Scott Barbara A, Avidan Michael S, Crowder C Michael
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science. 2002 Jun 28;296(5577):2388-91. doi: 10.1126/science.1072302. Epub 2002 Jun 13.
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.
为了确定缺氧细胞死亡的遗传决定因素，我们在秀丽隐杆线虫中筛选了抗缺氧（Hyp）突变体，发现胰岛素/胰岛素样生长因子（IGF）受体（INR）同源基因daf-2的特定功能降低（rf）突变体具有显著的抗缺氧能力。缺氧抗性在缺氧暴露前可迅速诱导产生，并且是通过AKT-1/PDK-1/叉头转录因子途径介导的，该途径与调节寿命和应激抗性的信号通路重叠但又有所不同。daf-2（+）在神经元和肌肉中的选择性表达可恢复缺氧死亡，而daf-2（rf）可预防缺氧诱导的肌肉和神经元细胞死亡，这表明INR调节在预防神经元和心肌细胞缺氧损伤方面具有潜力。
