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Dev Cell. 2015 Jun 8;33(5):507-21. doi: 10.1016/j.devcel.2015.04.021. Epub 2015 May 28.

HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes.

Author information

1
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.
2
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
5
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
6
Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, FL 32160, USA.
7
Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EG Cambridge, UK.
8
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
9
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.
10
Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA 91711, USA. Electronic address: azambon@kgi.edu.

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.

PMID:
26028220
PMCID:
PMC4509618
DOI:
10.1016/j.devcel.2015.04.021
[Indexed for MEDLINE]
Free PMC Article

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