Abstract
The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Cell Nucleus / metabolism
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Epistasis, Genetic
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Forkhead Transcription Factors
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Gene Expression Regulation
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Herbicides / pharmacology
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Host Cell Factor C1 / genetics
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Host Cell Factor C1 / metabolism*
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Longevity / physiology*
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Models, Genetic
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Oxidative Stress
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Paraquat / pharmacology
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Phenotype
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Promoter Regions, Genetic
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RNA Interference
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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Survival Rate
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
Substances
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Caenorhabditis elegans Proteins
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Forkhead Transcription Factors
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Herbicides
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Host Cell Factor C1
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Multiprotein Complexes
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Recombinant Fusion Proteins
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Transcription Factors
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daf-16 protein, C elegans
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hcf-1 protein, C elegans
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Paraquat