Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases.
Central to the role of p53 in cell regulation are its sequence-specific interactions with genes that control the cell cycle and apoptosis. p53 response elements contain two or more copies of a somewhat promiscuous consensus sequence: 5'-XXXC(A,T)(T,A)GYY-3' (where X is a purine and Y is a pyrimidine) (ref. 3). The sequence-specific DNA-binding region of p53 resides in its central conserved region. Although this region itself is not known to be phosphorylated, the amino and carboxy termini of human p53 contain sites for phosphorylation by several protein kinases. We have examined the role of cyclin-dependent kinase (Cdk) shown previously to phosphorylate human p53 at serine 315 (ref. 5). We report here that p53 is efficiently and selectively phosphorylated by S and G2/M Cdks. Such phosphorylation markedly stimulates sequence-specific DNA binding by p53 and also causes a distinctive conformational change in p53 as revealed by partial protease analysis. Strikingly, Cdk phosphorylation also confers binding-site preference on p53. These data suggest a potential regulatory mechanism of p53 activity.
Wang
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Y
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Prives
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C
D000818:Animals; D001483:Base Sequence; D042846:CDC2-CDC28 Kinases; D002460:Cell Line; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D018411:Spodoptera; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016213:Cyclins; D009838:Oligodeoxyribonucleotides; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases