MSK2 inhibits p53 activity in the absence of stress.
Mitogen- and stress-activated kinase 2 (MSK2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, MSK2 selectively suppressed the expression of a subset of p53 target genes. This basal inhibition of p53 by MSK2 occurred independently of its kinase activity and of upstream mitogen-activated protein kinase signaling to MSK2. Furthermore, MSK2 interacted with and inhibited the p53 coactivator p300 and associated with the Noxa promoter. Apoptotic stimuli promoted the degradation of MSK2, thus relieving its inhibition of p53 and enabling efficient p53-dependent transactivation of Noxa, which contributed to apoptosis. Together, these findings constitute a new mechanism for the regulation of p53 transcriptional activity in response to stress.
Spanish National Cancer Research Centre, Madrid, Spain. sllanos@cnio.es
Susana
S
Llanos
Ana
A
Cuadrado
Manuel
M
Serrano
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002460:Cell Line; D020935:MAP Kinase Signaling System / Q000502:physiology; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology
C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa