title: Angiomodulin is required for cardiogenesis of embryonic stem cells and is maintained by a feedback loop network of p63 and Activin-A.
abstract: The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and ΔNp63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development.
authors.affiliation: INSERTECH, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Wolchinsky
authors.affiliation: INSERTECH, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Shoham
authors.initials: S
authors.lastname: Shivtiel
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centrum, The Netherlands.
authors.forename: Evelyn Nathalie
authors.initials: EN
authors.lastname: Kouwenhoven
authors.affiliation: INSERTECH, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Daria
authors.initials: D
authors.lastname: Putin
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centrum, The Netherlands; Department of Molecular Developmental Biology, Radboud University Nijmegen, The Netherlands.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Laboratoire de PhysioMédecine Moléculaire, CNRS FRE-3472, Nice, France; University of Nice-Sophia Antipolis, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rouleau
authors.affiliation: INSERTECH, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; INSERM U976, Paris, France; University of Paris Diderot, France. Electronic address: daniel.aberdam@inserm.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aberdam
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000166:cytology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C422405:activin A; C103008:inhibin beta A subunit; C086009:tumor-derived adhesion factor; D028341:Activins; D028322:Inhibin-beta Subunits