LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism
LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism
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DOI：
10.1242/dev.01670
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发表时间：
2005-03-01
期刊：
影响因子：
4.6
通讯作者：
Dalton, S
中科院分区：
文献类型：
--
作者：
Cartwright, P;McLean, C;Dalton, S
小鼠胚胎干细胞可以通过依赖LIF/ stat3的信号传导维持为多能、自我更新的群体。这一途径的下游效应物以前没有被定义。在本报告中，我们通过显示STAT3直接调节Myc转录因子的表达，确定了LIF自我更新途径的一个关键靶点。小鼠ES细胞表达Myc水平升高，并且在liff戒断后，Myc mRNA水平下降，Myc蛋白在苏氨酸58 （T58）上磷酸化，触发其GSK3 β依赖性降解。维持稳定的Myc （T58A）的表达可以独立于LIF实现自我更新和维持多能性。相反，Myc显性阴性形式的表达会抑制自我更新并促进分化。STAT3的转录控制和T58磷酸化的抑制对ES细胞中Myc活性的调节至关重要，从而促进自我更新。总之，我们的研究结果建立了LIF和STAT3如何调节胚胎干细胞自我更新和多能性的机制。
Murine ES cells can be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. The downstream effectors of this pathway have not been previously defined. In this report, we identify a key target of the LIF self-renewal pathway by showing that STAT3 directly regulates the expression of the Myc transcription factor. Murine ES cells express elevated levels of Myc and following LIF withdrawal, Myc mRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering its GSK3 beta dependent degradation. Maintained expression of stable Myc (T58A) renders self-renewal and maintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form of Myc antagonizes self-renewal and promotes differentiation. Transcriptional control by STAT3 and suppression of T58 phosphorylation are crucial for regulation of Myc activity in ES cells and therefore in promoting self-renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate ES cell self-renewal and pluripotency.