title: HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes.
abstract: Transcriptional mediators of cell stress pathways, including HIF1α, ATF4, and p53, are key to normal development and play critical roles in disease, including ischemia and cancer. Despite their importance, mechanisms by which pathways mediated by these transcription factors interact with one another are not fully understood. In addressing the controversial role of HIF1α in cardiomyocytes (CMs) during heart development, we discovered a mid-gestational requirement for HIF1α for proliferation of hypoxic CMs, involving metabolic switching and a complex interplay among HIF1α, ATF4, and p53. Loss of HIF1α resulted in activation of ATF4 and p53, the latter inhibiting CM proliferation. Bioinformatic and biochemical analyses revealed unexpected mechanisms by which HIF1α intersects with ATF4 and p53 pathways. Our results highlight previously undescribed roles of HIF1α and interactions among major cell stress pathways that could be targeted to enhance proliferation of CMs in ischemia and may have relevance to other diseases, including cancer.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Biomedical Sciences Abel Salazar and GABBA Graduate Program, University of Porto, Porto 4050-313, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Guimarães-Camboa
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stowe
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Aneas
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Noboru
authors.initials: N
authors.lastname: Sakabe
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Cattaneo
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Henderson
authors.affiliation: Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, FL 32160, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EG Cambridge, UK.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Nobrega
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: syevans@ucsd.edu.
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA 91711, USA. Electronic address: azambon@kgi.edu.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Zambon
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C081452:Atf4 protein, mouse; D015415:Biomarkers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051701:Activating Transcription Factor 4