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A Role for p38 Stress-Activated Protein Kinase in Regulation of Cell Growth via TORC1

机译：p38应力激活蛋白激酶在通过TORC1调控细胞生长中的作用

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The target of rapamycin (TOR) complex 1 (TORC1) signaling pathway is a critical regulator of translation and cell growth. To identify novel components of this pathway, we performed a kinome-wide RNA interference (RNAi) screen in Drosophila melanogaster S2 cells. RNAi targeting components of the p38 stress-activated kinase cascade prevented the cell size increase elicited by depletion of the TOR negative regulator TSC2. In mammalian and Drosophila tissue culture, as well as in Drosophila ovaries ex vivo, p38-activating stresses, such as H2O2 and anisomycin, were able to activate TORC1. This stress-induced TORC1 activation could be blocked by RNAi against mitogen-activated protein kinase kinase 3 and 6 (MKK3/6) or by the overexpression of dominant negative Rags. Interestingly, p38 was also required for the activation of TORC1 in response to amino acids and growth factors. Genetic ablation either of p38b or licorne, its upstream kinase, resulted in small flies consisting of small cells. Mutants with mutations in licorne or p38b are nutrition sensitive; low-nutrient food accentuates the small-organism phenotypes, as well as the partial lethality of the p38b null allele. These data suggest that p38 is an important positive regulator of TORC1 in both mammalian and Drosophila systems in response to certain stresses and growth factors.
机译：雷帕霉素（TOR）复合物1（TORC1）信号通路的目标是翻译和细胞生长的关键调节器。为了鉴定该途径的新组成部分，我们在果蝇果蝇S2细胞中进行了全基因组RNA干扰（RNAi）筛选。靶向p38应力激活激酶级联反应的RNAi阻止了TOR负调节剂TSC2耗尽引起的细胞大小增加。在哺乳动物和果蝇的组织培养物中以及果蝇卵巢的离体体内，p38激活应激（例如H 2 < / sub> O 2 和茴香霉素能够激活TORC1。这种应激诱导的TORC1激活可以被RNAi对抗有丝分裂原激活的蛋白激酶激酶3和6（MKK3 / 6）或显性负性Rags的过度表达所阻断。有趣的是，响应氨基酸和生长因子，激活TORC1也需要p38。上游激酶 p38b 或 licorne 的遗传消融导致小苍蝇由小细胞组成。在 licorne 或 p38b 中具有突变的突变体对营养敏感;低营养食品突显了小生物表型以及 p38b 无效等位基因的部分杀伤力。这些数据表明，p38是哺乳动物和果蝇系统中响应某些压力和生长因子的重要TORC1正调节剂。

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