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

EMBO J. 2004 May 5;23(9):1949-56. doi: 10.1038/sj.emboj.7600196. Epub 2004 Apr 8.

Abstract

Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1alpha, a basic helix-loop-helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF-1alpha for hypoxia-induced growth arrest and activation of p21(cip1), a key cyclin-dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21(cip1) activation has been elusive. Here we demonstrate that HIF-1alpha, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21(cip1). The HIF-1alpha antagonism is mediated by displacing Myc binding from p21(cip1) promoter. Neither HIF-1alpha transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF-1alpha. In keeping with its antagonism of Myc, HIF-1alpha also downregulates Myc-activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF-1alpha pathway, which regulates a distinct group of Myc target genes in response to hypoxia.

Publication types

  • Comparative Study

MeSH terms

  • Adenoviridae
  • Animals
  • BRCA1 Protein / metabolism
  • Binding, Competitive / genetics
  • Blotting, Western
  • COS Cells
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Chlorocebus aethiops
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA Primers
  • DNA-Binding Proteins / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Genetic Vectors / genetics
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoprecipitation
  • Microscopy, Confocal
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Telomerase / metabolism
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • BRCA1 Protein
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA Primers
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MYC protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Telomerase