The hypoxia-induced paralogs scylla and charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila
The hypoxia-induced paralogs scylla and charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila
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DOI：
10.1101/gad.322704
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发表时间：
2004-12-01
影响因子：
10.5
通讯作者：
Hafen, E
中科院分区：
文献类型：
--
作者：
Reiling, JH;Hafen, E
不同的外在和内在的线索必须整合在一个发展中的有机体，以确保在细胞和有机体水平适当的增长。在果蝇中，胰岛素受体/TOR/S6 K信号网络在控制代谢和细胞生长中起着重要作用。在这里，我们表明，scylla和charybdis，两个同源基因被确定为生长抑制在EP（增强子/启动子）过表达屏幕，作为负调节生长。这两种基因的同时缺失产生的果蝇更容易受到氧浓度降低（缺氧）的影响，并表现出轻微的过度生长表型。相反，“锡拉”或“卡律布狄斯”的过度激活会降低生长。生长抑制与S6 K活性降低有关，但与PKB/Akt活性无关。遗传和生化分析将Scylla/Charybdis置于PKB的下游和TSC的上游。此外，我们表明，青蟹和charybdis诱导缺氧条件下，青蟹是果蝇HIF-1（缺氧诱导因子-1（hypoxia-inducible factor-1）的目标一样，其哺乳动物对应物RTP 801/REDD 1，从而建立一个潜在的串扰之间的增长和氧传感。
Diverse extrinsic and intrinsic cues must be integrated within a developing organism to ensure appropriate growth at the cellular and organismal level. In Drosophila, the insulin receptor/TOR/S6K signaling network plays a fundamental role in the control of metabolism and cell growth. Here we show that scylla and charybdis, two homologous genes identified as growth suppressors in an EP (enhancer/promoter) overexpression screen, act as negative regulators of growth. The simultaneous loss of both genes generates flies that are more susceptible to reduced oxygen concentrations (hypoxia) and that show mild overgrowth phenotypes. Conversely, scylla or charybdis overactivation reduces growth. Growth inhibition is associated with a reduction in S6K but not PKB/Akt activity. Together, genetic and biochemical analysis places Scylla/Charybdis downstream of PKB and upstream of TSC. Furthermore, we show that scylla and charybdis are induced under hypoxic conditions and that scylla is a target of Drosophila HIF-1 (hypoxia-inducible factor-1) like its mammalian counterpart RTP801/REDD1, thus establishing a potential cross-talk between growth and oxygen sensing.