Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
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DOI：
10.1101/gad.995802
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发表时间：
2002-06-15
影响因子：
10.5
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
Fingar, DC;Salama, S;Blenis, J
细胞周期进程和细胞生长的协调作用(细胞大小和细胞质量的增加)是细胞持续增殖的关键，然而控制细胞生长的生化信号很难确定，特别是在哺乳动物系统中。我们发现，在哺乳动物细胞中，细胞生长和细胞周期进程是可分离的过程，生长到合适的细胞大小需要依赖mTOR和PI3K的信号。雷帕霉素抗性突变体mTOR的表达以一种激酶依赖的方式挽救了雷帕霉素诱导的细胞尺寸缩小的表型，表明mTOR在控制细胞生长方面具有进化上的保守作用。具有部分RAP阿霉素抗性活性的S6K1突变体的表达或eIF4E的单独和相加表达部分挽救了雷帕霉素诱导的细胞尺寸减小。在没有雷帕霉素的情况下，S6K1或eIF4E的过表达会增加细胞大小，当它们共同表达时，它们会协同作用进一步增加细胞大小。表达4EBP1的磷酸化位点缺陷突变体，该突变体结构性地结合eIF4E-Cap复合体以抑制翻译起始，从而减小细胞大小并阻断eIF4E对细胞大小的影响。这些数据表明，mTOR信号向下传递到至少两个独立的靶点S6K1和4EBP1/eIF4E，它们在翻译控制中发挥作用，调节哺乳动物细胞的大小。
The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Expression of a rapamycin-resistant mutant of mTOR rescues the reduced cell size phenotype induced by rapamycin in a kinase-dependent manner, showing the evolutionarily conserved role of mTOR in control of cell growth. Expression of S6K1 mutants that possess partial rap amycin-resistant activity or overexpression of eIF4E individually and additively partially rescues the rapamycin-induced decrease in cell size. In the absence of rapamycin, overexpression of S6K1 or eIF4E increases cell size, and, when coexpressed, they cooperate to increase cell size further. Expression of a phosphorylation site-defective mutant of 4EBP1 that constitutively binds the eIF4E-Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. These data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size.