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Human T-lymphotropic virus type I Tax protein utilizes distinct pathways for p53 inhibition that are cell

C A Pise-Masison1, R Mahieux, M Radonovich

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

The Journal of Biological Chemistry
|October 19, 2000
PubMed

Insights

The human T-lymphotropic virus type I Tax protein inhibits p53 function through cell-type-specific mechanisms. Tax

Area of Science:

  • Molecular Biology
  • Virology
  • Cell Biology

Background:

  • p53 is crucial for cellular response to genotoxic stress, regulating cell cycle and apoptosis.
  • The human T-lymphotropic virus type I (HTLV-1) Tax protein is known to inhibit p53 function.
  • Previous studies suggest conflicting mechanisms for Tax-mediated p53 inhibition, involving NF-kappaB and p300 binding.

Purpose of the Study:

  • To elucidate the precise mechanisms by which HTLV-1 Tax inhibits p53.
  • To investigate the role of Tax activation functions and co-factor availability in p53 inhibition.
  • To resolve the controversy regarding the pathways utilized by Tax to suppress p53 activity.

Main Methods:

  • Analysis of Tax mutants (M47, K88A) to assess essential activation functions for p53 inhibition.
  • Examination of p53 transactivation recovery upon exogenous p300 expression in various cell lines.
  • Quantification of endogenous p300 levels in different cell types, including HTLV-1 infected cells.

Main Results:

  • The cAMP-response element-binding protein/activating transcription factor (CREB/ATF) activation function of Tax is essential for p53 inhibition in HeLa and H1299 cells.
  • Overexpression of p300 restored p53 transactivation in Tax-expressing H1299 cells, indicating p300 acts as a limiting factor.
  • Lower endogenous p300 levels were observed in H1299, Saos-2, and HeLa cells compared to Jurkat or HTLV-1 infected cells.

Conclusions:

  • HTLV-1 Tax employs distinct, cell type-dependent mechanisms to inhibit p53 function.
  • p300 availability is a critical determinant in the pathway of Tax-mediated p53 inhibition.
  • Understanding these mechanisms is vital for comprehending HTLV-1 pathogenesis and developing therapeutic strategies.

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