Article
- The EMBO Journal (2004) 23, 1949 - 1956
- doi:10.1038/sj.emboj.7600196
Published online: 8 April 2004
Subject Categories:
HIF-1
induces cell cycle arrest by functionally counteracting Myc
Minori Koshiji1, Yukio Kageyama1, Erin A Pete1, Izumi Horikawa2, J Carl Barrett2 and L Eric Huang1
- Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Biosystems and Cancer, NCI, National Institutes of Health, Bethesda, MD, USA
Correspondence to:
L Eric Huang, 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@mail.nih.gov
Received 19 November 2003; Accepted 9 March 2004
Abstract
Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1
, 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-1
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-1
, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21cip1. The HIF-1
antagonism is mediated by displacing Myc binding from p21cip1 promoter. Neither HIF-1
transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF-1
. In keeping with its antagonism of Myc, HIF-1
also downregulates Myc-activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF-1
pathway, which regulates a distinct group of Myc target genes in response to hypoxia.
Keywords:
- cell cycle,
- HIF-1
, - hypoxia,
- Myc,
- p21cip1
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