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 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-1, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21^cip1. The HIF-1 antagonism is mediated by displacing Myc binding from p21^cip1 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.