p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons.

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.