Evidence for a differential modulation of p53-phosphorylating kinases by the cyclin-dependent kinase inhibitor p21WAF1/CIP1.
Although initially described as a regulator of cell cycle progression, the cyclin-dependent kinase inhibitor p21 is now known to also modulate various other biological processes including transcription, differentiation and apoptosis. These versatile activities of p21 are mainly mediated via direct binding to various transcription factors, pro-apoptotic proteins and kinases that are usually inhibited by this interaction. Here we provide in vitro evidence that p21 not only inhibits, but also activates certain kinases in a remarkable substrate-dependent manner. Whereas phosphorylation of the tumor suppressor p53 by several isoforms of the cJun N-terminal kinases (JNKs) was greatly attenuated in the presence of p21, phosphorylation of cJun remained either unaffected or was even enhanced. Furthermore, p21 strongly increased phosphorylation of cFos and MBP by ERK1 and ERK2, while p53 phosphorylation was increased and inhibited, respectively. Also p38α and glycogen synthase kinase-3 beta (GSK-3β) were found differentially regulated by p21 in a substrate-dependent manner, while casein kinase-1 epsilon (CK1ε) was not affected. Together with our finding that the stress-induced p53 phosphorylation pattern differs greatly between p21-proficient and -deficient HCT116 colon carcinoma cells, our results suggest that p21 is able to influence kinase activities both in a negative and positive manner.
Neise
Denise
D
Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Düsseldorf, Germany.
Sohn
Dennis
D
Budach
Wilfried
W
Jänicke
Reiner U
RU
D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; C499048:MBP protein, human; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3