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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Cell Proliferation*
  • Cells, Cultured
  • Embryo, Mammalian / cytology*
  • Embryo, Mammalian / metabolism
  • Female
  • Fetus / cytology*
  • Fetus / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Hypoxia / physiopathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Atf4 protein, mouse
  • Biomarkers
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Activating Transcription Factor 4

Associated data

  • GEO/GSE61209
  • GEO/GSE61247