Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.
Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.
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诱导多能干细胞（iPS）可以通过在小鼠和人中引入Oct 3/4、Sox 2、Klf 4和c-Myc从体细胞产生。然而，这种方法的效率很低。多能性可以在没有c-Myc的情况下诱导，但效率甚至更低。最近显示p53 siRNA促进人iPS细胞生成，但特异性和机制仍有待确定。在这里，我们报告说，高达10%的转导小鼠胚胎成纤维细胞（MEF）缺乏p53成为iPS细胞，即使没有Myc逆转录病毒。p53缺失也促进了质粒转染的无整合小鼠iPS细胞的诱导。此外，在p53无效背景下，iPS细胞由终末分化的T淋巴细胞产生。p53的抑制也增加了人iPS细胞生成的效率。DNA微阵列分析确定了34个p53调控基因，这些基因在小鼠和人类成纤维细胞中很常见。这些基因的功能分析表明，p53-p21通路不仅在致瘤性中起保护作用，而且在iPS细胞生成中起保护作用。
Induced pluripotent stem (iPS) cells can be generated from somatic cells by introduction of Oct3/4, Sox2, Klf4 and c-Myc, in mouse and human. Efficiency of this process, however, is low. Pluripotency can be induced without c-Myc, but with even lower efficiency. A p53 siRNA was recently shown to promote human iPS cell generation, but specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts (MEF) lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. Suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53-p21 pathway serves as a safeguard not only in tumorigenicity, but also in iPS cell generation.