A p38 inhibitor allows to dissociate differentiation and apoptotic processes triggered upon LIF withdrawal in mouse embryonic stem cells

被引:56
作者
Duval, D
Malaisé, M
Reinhardt, B
Kedinger, C
Boeuf, H
机构
[1] Univ Bordeaux 2, CNRS, UMR 5164, CIRID, F-33076 Bordeaux, France
[2] ULP, CNRS, INSERM, Inst Genet & Biol Mol Cellulaire, F-67404 Illkirch Graffenstaden, CU Strasbourg, France
关键词
apoptosis; caspase-3; ES cells; cytokine; p38; PD169316; SB203580; bcl-2;
D O I
10.1038/sj.cdd.4401337
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mouse embryonic stem cells remain pluripotent when maintained in the presence of leukemia inhibitory factor (LIF). Upon LIF withdrawal, most cells differentiate into various lineages, while some die by apoptosis within 3 days. We have analyzed the activation pattern of the mitogen-activated protein kinase (MAPK) families and characterized the expression profile of selected genes modulated during differentiation or apoptosis. We show that p38 MAPKs are activated first, during the apoptotic crisis, while extracellular-regulated kinases and c-Jun N-terminal kinases are induced after the apoptotic crisis in differentiated cells. However, by using both p38 kinase inhibitors (PD169316 and SB203580) and a p38alpha(-/-) cell line, we demonstrate that p38alpha activation is rather a consequence than a cause of apoptosis. We thus reveal novel properties of PD169316, which induces cell survival without impairing cell differentiation, and identify PD169316-sensitive targets like the fibroblast growth factor-5, Brachyury and bcl-2 genes. Finally, we demonstrate that overexpression of the PD169316 - regulated bcl-2 gene prevents LIF withdrawal - induced cell death.
引用
收藏
页码:331 / 341
页数:11
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