TY - JOUR
T1 - MEK and ERK protect-hypoxic cortical neurons via phosphorylation of Bad
AU - Jin, Kunlin
AU - Mao, Xiao Ou
AU - Zhu, Yonghua
AU - Greenberg, David A.
PY - 2002/6/20
Y1 - 2002/6/20
N2 - 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.
AB - 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.
KW - Bad
KW - Cell death
KW - ERK
KW - Hypoxia
KW - MAP kinase
KW - MEK
UR - http://www.scopus.com/inward/record.url?scp=0036270263&partnerID=8YFLogxK
U2 - 10.1046/j.0022-3042.2001.00678.x
DO - 10.1046/j.0022-3042.2001.00678.x
M3 - Article
C2 - 11796750
AN - SCOPUS:0036270263
VL - 80
SP - 119
EP - 125
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -