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Mdm2 targets the p53 transcription cofactor JMY for degradation

Amanda S Coutts1, Houda Boulahbel, Anne Graham

  • 1Laboratory of Cancer Biology, Division of Medical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.

EMBO Reports
|December 16, 2006
PubMed

Insights

Mouse double minute 2 (Mdm2) targets the p53 cofactor JMY for degradation, independent of p53 activity. This reveals a new Mdm2 mechanism for suppressing the p53 response by controlling transcription cofactors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Regulation

Background:

  • The p53 tumor suppressor is a critical regulator of cellular responses to DNA damage.
  • Mdm2 (mouse double minute 2) is a key negative regulator of p53, primarily through ubiquitin-dependent degradation.
  • JMY is a transcription cofactor that enhances p53 activity.

Purpose of the Study:

  • To elucidate a novel mechanism by which Mdm2 regulates p53 activity.
  • To investigate the role of Mdm2 in controlling the stability and function of the p53 cofactor JMY.

Main Methods:

  • Utilized cell-based assays to study protein levels and interactions.
  • Employed small molecule inhibitors of Mdm2 activity.
  • Investigated the role of the Mdm2 RING finger domain in JMY regulation.

Main Results:

  • DNA damage and Mdm2 inhibition both lead to increased JMY protein levels.
  • Mdm2 targets JMY for ubiquitin-dependent degradation via its RING finger domain.
  • Mdm2 regulation of JMY is independent of the p53-binding domain and p53 activity.

Conclusions:

  • Mdm2 directly regulates the stability of the p53 cofactor JMY.
  • This regulation occurs independently of p53 itself, highlighting a novel pathway for Mdm2 to suppress p53-mediated responses.
  • Transcription cofactors are identified as crucial targets for Mdm2 in controlling the p53 pathway.

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