Cyclin K-containing Kinase Complexes Maintain Self-renewal in Murine Embryonic Stem Cells
Cyclin K-containing Kinase Complexes Maintain Self-renewal in Murine Embryonic Stem Cells
复制标题
含细胞周期蛋白 K 的激酶复合物维持小鼠胚胎干细胞的自我更新
DOI：
10.1074/jbc.m111.321760
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发表时间：
2012-07-20
影响因子：
4.8
通讯作者：
Li, Qintong
中科院分区：
文献类型：
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作者：
Dai, Qian;Lei, Tingjun;Li, Qintong
蛋白磷酸化在胚胎干细胞的自我更新和分化调控中起着重要作用。然而，负责的细胞内激酶并没有很好地表征。在这里，我们发现细胞周期蛋白K蛋白在多能胚胎干细胞中高度表达，但在其分化衍生物或组织特异性干细胞中表达较低。细胞分化后，细胞周期蛋白K水平降低。此外，cyclin K的敲低导致细胞分化，这可以通过抗RNA干扰的表达构建来挽救。令人惊讶的是，细胞周期蛋白K并不像之前认为的那样与细胞中的CDK9蛋白相互作用。相反，它与CrkRS（也称为CDK12）和CDC2L5（也称为CDK13）相关。与细胞周期蛋白K相似，CDK12和CDK13蛋白在小鼠胚胎干细胞中均有高表达，并在细胞分化过程中表达减少。重要的是，两种激酶的敲低都会导致分化。因此，我们的研究发现了两种维持胚胎干细胞自我更新的新型蛋白激酶复合物。
Protein phosphorylation plays an important role in the regulation of self-renewal and differentiation of embryonic stem cells. However, the responsible intracellular kinases are not well characterized. Here, we discovered that cyclin K protein was highly expressed in pluripotent embryonic stem cells but low in their differentiated derivatives or tissue-specific stem cells. Upon cell differentiation, the level of cyclin K protein was decreased. Furthermore, knockdown of cyclin K led to cell differentiation, which could be rescued by an expression construct resistant to RNA interference. Surprisingly, cyclin K did not interact with CDK9 protein in cells as thought previously. Instead, it associated with CrkRS (also known as CDK12) and CDC2L5 (also known as CDK13). Similar to cyclin K, both CDK12 and CDK13 proteins were highly expressed in murine embryonic stem cells and were decreased upon cell differentiation. Importantly, knockdown of either kinase resulted in differentiation. Thus, our studies have uncovered two novel protein kinase complexes that maintain self-renewal in embryonic stem cells.