Abstract
The Caenorhabditis elegans von Hippel-Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.
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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Aging / physiology*
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Amyloid beta-Peptides / toxicity
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Animals
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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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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Caloric Restriction
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Cullin Proteins / genetics
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Cullin Proteins / metabolism*
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Female
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Fertility
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Gene Expression Regulation
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Homeostasis
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Insulin / metabolism
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Longevity / physiology
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Male
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Models, Animal
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Oxygen / physiology*
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Peptides / toxicity
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Proteasome Endopeptidase Complex / metabolism*
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RNA Interference
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Ubiquitination
Substances
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Amyloid beta-Peptides
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Caenorhabditis elegans Proteins
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Cullin Proteins
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Egl-9 protein, C elegans
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HIF-1 protein, C elegans
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Insulin
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Peptides
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Transcription Factors
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VHL-1 protein, C elegans
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polyglutamine
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DAF-2 protein, C elegans
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Receptor, Insulin
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Proteasome Endopeptidase Complex
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Oxygen