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.

β-Synuclein Displays an Antiapoptotic p53-dependent Phenotype and Protects Neurons from 6-Hydroxydopamine-induced Caspase 3 Activation

“…Thus Mdm2 controls p53 expression mainly by regulating its ubiquitination/degradation rates (31). Conversely, phosphorylated p38 activates p53 by phosphorylation (32). In line with our observed decreased p53 expression, we found higher Mdm2-like immunoreactivity and reduced p38 expression in ␤-synuclein-expressing cells in both basal and staurosporine-stimulated conditions (Fig.…”

“…This indicated that ␤-synuclein likely controls p53 levels at a post-transcriptional level. In agreement with this hypothesis, phosphorylated p38 immunoreactivity, a clue to p53 activation (32), was lowered in ␤-synuclein-expressing neurons.…”

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis

“…6,11,12 We asked whether hypoxia would trigger a p53-dependent gene expression pattern distinct from those induced by other stress agents, such as g-irradiation and UV. Our analysis revealed significant p53-dependent induction or repression of only 27 genes among the 12 454 different genes represented on the microarray.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…Similarly, F35 mice show increased p53 phosphorylation during the pre-degenerate stage (76 days), as well increased activity of stress-related kinases such as ERK1/2 or p38 (Nicolas et al, 2007). Accordingly, p38 and MdM-2 activate p53 and promote death in neuronal cultures in hypoxic conditions (Zhu et al, 2002). Furthermore, lentiviral p53-mediated caspase-3 activation is delayed in BAXdeficient CGNs (Cregan et al, 1999).…”