PML regulates p53 acetylation and premature senescence induced by oncogenic Ras.
The tumour suppressor p53 induces cellular senescence in response to oncogenic signals. p53 activity is modulated by protein stability and post-translational modification, including phosphorylation and acetylation. The mechanism of p53 activation by oncogenes remains largely unknown. Here we report that the tumour suppressor PML regulates the p53 response to oncogenic signals. We found that oncogenic Ras upregulates PML expression, and overexpression of PML induces senescence in a p53-dependent manner. p53 is acetylated at lysine 382 upon Ras expression, an event that is essential for its biological function. Ras induces re-localization of p53 and the CBP acetyltransferase within the PML nuclear bodies and induces the formation of a trimeric p53-PML-CBP complex. Lastly, Ras-induced p53 acetylation, p53-CBP complex stabilization and senescence are lost in PML-/- fibroblasts. Our data establish a link between PML and p53 and indicate that integrity of the PML bodies is required for p53 acetylation and senescence upon oncogene expression.
European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
M
M
Pearson
R
R
Carbone
C
C
Sebastiani
M
M
Cioce
M
M
Fagioli
S
S
Saito
Y
Y
Higashimoto
E
E
Appella
S
S
Minucci
P P
PP
Pandolfi
P G
PG
Pelicci
D000107:Acetylation; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D011905:Genes, ras; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D008239:Lysine