Rheb promotes cell growth as a component of the insulin/TOR signalling network
Rheb promotes cell growth as a component of the insulin/TOR signalling network
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DOI：
10.1038/ncb996
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发表时间：
2003-06-01
影响因子：
21.3
通讯作者：
Edgar, BA
中科院分区：
文献类型：
--
作者：
Saucedo, LJ;Gao, XS;Edgar, BA
胰岛素信号是一种有效的细胞生长抑制信号，已被认为至少部分通过保守的蛋白激酶TOR(雷帕霉素的靶标)发挥作用。最近的研究表明，结节性硬化症复合体TSC1-TSC2可能将胰岛素信号与Tor活性偶联。然而，涉及的监管机制尚不清楚，很可能还涉及其他组成部分。在筛选新的生长调节因子时，我们发现了Rheb(大脑中富含的RAS同源蛋白)，它是GTP结合蛋白的RAS超家族的成员。果蝇体内Rheb水平的增加促进了细胞的生长，并改变了多种组织中的细胞周期动力学。在有丝分裂组织中，rheb的过表达加速了细胞通过G1-S期，而不影响细胞分裂率，而在内复制组织中，rheb的过表达增加了dna的倍性。Rheb基因突变使幼虫生长停滞，并阻止一龄至二龄幼虫的发育。遗传和生化测试表明，Rheb在TSC1-TSC2下游和TOR上游的胰岛素信号通路中发挥作用。Rheb的mRNA水平在蛋白质饥饿时迅速被诱导，并且过表达的Rheb可以推动饥饿动物的细胞生长，这表明Rheb在细胞生长的营养控制中发挥了作用。
Insulin signalling is a potent inhibitor of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin). Recent studies suggest a that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1-S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.