Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
J Biol Chem. 2010 Mar 19;285(12):9180-9. doi: 10.1074/jbc.M109.077958. Epub 2010 Jan 13.
Transcription factor Kruppel-like factor 4 (Klf4) is essential for somatic cell reprogramming. In addition, Klf4 seems to play a redundant role along with other Klf family proteins in embryonic stem (ES) cell self-renewal. However, how Klf4 regulates ES cell self-renewal and somatic cell reprogramming is still poorly understood. Here we report that Klf4 is required for both ES cell self-renewal and maintenance of pluripotency and that the expression of Klf4 prevents ES cell differentiation in response to withdrawal of leukemia inhibitory factor (LIF) or bone morphogenetic protein 4 (BMP4). In addition, Klf4 directly binds to the promoter region of Nanog and regulates its expression. Expression of Nanog prevents ES cell differentiation even when Klf4 gene expression is knocked down. On the other hand, knockdown of Nanog expression induces differentiation of ES cells that overexpress Klf4. Taken together, these results demonstrate that Klf4 functions upstream of Nanog in ES cell self-renewal and in preventing ES cell differentiation.
转录因子 Kruppel 样因子 4（Klf4）对于体细胞重编程是必需的。此外，Klf4 似乎与其他 Klf 家族蛋白在胚胎干细胞（ES 细胞）自我更新中发挥冗余作用。然而，Klf4 如何调节 ES 细胞自我更新和体细胞重编程仍然知之甚少。在这里，我们报告 Klf4 对于 ES 细胞自我更新和多能性的维持都是必需的，并且 Klf4 的表达可以防止 ES 细胞对白血病抑制因子（LIF）或骨形态发生蛋白 4（BMP4）的撤去做出反应而分化。此外，Klf4 可以直接结合 Nanog 的启动子区域并调节其表达。即使敲低 Klf4 基因表达，Nanog 的表达也可以防止 ES 细胞分化。另一方面，敲低 Nanog 的表达会诱导过表达 Klf4 的 ES 细胞分化。综上所述，这些结果表明，Klf4 在 ES 细胞自我更新和防止 ES 细胞分化中位于 Nanog 的上游。
