PMID:19372390

Citation	Mehta, R, Steinkraus, KA, Sutphin, GL, Ramos, FJ, Shamieh, LS, Huh, A, Davis, C, Chandler-Brown, D and Kaeberlein, M (2009) Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science 324:1196-8
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.
Links	PubMed PMC2737476 Online version:10.1126/science.1173507
Keywords	Aging/physiology; Amyloid beta-Peptides/toxicity; Animals; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans/physiology; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Caloric Restriction; Cullin Proteins/genetics; Cullin Proteins/metabolism; Female; Fertility; Gene Expression Regulation; Homeostasis; Insulin/metabolism; Longevity/physiology; Male; Models, Animal; Oxygen/physiology; Peptides/toxicity; Proteasome Endopeptidase Complex/metabolism; RNA Interference; Receptor, Insulin/genetics; Receptor, Insulin/metabolism; Signal Transduction; Transcription Factors/genetics; Transcription Factors/metabolism; Ubiquitination
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