Mdm2 targets the p53 transcription cofactor JMY for degradation.
We define here a new mechanism through which Mdm2 (mouse double minute 2) regulates p53 activity, by targeting the p53 transcription cofactor JMY. DNA damage causes an increase in JMY protein, and, in a similar manner, small molecule inhibitors of Mdm2 activity induce JMY in unperturbed cells. At a mechanistic level, Mdm2 regulation of JMY requires the Mdm2 RING (really interesting new gene) finger, which promotes the ubiquitin-dependent degradation of JMY. However, regulation of JMY occurs independently of the p53-binding domain in Mdm2 and p53 activity. These results define a new functional relationship between the p53 cofactor JMY and Mdm2, and indicate that transcription cofactors that facilitate p53 activity are important targets for Mdm2 in suppressing the p53 response.
Coutts
Amanda S
AS
Laboratory of Cancer Biology, Division of Medical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Boulahbel
Houda
H
Graham
Anne
A
La Thangue
Nicholas B
NB
D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004249:DNA Damage; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism*; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C485677:Jmy protein, mouse; C415788:Mtbp protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin