divergent mechanisms controlling hypoxic sensitivity and lifespan by the daf-2insulinigf-receptor pathway发散机制控制缺氧daf-2insulinigf-receptor敏感性和寿命的途径.pdfVIP

Divergent Mechanisms Controlling Hypoxic Sensitivity and Lifespan by the DAF-2/Insulin/IGF-Receptor Pathway 1,3 1 1,2,3 Meghann E. Mabon , Barbara A. Scott , C. Michael Crowder * 1 Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 3 The Division of Biology Biomedical Sciences, Program in Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America Abstract Organisms and their cells vary greatly in their tolerance of low oxygen environments (hypoxia). A delineation of the determinants of hypoxia tolerance is incomplete, despite intense interest for its implications in diseases such as stroke and myocardial infarction. The insulin/IGF-1 receptor (IGFR) signaling pathway controls survival of Caenorhabditis elegans from a variety of stressors including aging, hyperthermia, and hypoxia. daf-2 encodes a C. elegans IGFR homolog whose primary signaling pathway modulates the activity of the FOXO transcription factor DAF-16. DAF-16 regulates the transcription of a large number of genes, some of which have been shown to control aging. To identify genes that selectively regulate hypoxic sensitivity, we compared the whole-organismal transcriptomes of three daf-2 reduction-of-function alleles, all of which are hypoxia resistant, thermotolerant, and long lived, but differ in their rank of severities for these phenotypes. The transcript levels of 172 genes were increased in the most hypoxia resistant daf-2 allele, e1370, relative to the other alleles whereas transcript