A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells.
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 antidifferentiation 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.
Lee
Kyoung-Hwa
KH
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Li
Mangmang
M
Michalowski
Aleksandra M
AM
Zhang
Xinyue
X
Liao
Hongling
H
Chen
Lingyi
L
Xu
Yang
Y
Wu
Xiaolin
X
Huang
Jing
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology; D000071317:Nanog Homeobox Protein; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D017077:Culture Media, Conditioned; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D004317:Doxorubicin