Antagonistic control of cell fates by JNK and p38-MAPK signaling
Antagonistic control of cell fates by JNK and p38-MAPK signaling
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DOI：
10.1038/sj.cdd.4402222
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发表时间：
2008-01-01
影响因子：
12.4
通讯作者：
Penninger, J. M.
中科院分区：
文献类型：
--
作者：
Wada, T.;Stepniak, E.;Penninger, J. M.
在所有多细胞生物的发育和器官形成过程中，细胞命运决定细胞是否经历增殖、分化或老化。两种独立的应激激酶信号通路p38-MAPK和JNK已经进化出来，它们传递发育和环境线索来决定细胞反应。虽然多种刺激可以激活这两条应激激酶通路，但这些共同的第二信号级联之间的功能相互作用和分子串扰尚不清楚。在这里，我们报告说，JNK和p38-MAPK通路拮抗控制细胞衰老，致癌转化，并在原代小鼠胚胎成纤维细胞（MEFs）的增殖。类似地，JNK途径的遗传失活导致体外胎儿成肝细胞增殖受损和体内成体肝再生缺陷，这通过抑制p38-MAPK途径来挽救。因此，两种应激信号通路MKK 7-JNK和MKK 3/6-p38-MAPK之间的平衡决定细胞命运，并将环境和发育应激与细胞周期停滞、衰老、致癌转化和成体组织再生联系起来。
During the development and organogenesis of all multicellular organisms, cell fate decisions determine whether cells undergo proliferation, differentiation, or aging. Two independent stress kinase signaling pathways, p38-MAPK, and JNKs, have evolved that relay developmental and environmental cues to determine cell responses. Although multiple stimuli can activate these two stress kinase pathways, the functional interactions and molecular cross-talks between these common second signaling cascades are poorly elucidated. Here we report that JNK and p38-MAPK pathways antagonistically control cellular senescence, oncogenic transformation, and proliferation in primary mouse embryonic fibroblasts (MEFs). Similarly, genetic inactivation of the JNK pathway results in impaired proliferation of fetal hepatoblasts in vitro and defective adult liver regeneration in vivo, which is rescued by inhibition of the p38-MAPK pathway. Thus, the balance between the two stress-signaling pathways, MKK7-JNK and MKK3/6-p38-MAPK, determines cell fate and links environmental and developmental stress to cell cycle arrest, senescence, oncogenic transformation, and adult tissue regeneration.