Inhibition of cellular growth and proliferation by dTOR overexpression in Drosophila
Inhibition of cellular growth and proliferation by dTOR overexpression in Drosophila
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DOI：
10.1002/gene.10139
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发表时间：
2002-09-01
期刊：
影响因子：
1.5
通讯作者：
Neufeld, TP
中科院分区：
文献类型：
--
作者：
Hennig, KM;Neufeld, TP
蛋白激酶的雷帕霉素靶标（TOR）家族是真核细胞生长、增殖和代谢的保守调节剂（Schmelzle和Hall，2000; Raught等人，2001年）。在高等真核生物中，TOR活性是响应于有丝分裂原如胰岛素的信号转导所必需的。在酵母、果蝇和哺乳动物中的研究也表明，TOR蛋白在营养传感途径中起作用，并且在这种能力下可能作为促有丝分裂信号的独立检查点。然而，目前尚不清楚TOR活性或表达的增量增加是否可以增强细胞生长速率，或者TOR激活是否发送了生长所必需但不足以的许可信号。为了区分这些可能性，我们在发育过程中过表达果蝇TOR（dTOR）的全长和截短版本，并测定其对细胞生长、增殖和存活的影响。令人惊讶的是，dTOR过表达引起的表型与dTOR功能丧失突变的表型非常相似，包括细胞大小和增殖速率的减少，细胞在细胞周期G1期的积累以及特定的遗传相互作用。鉴于TOR蛋白的潜在支架功能，我们认为异常高的TOR表达可能会通过滴定和稀释必需的辅因子来减少信号输出，从而抑制功能性信号复合物的形成。
The Target of Rapamycin (TOR) family of protein kinases are conserved regulators of eukaryotic cell growth, proliferation, and metabolism (Schmelzle and Hall, 2000; Raught et al., 2001). In higher eukaryotes, TOR activity is required for signal transduction in response to mitogens such as insulin. Studies in yeast, Drosophila, and mammals also suggest that TOR proteins act in a nutrientsensing pathway and in this capacity may serve as an independent checkpoint on mitogenic signaling. However, it is unclear whether incremental increases in TOR activity or expression can potentiate cell growth rates, or whether TOR activation sends a permissive signal necessary but not sufficient for growth. To distinguish between these possibilities, we overexpressed full length and truncated versions of Drosophila TOR (dTOR) during development and assayed the effects on cell growth, proliferation, and survival. Surprisingly, dTOR overexpression caused phenotypes remarkably similar to those of dTOR loss of function mutations, including reductions in cell size and proliferation rate, accumulation of cells in the G1 phase of the cell cycle, and specific genetic interactions. In light of the potential scaffolding function of TOR proteins, we suggest that abnormally high TOR expression may reduce signaling output by titrating and diluting essential cofactors, thereby inhibiting formation of functional signaling complexes.