Abstract
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
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Adenoviridae
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Animals
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BRCA1 Protein / metabolism
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Binding, Competitive / genetics
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Blotting, Western
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COS Cells
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Cell Cycle / physiology*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Chlorocebus aethiops
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Chromatin Immunoprecipitation
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Cyclin-Dependent Kinase Inhibitor p21
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DNA Primers
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DNA-Binding Proteins / metabolism*
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Enzyme-Linked Immunosorbent Assay
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Fluorescent Antibody Technique
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Gene Expression Regulation*
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Genetic Vectors / genetics
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Humans
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Hypoxia / metabolism*
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunoprecipitation
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Microscopy, Confocal
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Nuclear Proteins / metabolism*
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / physiology*
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Telomerase / metabolism
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Transcription Factors / metabolism*
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Transfection
Substances
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BRCA1 Protein
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA Primers
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DNA-Binding Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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MYC protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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Transcription Factors
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Telomerase