Selenium compounds regulate p53 by common and distinctive mechanisms

Anticancer Res. May-Jun 2004;24(3a):1401-8.

Abstract

Selenium compounds show much promise in the prevention of prostate and other human cancers. Various selenium chemical forms have been shown to differ widely in their anticancer properties. The main dietary form is selenomethionine, which we showed modulated p53 activity by causing redox regulation of key p53 cysteine residues. In the current study we included other selenium chemical forms, sodium selenite and methyl-seleninic acid. All three forms are relevant selenium sources in human populations. All three forms can affect p53 activity defined as trans-activation of a p53-dependent reporter gene. In addition to the reduction of cysteine sulfhydryl groups, p53 phosphorylation was also affected in cells treated with selenium compounds. Methyl-seleninic acid caused phosphorylation of one or more p53 threonine residues, but did not affect any known serine phosphorylation sites. By contrast sodium selenite caused phosphorylation of p53 serines 20, 37 and 46 known to mediate apoptosis. Selenomethionine did not cause detectable phosphorylation of p53 serines or threonines. Our data show that, although p53 modulation may be a common denominator of selenium compounds, specific mechanisms of p53 activation differ among selenium chemical forms. Post-translational modifications of p53 are determinants of p53 activity and probably affect the threshold for p53-mediated functions. Different selenium chemical forms may differentially modify p53 for DNA repair or apoptosis in conjunction with a given level of endogenous or exogenous DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cysteine / metabolism
  • DNA Repair
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / antagonists & inhibitors
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / physiology
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Organoselenium Compounds / pharmacology*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects*
  • Selenomethionine / pharmacology*
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sodium Selenite / pharmacology*
  • Threonine / metabolism
  • Transcriptional Activation / drug effects
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Organoselenium Compounds
  • Tumor Suppressor Protein p53
  • Threonine
  • Serine
  • Selenomethionine
  • methylselenic acid
  • APEX1 protein, human
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • Sodium Selenite
  • Cysteine