Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation
Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation
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Stk40缺失提高c-JUN蛋白水平并损害中胚层分化
DOI：
10.1074/jbc.ra119.007840
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发表时间：
2019-06-21
影响因子：
4.8
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Hu, Jing;Li, Shuang;Jin, Ying
中胚层发育是由多能性上胚层细胞分化启动的精细调节过程。丝氨酸/苏氨酸激酶40（STK 40）控制几种中胚层来源的细胞类型的发育，其过表达诱导小鼠胚胎干细胞（mESC）向胚外内胚层分化，并且StK 40敲除（KO）导致多器官衰竭，并且在小鼠围产期是致命的。然而，STK 40在中胚层分化中的生理功能的分子机制仍然难以捉摸。在这里，我们报告说，Stk 40消融损害中胚层分化在体外和体内。从机制上讲，STK 40与E3泛素连接酶哺乳动物组成型光形态发生蛋白1（COP 1）和转录调节因子原癌基因c-Jun（c-JUN）相互作用，促进c-JUN蛋白降解。因此，Stk 40敲除导致c-JUN蛋白积累，这反过来又明显抑制WNT信号传导活性并损害中胚层分化过程。总体而言，这项研究表明，STK 40与COP 1一起代表了一个以前未知的调节轴，该轴在mESC中胚层分化期间将c-JUN蛋白水平调节在适当的范围内。我们的研究结果为调节c-JUN蛋白水平的分子机制提供了重要的见解，并可能对管理c-JUN功能障碍引起的细胞疾病具有潜在的意义。
Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo. Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.