Linking the p53 tumour suppressor pathway to somatic cell reprogramming.
Linking the p53 tumour suppressor pathway to somatic cell reprogramming.
复制标题
作者：
通过表达多能性因子和癌基因已经完成了将体细胞重编程为诱导多能干细胞（iPS），但是低频率和诱导恶性转化的倾向损害了这种强大方法的临床实用性。我们通过研究限制体细胞重编程效率的机制来解决这两个问题。我们发现重编程因子可以激活p53通路。通过表达其负调控因子之一的突变版本、通过缺失或沉默p53或其靶基因p21或通过拮抗凋亡来减少p53的信号传导增强了三因子（Oct4/Sox2/Klf4）介导的小鼠成纤维细胞重编程。值得注意的是，降低p53蛋白水平使成纤维细胞能够产生能够仅使用Oct4和Sox 2产生生殖系传递嵌合小鼠的iPS细胞。此外，沉默p53显著增加了人类体细胞的重编程效率。这些结果提供了对重编程机制的见解，并提出了更有效的重编程新途径，同时最大限度地减少了癌基因的使用。
Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. We show that reprogramming factors can activate the p53 pathway. Reducing signaling to p53 by expressing a mutated version of one of its negative regulators, by deleting or silencing p53 or its target gene, p21, or by antagonizing apoptosis enhanced three factor (Oct4/Sox2/Klf4)-mediated reprogramming of mouse fibroblasts. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline transmitting chimeric mice using only Oct4 and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.
登录
查看更多内容
影响因子：
23.9
作者：
Shi, Yan;Desponts, Caroline;Ding, Sheng
通讯作者：
Ding, Sheng
影响因子：
21.3
作者：
Jiang, Jianming;Chan, Yun-Shen;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
影响因子：
64.8
作者：
Park, In-Hyun;Zhao, Rui;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
4
作者：
Marine, Jean-Christophe W.;Dyer, Michael A.;Jochemsen, Aart G.
通讯作者：
Jochemsen, Aart G.
影响因子：
23.9
作者：
Kim D;Kim CH;Moon JI;Chung YG;Chang MY;Han BS;Ko S;Yang E;Cha KY;Lanza R;Kim KS
通讯作者：
Kim KS