title: The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells.
abstract: In this study, we outline a regulatory network that involves the p53 tumor suppressor family and the Wnt pathway acting together with the TGF-β pathway in mesendodermal differentiation of mouse and human embryonic stem cells. Knockout of all three members, p53, p63, and p73, shows that the p53 family is essential for mesendoderm specification during exit from pluripotency in embryos and in culture. Wnt3 and its receptor Fzd1 are direct p53 family target genes in this context, and induction of Wnt signaling by p53 is critical for activation of mesendodermal differentiation genes. Globally, Wnt3-activated Tcf3 and nodal-activated Smad2/3 transcription factors depend on each other for co-occupancy of target enhancers associated with key differentiation loci. Our results therefore highlight an unanticipated role for p53 family proteins in a regulatory network that integrates essential Wnt-Tcf and nodal-Smad inputs in a selective and interdependent way to drive mesendodermal differentiation of pluripotent cells.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Nowotschin
authors.affiliation: Rodent Genetic Engineering Core, Langone Medical Center, New York University, New York, NY 10016, USA.
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY 10065, USA.
authors.forename: Qing V
authors.initials: QV
authors.lastname: Li
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chew-Li
authors.initials: CL
authors.lastname: Soh
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Medicine and Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Shu
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Qiaoran
authors.initials: Q
authors.lastname: Xi
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Danwei
authors.initials: D
authors.lastname: Huangfu
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: j-massague@ski.mskcc.org.
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D047108:Embryonic Development; D004707:Endoderm / Q000166:cytology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D055457:Nodal Protein / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D051785:Smad Proteins / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D000072160:Tumor Protein p73 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D060508:Wnt3 Protein / Q000378:metabolism*
chemical_list: D055457:Nodal Protein; D010750:Phosphoproteins; D051785:Smad Proteins; D051820:TCF Transcription Factors; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D060508:Wnt3 Protein
keywords: Smad; TGF-β; Tcf; Wnt; embryonic stem cells; mesendoderm differentiation; p53 tumor suppressor; transcription