Regulation of hypoxic death in C. elegans by the insulin/IGF receptor homolog DAF-2.
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.
Scott
Barbara A
BA
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Avidan
Michael S
MS
Crowder
C Michael
CM
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000483:Alleles; D000818:Animals; D001369:Axons / Q000648:ultrastructure; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D002467:Cell Nucleus / Q000648:ultrastructure; D002470:Cell Survival; D051858:Forkhead Transcription Factors; D017238:Genes, Helminth; D000860:Hypoxia / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008136:Longevity; D009068:Movement; D009132:Muscles / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D014157:Transcription Factors; C116661:DAF-18 protein, C elegans; C108831:daf-16 protein, C elegans; C442437:tkr-1 protein, C elegans; C100662:AGE-1 protein, C elegans; C107483:DAF-2 protein, C elegans