STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells
STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells
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DOI：
10.1093/emboj/18.15.4261
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发表时间：
1999-08-02
期刊：
影响因子：
11.4
通讯作者：
Yokota, T
中科院分区：
文献类型：
--
作者：
Matsuda, T;Nakamura, T;Yokota, T
在白血病抑制因子（LIF）存在的情况下，胚胎干（ES）细胞可以维持未分化状态。 LIF 通过由低亲和力 LIF 受体 (LIFR beta) 和 gp130 组成的受体复合物发挥作用，我们报道 gp130 的胞内结构域在 ES 细胞的自我更新中发挥重要作用。在本研究中，我们研究了 gp130 促进 ES 细胞自我更新的信号通路。对gp130胞质结构域的突变分析表明，gp130中负责STAT3激活的酪氨酸残基对于ES细胞的自我更新是必需的，而SHP2和MAP激酶激活所需的酪氨酸残基是可有可无的。接下来，我们构建了由 STAT3 的整个编码区和雌激素受体的配体结合域组成的融合蛋白。在合成配体 4-羟基他莫昔芬 (4HT) 存在的情况下，该构建体 (STAT3ER) 诱导 ES 细胞中 junB（STAT3 的靶标之一）的表达，从而表明 STAT3ER 是一种条件活性形式。转染STAT3ER的ES细胞在4HT存在下培养，维持未分化状态。总而言之，这些结果强烈表明 STAT3 激活是必要的，并且足以维持 ES 细胞的未分化状态。
Embryonic stem (ES) cells can be maintained in an undifferentiated state in the presence of leukemia inhibitory factor (LIF). LIF acts through a receptor complex composed of a low affinity LIF receptor (LIFR beta) and gp130, We reported that the intracellular domain of gp130 plays an important role in self-renewal of ES cells. In the present study, we examined the signaling pathway through which gp130 contributes to the self-renewal of ES cells. Mutational analysis of the cytoplasmic domain of gp130 revealed that the tyrosine residue of gp130 responsible for STAT3 activation is necessary for self-renewal of ES cells, while that required for SHP2 and MAP kinase activation was dispensable. Next, we constructed a fusion protein composed of the entire coding region of STAT3 and the ligand binding domain of the estrogen receptor, This construction (STAT3ER) induced expression of junB (one of the targets of STAT3) in ES cells in the presence of the synthetic ligand 4-hydroxytamoxifen (4HT), thereby indicating that STAT3ER is a conditionally active form. ES cells transfected with STAT3ER cultured in the presence of 4HT maintained an undifferentiated state. Taken together, these results strongly suggest that STAT3 activation is required and sufficient to maintain the undifferentiated state of ES cells.