Article
HIF1a Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes
Highlights Authors d HIF1a is required for proliferation of a subset of Nuno Guimara˜ es-Camboa, cardiomyocytes at mid-gestation Jennifer Stowe, ..., Sylvia M. Evans, Alexander C. Zambon d HIF1a targets genes regulating both energy metabolism and the cell cycle Correspondence [email protected] (S.M.E.), d HIF1a promotes Mif expression to prevent p53 activation [email protected] (A.C.Z.) d HIF1a represses ATF4 signaling In Brief Guimara˜ es-Camboa et al. demonstrate that before completion of cardiac angiogenesis, subsets of highly proliferative fetal cardiomyocytes display nuclear accumulation of HIF1a. Cardiac ablation of HIF1a and subsequent mechanistic analyses suggest that this transcription factor promotes proliferation of hypoxic fetal cardiomyocytes by regulating multiple cellular functions, including ATF4 and p53 signaling.
Accession Numbers GSE61209 GSE61247
Guimara˜ es-Camboa et al., 2015, Developmental Cell 33, 507–521 June 8, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.devcel.2015.04.021 Developmental Cell Article
HIF1a Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes
Nuno Guimara˜ es-Camboa,1,2 Jennifer Stowe,3 Ivy Aneas,4 Noboru Sakabe,4 Paola Cattaneo,1 Lindsay Henderson,5 Michael S. Kilberg,6 Randall S. Johnson,7 Ju Chen,8 Andrew D. McCulloch,3 Marcelo A. Nobrega,4 Sylvia M. Evans,1,5,8,* and Alexander C. Zambon9,* 1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA 2Institute for Biomedical Sciences Abel Salazar and GABBA Graduate Program, University of Porto, Porto 4050-313, Portugal 3Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA 4Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA 5Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA 6Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, FL 32160, USA 7Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EG Cambridge, UK 8Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA 9Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA 91711, USA *Correspondence: [email protected] (S.M.E.), [email protected] (A.C.Z.) http://dx.doi.org/10.1016/j.devcel.2015.04.021
SUMMARY proliferate. Understanding the pathways that regulate prolifera- tion of fCMs will allow a better understanding of congenital heart Transcriptional mediators of cell stress pathways, disease, the most prevalent human birth defect, and may also including HIF1a, ATF4, and p53, are key to normal provide potential pathways for triggering adult CM regeneration. development and play critical roles in disease, To identify regulators of fCM proliferation, we undertook an including ischemia and cancer. Despite their impor- in silico screen that suggested that hypoxia inducible factor a a tance, mechanisms by which pathways mediated 1 (HIF1 ), a transcription factor (TF) activated by low oxygen, by these transcription factors interact with one mediates a pro-proliferative response during cardiac develop- ment. In well-perfused tissues, HIF1a subunits are hydroxylated another are not fully understood. In addressing the and targeted for proteasomal degradation via VHL-mediated controversial role of HIF1a in cardiomyocytes (CMs) ubiquitination. Hypoxia ([O2]<