation of p53 at Ser-15 and Ser-392.
  • Tax-induced p53 inhibition correlates with NF-kappaB activation, but not p300 binding or CREB trans-activation.
  • Blocking NF-kappaB activation prevents Tax-mediated p53 inhibition, and p65 is essential for this process.
  • Phosphorylation of p53 at Ser-15 and Ser-392 by Tax is critical for p53 inhibition, as alanine mutants are resistant.

Conclusions:

  • The HTLV-1 Tax protein inhibits p53 function via a mechanism dependent on NF-kappaB transcriptional activation.
  • Constitutive phosphorylation of p53 at Ser-15 and Ser-392 by Tax is a key event in this inhibitory pathway.
  • Understanding this mechanism provides insights into viral oncogenesis and potential therapeutic targets in HTLV-1-associated malignancies.

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