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Published on: August 4, 2019

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

A Morita1, J Zhu, N Suzuki

  • 1Department of Radiological Health, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan. morita@m.u-tokyo.ac.jp

Cell Death and Differentiation
|September 3, 2005
PubMed

Insights

Sodium orthovanadate (vanadate) inhibits apoptosis by suppressing caspase activation and p53 DNA-binding activity. This finding is crucial for understanding vanadate

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Biology

Background:

  • p42/SETbeta is a substrate for caspase-7 in irradiated MOLT-4 cells.
  • Sodium orthovanadate (vanadate) inhibits p42/SETbeta's caspase-mediated cleavage.

Purpose of the Study:

  • To elucidate the mechanism by which vanadate inhibits caspase-mediated cleavage of p42/SETbeta.
  • To investigate the upstream effects of vanadate on apoptotic pathways.
  • To determine vanadate's impact on p53 activity and p53-dependent apoptosis.

Main Methods:

  • Cell culture (MOLT-4 cells)
  • Irradiation
  • Sodium orthovanadate treatment
  • Caspase activity assays
  • Mitochondrial membrane potential assessment
  • Bax conformational change analysis
  • p53 transactivation assays
  • Western blotting
  • Gel-shift assays
  • Chromatin immunoprecipitation assays

Main Results:

  • Vanadate suppresses caspase activation, not caspase activity.
  • Vanadate inhibits upstream apoptotic events including mitochondrial membrane potential loss, Bax conformational change, and p53 transactivation.
  • Vanadate suppresses p53-dependent apoptosis but not p53-independent apoptosis.
  • Vanadate inhibits the DNA-binding activity of p53.

Conclusions:

  • Vanadate's inhibitory effect on p42/SETbeta cleavage is mediated by the suppression of caspase activation.
  • Vanadate interferes with key apoptotic signaling pathways upstream of caspase activation.
  • Vanadate specifically inhibits p53-dependent apoptosis by blocking p53 DNA-binding activity.
  • The use of vanadate should consider its impact on p53 function in addition to its role as a protein tyrosine phosphatase inhibitor.

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