Phosphorylation of serine 392 in p53 is a common and integral event during p53 induction by diverse stimuli.
Post-translational modifications play important roles during the stabilisation and activation of p53 by various genotoxic and non-genotoxic stresses. Ser392 has been reported to be a major UV-stimulated phosphorylation site that is modified through the p38 MAPK pathway in a manner that may involve recruitment of CK2. Here we show that phosphorylation of Ser392 is an integral event that occurs not only in response to UV, but also during the induction of p53 by a range of stimuli including treatment of cells with the MDM2 inhibitor, Nutlin 3a. Strikingly, phosphorylation of Ser392 and Ser33 was also observed following induction of the p53 pathway by ARF which has previously been thought to induce p53 in a phosphorylation-independent manner. The induction of Ser392 phosphorylation by diverse stimuli can be explained by a common mechanism in which its phosphorylation at a low rate, coupled with the rapid turnover of p53, limits the accumulation of phosphorylated molecules until a stimulus stabilises p53 and allows the Ser392-phosphorylated p53 to accumulate. We also provide biological evidence that Ser392 phosphorylation is not mediated by a UV-associated route involving p38 MAPK, either directly or indirectly via CK2. These data suggest that, physiologically, Ser392 may be phosphorylated by an, as yet, unidentified protein kinase.
Cox
Miranda L
ML
Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
Meek
David W
DW
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012694:Serine; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D047390:Casein Kinase II; D048051:p38 Mitogen-Activated Protein Kinases; D020727:ADP-Ribosylation Factors