Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF.
Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19ARF. This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19ARF. Levels of p53 are therefore determined by opposing effects of Raf-induced p19ARF and Mdm2.
Ries
S
S
University of California, San Francisco Cancer Research Institute, 94115, USA.
Biederer
C
C
Woods
D
D
Shifman
O
O
Shirasawa
S
S
Sasazuki
T
T
McMahon
M
M
Oren
M
M
McCormick
F
F
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005720:Gamma Rays / Q000009:adverse effects; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D051736:Proto-Oncogene Proteins c-mdm2; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D020218:Response Elements; D015398:Signal Transduction; D018808:Transcription Factor AP-1; D014157:Transcription Factors / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D009153:Mutagens; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins