Article

Regulation of hypoxic death in C-elegans by the insulin/IGF receptor homolog DAF-2

Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 31.48). 07/2002; 296(5577):2388-91. DOI: 10.1126/science.1072302
Source: PubMed

ABSTRACT To identify genetic determinants of hypoxic cell death, we screened for hypoxia-resistant (Hyp) mutants in Caenorhabditis elegans and found that specific reduction-of-function (rf) mutants of daf-2, an insulin/insulinlike growth factor (IGF) receptor (INR) homolog gene, were profoundly Hyp. The hypoxia resistance was acutely inducible just before hypoxic exposure and was mediated through an AKT-1/PDK-1/forkhead transcription factor pathway overlapping with but distinct from signaling pathways regulating life-span and stress resistance. Selective neuronal and muscle expression of daf-2(+) restored hypoxic death, and daf-2(rf) prevented hypoxia-induced muscle and neuronal cell death, which demonstrates a potential for INR modulation in prophylaxis against hypoxic injury of neurons and myocytes.

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    • "Owing to its broad oxygen tolerance and lack of a circulatory system, C. elegans has been a particularly useful model system to study the genetic responses to hypoxia and the effects of hypoxia on longevity. Adult worms can survive prolonged anoxia and, interestingly, lifespanextending mutations in the worm insulin-like receptor daf2 also lead to increased survival in high temperature hypoxia or extended anoxia (Mendenhall, LaRue, & Padilla, 2006; Scott, Avidan, & Crowder, 2002; Van Voorhies & Ward, 2000). A simple interpretation of this result is that reduced insulin-like signaling preconditions animals for decreased oxygen consumption and increased reliance on glycolysis. "
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    • "3.3. daf-2 alleles have opposite selenium responsive phenotypes under high temperature stress There are over 40 daf-2 alleles that have been isolated and these have been described to express a range of phenotypes in response to environmental and oxidative stressors (Ackerman and Gems, 2012; Honda and Honda, 2002; Scott et al., 2002; Gems et al., 1998). Most recently, Vaccaro et al. (2012) showed that the e1370 allele enhanced neurodegeneration in a worm TDP43/TDP-1 ALS model while another allele e1368 suppressed the neurodegeneration . "
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    • "This conserved function is manifested in regulation of dauer formation, stress resistance, and lifespan in C. elegans. Mutations affecting the sole insulinlike receptor DAF-2/InsR (Figure 2) form dauers constitutively (Riddle et al. 1981; Hu 2007), are stress resistant (Honda and Honda 1999; Scott et al. 2002; Lamitina and Strange 2005), and extend adult lifespan (Kenyon et al. 1993; Kimura et al. 1997). Strong loss-of-function alleles also display constitutive L1 arrest (Gems et al. 1998). "
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