title: p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons.
abstract: The multifunctional tumor suppressor protein, p53, inhibits cell growth and promotes differentiation and programmed cell death. p53 activity is controlled by transcriptional, translational, and post-translational regulation. A major pathway for post-translational regulation of p53 comprises its nucleocytoplasmic transport and subsequent proteasomal degradation, which involves binding to the oncoprotein, murine double minute-2 (Mdm2). Hypoxia and other stress signals cause cellular injury partly through the action of p53. In this study, we show that hypoxia induces down-regulation of Mdm2 as well as serine 15 phosphorylation and nuclear accumulation of p53 in cultured cortical neurons from E16 mice. These effects are diminished by the p38 mitogen-activated protein kinase inhibitors SB203580 and SB202190, but not by the inactive analog SB202474, and by a dominant-interfering mutant of the p38-activating kinase mitogen-activated protein kinase kinase 3 (MKK3). Hypoxic neuronal death was also reduced by p38 inhibitors, by dominant-interfering MKK3, and by a p53-antisense oligodeoxynucleotide and was increased by a constitutively active form of p38 and by an Mdm2-antisense oligodeoxynucleotide. These results demonstrate that p38 and Mdm2 have roles in coupling hypoxic-ischemic neuronal insults to activation of p53 and hypoxic cell death.
authors.affiliation: Buck Institute for Age Research, Novato, California 94945, USA.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiao Ou
authors.initials: XO
authors.lastname: Mao
authors.forename: Yunjuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Zhengui
authors.initials: Z
authors.lastname: Xia
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D000860:Hypoxia; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011725:Pyridines / Q000494:pharmacology; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D012694:Serine; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole