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Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-kappaB pathway and is

C A Pise-Masison1, R Mahieux, H Jiang

  • 1Virus Tumor Biology Section, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. masionc@dce41.nci.nih.gov

Molecular and Cellular Biology
|April 25, 2000
PubMed

Insights

The human T-cell lymphotropic virus type 1 (HTLV-1) Tax protein inactivates the tumor suppressor p53 in T cells by activating NF-kappaB. This inactivation is dependent on the p65 subunit and involves p53 phosphorylation.

Area of Science:

  • Cellular Biology
  • Virology
  • Oncology

Background:

  • p53 is a critical tumor suppressor that guards against DNA damage and cellular transformation.
  • The human T-cell lymphotropic virus type 1 (HTLV-1) Tax protein is known to interfere with cellular processes.
  • Previous work showed HTLV-1 Tax inactivates p53 transactivation function in lymphocytes.

Purpose of the Study:

  • To investigate the mechanism by which HTLV-1 Tax inactivates p53 in T cells.
  • To determine the role of NF-kappaB activation in Tax-induced p53 inactivation.
  • To identify specific molecular events linking Tax, NF-kappaB, and p53.

Main Methods:

  • Analysis of Tax mutants for NF-kappaB induction, p300 binding, and CREB transactivation.
  • Overexpression of dominant IkappaB mutant and p300 to assess rescue of p53 activity.
  • Utilizing wild-type and p65 knockout mouse embryo fibroblasts (MEFs) to assess p65 requirement.
  • Restoration of Tax-induced p53 inactivation by expressing p65 in knockout MEFs.
  • Examination of p53 phosphorylation at serines 15 and 392.

Main Results:

  • HTLV-1 Tax-induced p53 inactivation in T cells is dependent on NF-kappaB activation.
  • Tax mutants that induce NF-kappaB also inactivate p53, independent of p300 binding or CREB transactivation.
  • Overexpression of a dominant IkappaB mutant rescues p53 activity, indicating NF-kappaB's role.
  • p53 inactivation by Tax requires the p65 subunit of NF-kappaB, as demonstrated in p65 knockout MEFs.
  • Phosphorylation of p53 at serines 15 and 392 correlates with Tax-induced inactivation.

Conclusions:

  • HTLV-1 Tax inactivates p53 function in T cells through an NF-kappaB-dependent pathway.
  • The p65 subunit of NF-kappaB is essential for this Tax-mediated p53 inactivation.
  • Posttranslational modification, specifically phosphorylation of p53, is implicated in its inactivation by Tax.
  • These findings suggest cross-regulation between NF-kappaB and p53 pathways at multiple levels.

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