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23 (9): 1949-1956

Copyright © 2004 by the European Molecular Biology Organization.

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

Minori Koshiji1, Yukio Kageyama1, Erin A Pete1, Izumi Horikawa2, J Carl Barrett2, and L Eric Huang1,+

1 Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD, USA
2 Laboratory of Biosystems and Cancer, NCI, National Institutes of Health, Bethesda, MD, USA

Abstract: Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1{alpha}, 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{alpha} 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{alpha}, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21cip1. The HIF-1{alpha} antagonism is mediated by displacing Myc binding from p21cip1 promoter. Neither HIF-1{alpha} transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF-1{alpha}. In keeping with its antagonism of Myc, HIF-1{alpha} also downregulates Myc-activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF-1{alpha} pathway, which regulates a distinct group of Myc target genes in response to hypoxia.

Key Words: cell cycle • HIF-1{alpha} • hypoxia • Myc • p21cip1

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882