MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad
Article first published online: 28 DEC 2001
Journal of Neurochemistry
Volume 80, Issue 1, pages 119–125, January 2002
How to Cite
Jin, K., Mao, X. O., Zhu, Y. and Greenberg, D. A. (2002), MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. Journal of Neurochemistry, 80: 119–125. doi: 10.1046/j.0022-3042.2001.00678.x
- Issue published online: 28 DEC 2001
- Article first published online: 28 DEC 2001
- Received August 1, 2001; revised manuscript received October 4, 2001; accepted October 5, 2001.
- cell death;
- MAP kinase;
We investigated the role of mitogen-activated protein kinase (MAPK) pathways in hypoxic neuronal injury using primary cultures from murine cerebral cortex. Hypoxia caused the death of ∼50% of neurons at 16 h and ∼65% of neurons at 24 h. This was associated with phospho-activation of the MAPK/extracellular signal-regulated kinase (ERK) kinase MEK1/2 and its downstream target ERK1/2, but not p38 MAPK or c-Jun N-terminal kinase (JNK), as detected by western blotting. The MEK1/2 inhibitor, PD98059, increased neuronal death in hypoxic cultures, suggesting that MEK1/2 promotes neuronal survival, whereas the p38 inhibitors, SB202190 and SB203580, had no effect. To identify downstream effects of ERK1/2 that might regulate hypoxic neuronal death, we measured hypoxia-induced phosphorylation of three ERK1/2 targets: the 90-kDa ribosomal protein S6 kinase (RSK), the transcription factor ELK1, and the pro-apoptotic Bcl-2 family protein Bad. We observed increased abundance of inactivated (phospho-)Bad, but no change in phospho-RSK or phospho-ELK1. Moreover, the MEK inhibitor PD98059 reduced phospho-inactivation of Bad in hypoxic cultures. These findings suggest that a cell-survival program involving phospho-activation of MEK1/2 and ERK1/2 and inactivation of Bad is mobilized in hypoxic neurons, and may help to regulate neuronal fate following hypoxic-ischemic injury.