共 38 条
The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death
被引:111
作者:
Xiao, Lei
[2
,3
,4
]
Chen, Dongmei
[2
,3
]
Hu, Peng
[2
,3
]
Wu, Junbing
[2
,3
,4
]
Liu, Weizhe
[5
]
Zhao, Yanhong
[2
,3
]
Cao, Mou
[2
,3
]
Fang, Yuan
[1
]
Bi, Wenzhi
Zheng, Zheng
[3
,6
]
Ren, Jian
[2
,3
]
Ji, Guangju
[3
]
Wang, Yan
[1
]
Yuan, Zengqiang
[2
,3
]
机构:
[1] Chinese Peoples Liberat Army Gen Hosp, Dept Orthopaed, Beijing 100853, Peoples R China
[2] State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
[3] Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China
[4] Chinese Acad Sci, Coll Life Sci, Grad Sch, Beijing 100049, Peoples R China
[5] Shandong Univ, Coll Life Sci, Jinan 250100, Shangdong, Peoples R China
[6] Capital Med Univ, Xuanwu Hosp, Beijing Inst Geriatr, Beijing 100053, Peoples R China
基金:
美国国家科学基金会;
关键词:
UBIQUITIN LIGASE CHIP;
ABL TYROSINE KINASE;
C-ABL;
MST1;
KINASE;
PHOSPHORYLATION;
PROTEIN;
ACTIVATION;
AGGREGATION;
DEGRADATION;
APOPTOSIS;
D O I:
10.1523/JNEUROSCI.0035-11.2011
中图分类号:
Q189 [神经科学];
学科分类号:
071006 ;
摘要:
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.
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页码:9611 / 9619
页数:9
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