A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells
A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells
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DOI：
10.1073/pnas.0909734107
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
Huang, Jing
中科院分区：
文献类型：
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作者：
Lee, Kyoung-Hwa;Li, Mangmang;Huang, Jing
p53和Wnt信号通路在调节小鼠胚胎干细胞（mESCs）分化中起重要作用。然而，尚不清楚它们是否在mESC中直接和/或功能性地串扰。在这里，我们报告了一个令人惊讶的抗分化功能的p53在mESCs通过直接调节Wnt信号通路。基于染色质免疫沉淀的微阵列（ChIP芯片）和基因表达微阵列分析显示，Wnt信号通路在mESC中的p53调控基因中显著（P值0.000048）过度表达。五个Wnt配体基因的表达是强烈诱导的各种基因毒性和非基因毒性的侮辱在p53依赖性的方式。此外，这些Wnt基因的诱导在小鼠胚胎成纤维细胞（MEF）细胞和ESC衍生的神经干/祖细胞中大大减弱，表明诱导是mESC特异性的。已经确定Wnt信号通路的激活抑制mESC的分化。与这一概念相一致，我们检测到从UV（UV）处理的mESC收集的条件培养基（CM）的抗分化活性。这种抗分化活性可以通过向CM中加入Wnt拮抗剂或降低UV处理的mESC中的p53水平来降低。因此，p53在体细胞中具有死亡和存活的双重功能，似乎可以调节mESC中的促分化和抗分化程序。我们的研究结果揭示了p53和Wnt信号通路之间的直接和功能性联系，并扩大了mESC中p53调控基因的目录。
Both p53 and the Wnt signaling pathway play important roles in regulating the differentiation of mouse embryonic stem cells (mESCs). However, it is not known whether they directly and/or functionally crosstalk in mESCs. Here we report a surprising anti-differentiation function of p53 in mESCs through directly regulating the Wnt signaling pathway. A chromatin-immunoprecipitation-based microarray (ChIP-chip) and gene expression microarray assays reveal that the Wnt signaling pathway is significantly (P value, 0.000048) overrepresented in p53-regulated genes in mESCs. The expression of five Wnt ligand genes is robustly induced by various genotoxic and nongenotoxic insults in a p53-dependent manner. Moreover, the induction of these Wnt genes is greatly attenuated in mouse embryonic fibroblast (MEF) cells and ESC-derived neural stem/progenitor cells, suggesting that the induction is mESC specific. It is established that the activation of the Wnt signaling pathway inhibits the differentiation of mESCs. Consistent with this notion, we detected an antidifferentiation activity from the conditioned medium (CM) collected from UV (UV)-treated mESCs. This antidifferentiation activity can be lowered by either the addition of Wnt antagonists into the CM or the reduction of p53 levels in UV-treated mESCs. Therefore, reminiscent of its dual functions on death and survival in somatic cells, p53 appears to regulate both prodifferentiation and antidifferentiation programs in mESCs. Our findings uncover a direct and functional connection between p53 and the Wnt signaling pathway, and expand the catalog of p53 regulated genes in mESCs.