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P-TEFb inhibitors interfere with activation of p53 by DNA-damaging agents

S K Radhakrishnan1, U G Bhat, M Halasi

  • 1Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Oncogene
|August 29, 2007
PubMed

Insights

Positive transcription elongation factor b (P-TEFb) inhibitors can block DNA-damaging agent-induced p53 activation. This suggests P-TEFb inhibitors may antagonize DNA-damage response in wild-type p53 tumors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Tumor suppressor p53 is activated by DNA damage, inducing cell-cycle arrest or apoptosis.
  • P-TEFb inhibitors, like flavopiridol, increase p53 protein but decrease its target gene expression.
  • DNA-damaging agents are used with P-TEFb inhibitors in cancer clinical trials.

Purpose of the Study:

  • To investigate the effect of P-TEFb inhibitors on DNA-damage-induced p53 activation.
  • To determine if P-TEFb inhibitors interfere with p53's transcriptional activity.

Main Methods:

  • Treating cells with doxorubicin (a DNA-damaging agent) and P-TEFb inhibitors.
  • Assessing p53 phosphorylation levels.
  • Analyzing p53 binding to DNA and its transcriptional activity.

Main Results:

  • P-TEFb inhibitors blocked doxorubicin-induced p53 phosphorylation.
  • Combined treatment inhibited doxorubicin-induced p53 binding to DNA.
  • P-TEFb inhibitors reduced p53 transcriptional activity in response to doxorubicin.

Conclusions:

  • P-TEFb inhibitors antagonize the activation of p53 by DNA-damaging agents.
  • This antagonism occurs through inhibition of p53 phosphorylation and DNA binding.
  • Findings are relevant for tumors with wild-type p53 undergoing DNA-damaging therapy.

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