Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein

The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.     

A mechanism of extreme growth and reliable signaling in sexually selected ornaments and weapons

Many male animals wield ornaments or weapons of exaggerated proportions. We propose that increased cellular sensitivity to signaling through the insulin/insulin-like growth factor (IGF) pathway may be responsible for the extreme growth of these structures. We document how rhinoceros beetle horns, a sexually selected weapon, are more sensitive to nutrition and more responsive to perturbation of the insulin/IGF pathway than other body structures. We then illustrate how enhanced sensitivity to insulin/IGF signaling in a growing ornament or weapon would cause heightened condition sensitivity and increased variability in expression among individuals--critical properties of reliable signals of male quality. The possibility that reliable signaling arises as a by-product of the growth mechanism may explain why trait exaggeration has evolved so many different times in the context of sexual selection.     

马铃薯甲虫LdATPaseE调控幼虫蜕皮的分子机制

【目的】研究LdATPaseE通过类胰岛素信号通路影响保幼激素和蜕皮激素通路,调节马铃薯甲虫幼虫化蛹的分子机制。【方法】LdATPaseE cDNA序列通过马铃薯甲虫转录组数据分析和RT-PCR克隆获得;qPCR检测其在马铃薯甲虫各发育阶段,以及四龄幼虫不同组织的相对表达量;采用喂食幼虫dsRNA的方法,分析该基因在马铃薯甲虫幼虫的生长发育过程中的影响,并测定类胰岛素、保幼激素和蜕皮激素通路基因对该基因的表达响应机制。【结果】喂食二龄幼虫dsLdATPaseE后,成功敲低了靶标基因,阻止二龄幼虫的生长,显著增加了二龄幼虫的死亡率。三龄和四龄幼虫喂食dsLdATPaseE-1和dsLdATPaseE-2,在极低浓度下即敲低了靶标基因,阻止了幼虫生长,显著降低马铃薯甲虫幼虫的化蛹率。敲低LdATPaseE还显著升高了LdInR与Ld4EBP的表达量,抑制一个蜕皮激素合成基因的转录,降低20E滴度并降低了一个20E响应基因的表达。敲低LdATPaseE还抑制了一个JH合成酶基因的表达,降低了JH滴度,下调了一个JH早期响应基因的表达量。【结论】沉默LdATPaseE后,其可能通过抑制IIS信号途径,降低20E和JH的滴度、下调20E和JH信号从而影响幼虫生长和发育。     

A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis

Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information is processed as a network. We constructed a systems model of 7980 intracellular signaling events that directly links measurements to 1440 response outputs associated with apoptosis. The model accurately predicted multiple time-dependent apoptotic responses induced by a combination of the death-inducing cytokine tumor necrosis factor with the prosurvival factors epidermal growth factor and insulin. By capturing the role of unsuspected autocrine circuits activated by transforming growth factor-alpha and interleukin-1alpha, the model revealed new molecular mechanisms connecting signaling to apoptosis. The model derived two groupings of intracellular signals that constitute fundamental dimensions (molecular "basis axes") within the apoptotic signaling network. Projection along these axes captures the entire measured apoptotic network, suggesting that cell survival is determined by signaling through this canonical basis set.     

Suppression of aging in mice by the hormone Klotho

A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.     

鲮胰岛素样生长因子Ⅰ(IGF-Ⅰ)cDNA的分子克隆和序列分析

采用逆转录-聚合酶链式反应（RT-PCR）方法，从鲮肝脏总RNA中扩增出胰岛素样生长因子-I（IGF-I）基因，克隆至质粒PUGm-T。测定该基因序列，推导其编码的蛋白质序列。克隆的鲮IGF-IcDNA编码序列包括信号肽、B、C、A、D和E6个区域，共161个氨基酸残基。与鲤IGF-I比较，信号肽由44个氨基酸残基组成比鲤少17个，成熟肽核苷酸序列和氨基酸序列的同源性分别为95.2%和100%,E区域分析结果表明，克隆的鲮IGF-I序列属于IGF-I Ea-2亚型。     

鲮胰岛素样生长因子Ⅰ(IGF-Ⅰ)cDNA的分子克隆和序列分析

采用逆转录-聚合酶链式反应（RT-PCR）方法，从鲮肝脏总RNA中扩增出胰岛素样生长因子-I（IGF-I）基因，克隆至质粒PUGm-T。测定该基因序列，推导其编码的蛋白质序列。克隆的鲮IGF-IcDNA编码序列包括信号肽、B、C、A、D和E6个区域，共161个氨基酸残基。与鲤IGF-I比较，信号肽由44个氨基酸残基组成比鲤少17个，成熟肽核苷酸序列和氨基酸序列的同源性分别为95.2%和100%,E区域分析结果表明，克隆的鲮IGF-I序列属于IGF-I Ea-2亚型。     

An activating mutation of AKT2 and human hypoglycemia

Pathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules or by inborn errors of metabolism impairing liver glucose production. We studied three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and in one case in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. Thus, systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.