Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002
Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002
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DOI：
10.1002/j.1460-2075.1996.tb00911.x
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发表时间：
1996-10-01
期刊：
影响因子：
11.4
通讯作者：
Abraham, RT
中科院分区：
文献类型：
--
作者：
Brunn, GJ;Williams, J;Abraham, RT
免疫抑制剂雷帕霉素通过干扰一种新型激酶的功能来抑制细胞生长。称为雷帕霉素的哺乳动物靶蛋白（mTOR）。mTOR的推定催化结构域类似于哺乳动物和酵母磷脂酰肌醇（PI）3-激酶。这项研究表明，mTOR是一个组成部分的嘌呤触发的蛋白激酶级联导致磷酸化的真核起始因子-4E（eIF-4 E）结合蛋白，PHAS-1，在活化的T淋巴细胞。该事件通过刺激eIF-4 E依赖性翻译起始来促进G（1）期进展。选择对雷帕霉素的生长抑制作用具有抗性的突变YAC-1 T淋巴瘤细胞系，相应地对该药物对PHAS-1磷酸化的抑制作用具有抗性。相反，PI 3-激酶抑制剂渥曼青霉素，在雷帕霉素敏感和耐药T细胞中，在相似的药物浓度下，（0.1-1 μ M），渥曼青霉素不可逆地抑制mTOR的丝氨酸特异性自激酶活性，mTOR的自身激酶活性也对结构上不同的PI 3-激酶抑制剂LY 294002敏感，浓度（1-30 μ M）几乎与抑制哺乳动物p85-p110异二聚体的脂质激酶活性所需的浓度相同。这些研究表明，mTOR的信号传导功能，以及潜在的其他高分子量PI 3-激酶同源物的信号传导功能，直接受到渥曼青霉素或LY 294002的细胞处理的影响。
The immunosuppressant, rapamycin, inhibits cell growth by interfering with the function of a novel kinase. termed mammalian target of rapamycin (mTOR). The putative catalytic domain of mTOR is similar to those of mammalian and yeast phosphatidyl-inositol (PI) 3-kinases. This study demonstrates that mTOR is a component of a cytokine-triggered protein kinase cascade leading to the phosphorylation of the eukaryotic initiation factor-4E (elF-4E) binding protein, PHAS-1, in activated T lymphocytes. This event promotes G(1) phase progression by stimulating eIF-4E-dependent translation initiation, A mutant YAC-1 T lymphoma cell line, which was selected for resistance to the growth-inhibitory action of rapamycin, was correspondingly resistant to the suppressive effect of this drug on PHAS-1 phosphorylation, In contrast, the PI 3-kinase inhibitor, wortmannin, reduced the phosphorylation of PHAS-1 in both rapamycin-sensitive and -resistant T cells, At similar drug concentrations (0.1-1 mu M), wortmannin irreversibly inhibited the serine-specific autokinase activity of mTOR, The autokinase activity of mTOR was also sensitive to the structurally distinct PI 3-kinase inhibitor, LY294002, at concentrations (1-30 mu M) nearly identical to those required for inhibition of the lipid kinase activity of the mammalian p85-p110 heterodimer. These studies indicate that the signaling functions of mTOR, and potentially those of other high molecular weight PI 3-kinase homologs, are directly affected by cellular treatment with wortmannin or LY294002.