HIF‐1α induces cell cycle arrest by functionally counteracting Myc

Minori Koshiji, Yukio Kageyama, Erin A Pete, Izumi Horikawa, J Carl Barrett, L Eric Huang

Author Affiliations

  1. Minori Koshiji1,
  2. Yukio Kageyama1,
  3. Erin A Pete1,
  4. Izumi Horikawa2,
  5. J Carl Barrett2 and
  6. L Eric Huang*,1
  1. 1 Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD, USA
  2. 2 Laboratory of Biosystems and Cancer, NCI, National Institutes of Health, Bethesda, MD, USA
  1. *Corresponding author. NIH, National Cancer Institute, Bldg 37, Room 3044B, 37 Convent Dr. MSC4255, Bethesda, MD 20892, USA. Tel.: +1 301 402 8785; Fax: +1 301 480 1264; E-mail: huange{at}
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Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF‐1α, 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‐1α for hypoxia‐induced growth arrest and activation of p21cip1, a key cyclin‐dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21cip1 activation has been elusive. Here we demonstrate that HIF‐1α, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21cip1. The HIF‐1α antagonism is mediated by displacing Myc binding from p21cip1 promoter. Neither HIF‐1α transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF‐1α. In keeping with its antagonism of Myc, HIF‐1α also downregulates Myc‐activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF‐1α pathway, which regulates a distinct group of Myc target genes in response to hypoxia.

  • Received November 19, 2003.
  • Accepted March 9, 2004.
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