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Mutant p53 protects cells from 12-O-tetradecanoylphorbol-13-acetate-induced death by attenuating activating

Yosef Buganim1, Eyal Kalo, Ran Brosh

  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Cancer Research
|November 17, 2006
PubMed

Insights

Mutant p53 hinders the induction of activating transcription factor 3 (ATF3) and reduces cell death sensitivity. This occurs through direct promoter interaction and reduced MEF2D expression, revealing mutant p53 gain-of-function mechanisms.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Mutations in the p53 tumor suppressor gene are common in human cancers.
  • Some p53 mutations exhibit gain-of-function (GOF) properties beyond loss of wild-type (WT) activity.
  • The immediate early response gene activating transcription factor 3 (ATF3) plays roles in stress response and apoptosis.

Purpose of the Study:

  • To investigate the impact of p53 status on ATF3 induction within the 12-O-tetradecanoylphorbol-13-acetate (TPA)-protein kinase C (PKC) pathway.
  • To elucidate the mechanisms by which mutant p53 influences ATF3 expression and TPA-induced cell death.

Main Methods:

  • Utilized cell models with wild-type, mutant, or null p53.
  • Administered TPA and assessed ATF3 expression levels.
  • Performed ATF3 promoter mutagenesis analysis to identify regulatory elements.
  • Investigated protein-protein interactions between mutant p53 and ATF3 regulatory regions.
  • Quantified MEF2D expression levels.

Main Results:

  • High-dose TPA induced ATF3 independently of WT p53, correlating with PKC depletion and cell death.
  • Cells with mutant p53 showed attenuated ATF3 induction and reduced sensitivity to TPA-induced death compared to p53-null cells.
  • The ATF3 promoter contains cyclic AMP-responsive element binding protein/ATF and MEF2 regulatory motifs crucial for TPA-induced activation.
  • Mutant p53 suppressed ATF3 expression via direct interaction with the ATF3 promoter at the MEF2 site and by reducing MEF2D transcriptional expression.

Conclusions:

  • Mutant p53 gain-of-function impairs ATF3 induction and confers resistance to TPA-induced cell death.
  • Mutant p53 exerts its inhibitory effect on ATF3 through dual mechanisms: direct promoter interference and downregulation of the transcriptional activator MEF2D.
  • These findings offer critical insights into the oncogenic functions of mutant p53 and its role in tumor progression.

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