来自美国西奈山医学院、英国曼彻斯特大学和美国MD安德森癌症中心的研究人员发现一种致癌信号通路在胚胎干细胞(MSCs)自我更新以及在将成体细胞重编程为类似胚胎干细胞状态的诱导性多能干细胞(iPSCs)中发挥着新的作用。这项研究发表在2012年8月3日那期Cell Stem Cell期刊上。
在这项研究中,研究人员利用一种功能性基因组策略而鉴定出蛋白激酶极光激酶A(Aurora A, Aurka)是ESC功能中的一个必不可少的组分。他们还发现Aurka 通过让众所周知的肿瘤抑制记忆p53失活而发挥作用。p53蛋白是“基因组的卫士”,而且p53基因突变和删除与一系列肿瘤相关联。当Aurka缺失时,上调的p53信号通路导致ESCs分化,因而失去它们的干细胞状态。通过将Aurka缺失与p53再次激活连接起来,研究人员发现Aurka加入一个磷酸基团(该过程被称作磷酸化)到p53中的一个氨基酸上,因而将ESCs从倾向分化的状态转化为自我更新状态。
有意思的是,不同于成熟细胞中的低水平p53,这种蛋白在ESCs和iPSCs中高度表达。此外,p53还在促进细胞凋亡中发挥着有限的作用,同时也在抑制多能性细胞的细胞周期中发挥着有限作用。这些发现将有助于开发未来的抗癌疗法,而且也促进人们理解ESC的自我更新机制,同时也有助于人们深入认识一种在几种癌症中高表达的癌蛋白Aurka所发挥的作用。(生物谷:Bioon.com)
本文编译自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.