MEK and ERK protect-hypoxic cortical neurons via phosphorylation of Bad

Kunlin Jin, Xiao Ou Mao, Yonghua Zhu, David A. Greenberg

Research output: Contribution to journalArticlepeer-review

155 Scopus citations


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 down-stream 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 proapoptotic 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.

Original languageEnglish
Pages (from-to)119-125
Number of pages7
JournalJournal of Neurochemistry
Issue number1
StatePublished - 20 Jun 2002


  • Bad
  • Cell death
  • ERK
  • Hypoxia
  • MAP kinase
  • MEK


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