Essential roles of mTOR/Akt pathway in Aurora-A cell transformation.
Essential roles of mTOR/Akt pathway in Aurora-A cell transformation.
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DOI：
10.7150/ijbs.5.444
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发表时间：
2009-06-19
影响因子：
9.2
通讯作者：
Ouchi T
中科院分区：
文献类型：
--
作者：
Taga M;Hirooka E;Ouchi T
我们最近证明，在MMTV启动子下表达Aurora-A激酶是小鼠乳腺肿瘤的潜在致癌基因。这些肿瘤含有Akt和mTOR的磷酸化形式，表明Akt-mTOR通路参与了Aurora-A诱导的表型转化。在本研究中，我们发现表达Aurora-A的稳定细胞系在细胞培养的较长传代后含有Akt Ser473的磷酸化，而在细胞培养的早期细胞中没有磷酸化。PTEN肿瘤抑制因子的水平在这些晚期传代细胞中显著降低，至少部分原因是该蛋白的多泛素化增加。akt激活的Aurora-A细胞在软琼脂中形成更大的菌落，并对紫外线诱导的细胞凋亡具有抗性。Aurora-A抑制剂VX-680可导致Akt未被激活的Aurora-A细胞死亡。sirna介导的mTOR缺失导致Akt Ser473磷酸化降低，表明TORC2复合物在Aurora-A细胞中磷酸化Akt。用mTOR抑制剂处理晚传代的Aurora-A细胞可减少软琼脂中菌落的形成。这些结果强烈表明，Aurora-A对细胞转化的承诺至少是由Akt/mTOR通路的共激活决定的。
We have recently demonstrated that Aurora-A kinase is a potential oncogene to develop mammary gland tumors in mice, when expressed under MMTV promoter. These tumors contain phosphorylated forms of Akt and mTOR, suggesting that Akt-mTOR pathway is involved in transformed phenotype induced by Aurora-A. In the present studies, we discovered that stable cell lines expressing Aurora-A contain phosphorylation of Akt Ser473 after prolonged passages of cell culture, not in cells of the early period of cell culture. Levels of PTEN tumor suppressor are significantly reduced in these late passage cells at least in part due to increased poly ubiquitination of the protein. Akt-activated Aurora-A cells formed larger colonies in soft agar and are resistant to UV-induced apoptosis. Aurora-A inhibitor, VX-680, can cause cell death of Aurora-A cells in which Akt is not activated. siRNA-mediated depletion of mTOR in those cells resulted in decreased phosphorylation of Akt Ser473, suggesting that TORC2 complex phosphorylates Akt in Aurora-A cells. Treatment of late-passage Aurora-A cells with mTOR inhibitor reduced colony formation in soft agar. These results strongly suggest that commitment of cell transformation by Aurora-A is determined by at least co-activation of Akt/mTOR pathway.
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影响因子：
4.8
作者：
Ouchi, M;Fujiuchi, N;Ouchi, T
通讯作者：
Ouchi, T
影响因子：
3.3
作者：
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11.5
作者：
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11.5
作者：
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64.5
作者：
Hirota, T;Kunitoku, N;Saya, H
通讯作者：
Saya, H