HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.
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.
Mesh Terms:
Adenoviridae, Animals, Anoxia, BRCA1 Protein, Binding, Competitive, Blotting, Western, COS Cells, Cell Cycle, Cell Cycle Proteins, Cercopithecus aethiops, Chromatin Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, DNA Primers, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Gene Expression Regulation, Genetic Vectors, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoprecipitation, Microscopy, Confocal, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Telomerase, Transcription Factors, Transfection
Adenoviridae, Animals, Anoxia, BRCA1 Protein, Binding, Competitive, Blotting, Western, COS Cells, Cell Cycle, Cell Cycle Proteins, Cercopithecus aethiops, Chromatin Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, DNA Primers, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Gene Expression Regulation, Genetic Vectors, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoprecipitation, Microscopy, Confocal, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Telomerase, Transcription Factors, Transfection
EMBO J.
Date: May. 05, 2004
PubMed ID: 15071503
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