Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cell Stem Cell. 2012 Aug 3;11(2):179-94. doi: 10.1016/j.stem.2012.05.020.
Many signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming.
许多信号必须被整合，以维持胚胎干细胞（ESCs）的自我更新和多能性，并使诱导多能干细胞（iPSC）重编程。然而，确切的分子调控机制仍不清楚。为了解开维持 ESC 状态所需的内在和外在信号的基本原理，我们对 104 个与 ESC 相关的磷酸化调节剂进行了短发夹（sh）RNA 筛选。这种分子之一的 Aurora 激酶 A（Aurka）的缺失导致自我更新受损，随后出现分化。通过整合全基因表达和计算分析，我们发现 Aurka 的缺失会导致 p53 活性上调，从而触发 ESC 分化。具体来说，Aurka 通过磷酸化介导的对 p53 指导的外胚层和中胚层基因表达的抑制来调节多能性。p53 的磷酸化不仅会损害 p53 诱导的 ESC 分化，还会抑制 p53 介导的 iPSC 重编程。我们的研究表明，Aurka-p53 信号在调节自我更新、分化和体细胞重编程方面起着重要作用。
