A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt
A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt
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DOI：
10.1073/pnas.011528498
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发表时间：
2001-01-02
影响因子：
11.1
通讯作者：
Vogt, PK
中科院分区：
文献类型：
--
作者：
Aoki, M;Blazek, E;Vogt, PK
癌蛋白P3 k（IA类磷酸肌醇3-激酶的催化亚基的同源物）和Akt（蛋白激酶B）诱导鸡胚成纤维细胞的致癌转化。转化的细胞显示翻译p70 S6激酶（S6 K）的正调节物和真核起始因子4 E-BP 1结合蛋白（4 E-BP 1）（翻译的负调节物）的组成性磷酸化。磷酸化激活S6 K并灭活4 E-BP 1。保留激酶活性但不诱导S6 K或4 E-BP 1磷酸化的Akt突变体不能转化鸡胚成纤维细胞，表明Akt的致癌性与S6 K和4 E-BP 1的磷酸化之间存在相关性。大环内酯类抗生素雷帕霉素可有效阻断P3 k或Akt诱导的致癌转化，但不会降低其他11种癌蛋白的转化活性。雷帕霉素抑制激酶mTOR。一种重要的翻译调节因子，这种抑制作用需要抗生素与亲免素FKBP 12结合。雷帕霉素从FKBP 12的置换解除了mTOR的抑制，并且还恢复了P3 k诱导的转化。这些数据雅阁P3 k或Akt的转化涉及翻译控制干预的假设。
The oncoproteins P3k (homolog of the catalytic subunit of class IA phosphoinositide 3-kinase) and Akt (protein kinase B) induce oncogenic transformation of chicken embryo fibroblasts. The transformed cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase (S6K) and of the eukaryotic initiation factor 4E-BP1 binding protein (4E-BP1), a negative regulator of translation. Phosphorylation activates S6K and inactivates 4E-BP1. A mutant of Akt that retains kinase activity but does not induce phosphorylation of S6K or of 4E-BP1 fails to transform chicken embryo fibroblasts, suggesting a correlation between the oncogenicity of Akt and phosphorylation of S6K and 4E-BP1. The macrolide antibiotic rapamycin effectively blocks oncogenic transformation induced by either P3k or Akt but does not reduce the transforming activity of 11 other oncoproteins. Rapamycin inhibits the kinase mTOR. an important regulator of translation, and this inhibition requires binding of the antibiotic to the immunophilin FKBP12. Displacement of rapamycin from FKBP12 relieves the inhibition of mTOR and also restores P3k-induced transformation. These data are in accord with the hypothesis that transformation by P3k or Akt involves intervention in translational controls.