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Related Experiment Videos

HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.

Minori Koshiji1, Yukio Kageyama, Erin A Pete

  • 1Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD 20892, USA.

The EMBO Journal
|April 9, 2004
PubMed
Summary

Hypoxia-inducible factor 1-alpha (HIF-1alpha) triggers cell cycle arrest by counteracting Myc, independent of hypoxia. This mechanism derepresses p21(cip1), revealing a novel HIF-1alpha-Myc pathway in oxygen homeostasis.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Hypoxia (low oxygen) is a critical factor influencing cell behavior, promoting survival through angiogenesis and glycolysis, but also inducing growth arrest and apoptosis.
  • HIF-1alpha (Hypoxia-inducible factor 1-alpha) is a key transcription factor regulating the cellular response to oxygen levels.
  • The precise mechanism by which HIF-1alpha induces cell cycle arrest and p21(cip1) activation under hypoxia has remained unclear.

Purpose of the Study:

  • To elucidate the mechanism of HIF-1alpha-mediated cell cycle arrest and p21(cip1) activation.
  • To investigate the interaction between HIF-1alpha and Myc in regulating cell cycle progression.
  • To identify novel pathways involved in cellular response to hypoxia.

Main Methods:

Related Experiment Videos

  • Investigated HIF-1alpha's role in cell cycle arrest independent of hypoxic conditions.
  • Analyzed the functional antagonism between HIF-1alpha and Myc.
  • Examined the impact of HIF-1alpha on Myc binding to the p21(cip1) promoter.
  • Assessed the necessity of HIF-1alpha transcriptional activity and DNA binding for cell cycle arrest.
  • Evaluated the effect of HIF-1alpha on Myc-activated gene expression (hTERT, BRCA1).

Main Results:

  • HIF-1alpha induces cell cycle arrest even without hypoxic signals by functionally counteracting Myc.
  • HIF-1alpha derepresses p21(cip1) by displacing Myc from the p21(cip1) promoter.
  • Neither HIF-1alpha's transcriptional activity nor its DNA binding is required for this cell cycle arrest, suggesting a non-canonical role.
  • HIF-1alpha downregulates Myc-activated genes, including hTERT and BRCA1.

Conclusions:

  • A novel pathway exists where HIF-1alpha antagonizes Myc to regulate cell cycle progression and gene expression.
  • Myc is an integral component of a HIF-1alpha-mediated pathway that controls specific Myc target genes in response to hypoxia.
  • HIF-1alpha plays a divergent role in cell cycle regulation, separate from its canonical transcriptional functions.