TY - JOUR
T1 - ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning
AU - Su, Chang
AU - Sun, Fen
AU - Cunningham, Rebecca L.
AU - Rybalchenko, Nataliya
AU - Singh, Meharvan
N1 - Funding Information:
from the American Federation of Aging Research, and American Heart Association to CS, funds from the National Institutes of Health (NIA, AG022550, AG027956), the Alzheimer's Association, and the Texas Garvey Foundation to MS, and funds from the Texas Garvey Foundation, and American Heart Association to RLC.
PY - 2014/8
Y1 - 2014/8
N2 - Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H2O 2)- induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H2O 2-caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC. Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF- or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H 2O2-stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death.
AB - Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H2O 2)- induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H2O 2-caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC. Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF- or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H 2O2-stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death.
KW - ERK5
KW - KLF4
KW - NGF
KW - Neuroprotection
KW - Oxidative stress
KW - Preconditioning
UR - http://www.scopus.com/inward/record.url?scp=84903863414&partnerID=8YFLogxK
U2 - 10.1007/s11357-014-9685-5
DO - 10.1007/s11357-014-9685-5
M3 - Article
C2 - 25015774
AN - SCOPUS:84903863414
SN - 0161-9152
VL - 36
JO - Age
JF - Age
IS - 4
M1 - 9685
ER -