title: Murine protein serine-threonine kinase 38 activates p53 function through Ser15 phosphorylation.
abstract: Murine protein serine-threonine kinase 38 (MPK38) is a member of the AMP-activated protein kinase-related serine/threonine kinase family. In this study, we show that MPK38 physically associates with p53 via the carboxyl-terminal domain of MPK38 and the central DNA-binding domain of p53. This interaction is increased by 5-fluorouracil or doxorubicin treatment and is responsible for Ser(15) phosphorylation of p53. Ectopic expression of wild-type Mpk38, but not kinase-dead Mpk38, stimulates p53-mediated transcription in a dose-dependent manner and up-regulates p53 targets, including p53, p21, MDM2, and BAX. Consistently, knockdown of MPK38 shows an opposite trend, inhibiting p53-mediated transcription. MPK38 functionally enhances p53-mediated apoptosis and cell cycle arrest in a kinase-dependent manner by stimulating p53 nuclear translocation. We also demonstrate that MPK38-mediated p53 activation is induced by removing MDM2, a negative regulator of p53, from the p53-MDM2 complex as well as by stabilization of interaction between p53 and its positive regulators, including NM23-H1, serine/threonine kinase receptor-associated protein, and 14-3-3. This leads to the enhancement of p53 stability. Together, these results suggest that MPK38 may act as a novel regulator for promoting p53 activity through direct phosphorylation of p53 at Ser(15).
authors.affiliation: Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea.
authors.forename: Hyun-A
authors.initials: HA
authors.lastname: Seong
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Ha
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; C494827:Bax protein, mouse; D054778:NM23 Nucleoside Diphosphate Kinases; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C108524:Melk protein, mouse; D017346:Protein Serine-Threonine Kinases; D005472:Fluorouracil