Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation

Cell Death Differ. 2008 Apr;15(4):672-7. doi: 10.1038/sj.cdd.4402302. Epub 2008 Jan 11.


The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1alpha. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the proto-oncoprotein c-Myc appears to be the diametrical opposite of HIF-1alpha in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-alpha-c-Myc molecular pathway in the hypoxic response. It has been shown that HIF-alpha engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of c-Myc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF-alpha for the regulation of hypoxia-responsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Cycle
  • Cell Hypoxia
  • Cell Proliferation
  • DNA Repair Enzymes / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mitochondria / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins c-myc
  • endothelial PAS domain-containing protein 1
  • DNA Repair Enzymes