來自美國西奈山醫(yī)學院,、英國曼徹斯特大學和美國MD安德森癌癥中心的研究人員發(fā)現(xiàn)一種致癌信號通路在胚胎干細胞(MSCs)自我更新以及在將成體細胞重編程為類似胚胎干細胞狀態(tài)的誘導性多能干細胞(iPSCs)中發(fā)揮著新的作用,。這項研究發(fā)表在2012年8月3日那期Cell Stem Cell期刊上。
在這項研究中,，研究人員利用一種功能性基因組策略而鑒定出蛋白激酶極光激酶A(Aurora A, Aurka)是ESC功能中的一個必不可少的組分,。他們還發(fā)現(xiàn)Aurka 通過讓眾所周知的腫瘤抑制記憶p53失活而發(fā)揮作用。p53蛋白是“基因組的衛(wèi)士”,，而且p53基因突變和刪除與一系列腫瘤相關聯(lián),。當Aurka缺失時，上調的p53信號通路導致ESCs分化,，因而失去它們的干細胞狀態(tài),。通過將Aurka缺失與p53再次激活連接起來，研究人員發(fā)現(xiàn)Aurka加入一個磷酸基團(該過程被稱作磷酸化)到p53中的一個氨基酸上,，因而將ESCs從傾向分化的狀態(tài)轉化為自我更新狀態(tài),。
有意思的是，不同于成熟細胞中的低水平p53,，這種蛋白在ESCs和iPSCs中高度表達,。此外，p53還在促進細胞凋亡中發(fā)揮著有限的作用,，同時也在抑制多能性細胞的細胞周期中發(fā)揮著有限作用,。這些發(fā)現(xiàn)將有助于開發(fā)未來的抗癌療法，而且也促進人們理解ESC的自我更新機制,，同時也有助于人們深入認識一種在幾種癌癥中高表達的癌蛋白Aurka所發(fā)揮的作用,。(生物谷：Bioon.com)
本文編譯自Aurka-to-p53 signaling: A link between stem cell regulation and cancer
doi: 10.1016/j.stem.2012.05.020
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Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling
Dung-Fang Lee, Jie Su, Yen-Sin Ang, Xonia Carvajal-Vergara, Sonia Mulero-Navarro, Carlos F. Pereira, Julian Gingold, Hung-Liang Wang, Ruiying Zhao, Ana Sevilla, Henia Darr, Andrew J.K. Williamson, Betty Chang, Xiaohong Niu, Francesca Aguilo, Elsa R. Flores, Yuh-Pyng Sher, Mien-Chie Hung, Anthony D. Whetton, Bruce D. Gelb, Kateri A. Moore, Hans-Willem Snoeck, Avi Ma’ayan, Christoph Schaniel, Ihor R. Lemischka
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.
