The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase.
The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase.
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DOI：
10.1371/journal.pone.0088891
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Okada M
中科院分区：
文献类型：
--
作者：
Mori S;Nada S;Kimura H;Tajima S;Takahashi Y;Kitamura A;Oneyama C;Okada M
雷帕霉素的机制靶点（mTOR）是两个大复合物mTORC 1和mTORC 2的组成部分，它们在调节细胞生长和稳态方面发挥着至关重要的作用。然而，mTOR控制细胞增殖的分子机制仍然难以捉摸。在这里，我们表明，FoxO3a转录因子的mTORC 1和mTORC 2协调调节，并在控制细胞增殖中起着至关重要的作用。为了剖析mTOR信号传导，mTORC 1通过耗尽p18（mTORC 1在溶酶体上的必需锚）而特异性失活。mTORC1失活导致细胞增殖显著阻滞，这与细胞周期蛋白依赖性激酶抑制剂（CDKIs）的上调有关。虽然Akt被mTORC 1失活激活，但FoxO3a通过表观遗传机制上调，并在Ser314处低磷酸化，导致其核积累。同样，mTORC1失活诱导血清和糖皮质激素诱导的激酶1（SGK1），负责Ser314磷酸化的激酶下调。在Ser314处突变的FoxO3a的表达通过诱导CDKI表达来抑制细胞增殖。SGK1过表达抑制p18缺陷细胞中的CDKI表达，而SGK1敲低诱导野生型细胞中的CDKI表达，导致细胞增殖抑制。这些结果表明，mTORC1，与mTORC2协调，通过调节FoxO3a基因表达和SGK1介导的FoxO3a在Ser314的磷酸化来控制细胞增殖。
The mechanistic target of rapamycin (mTOR) functions as a component of two large complexes, mTORC1 and mTORC2, which play crucial roles in regulating cell growth and homeostasis. However, the molecular mechanisms by which mTOR controls cell proliferation remain elusive. Here we show that the FoxO3a transcription factor is coordinately regulated by mTORC1 and mTORC2, and plays a crucial role in controlling cell proliferation. To dissect mTOR signaling, mTORC1 was specifically inactivated by depleting p18, an essential anchor of mTORC1 on lysosomes. mTORC1 inactivation caused a marked retardation of cell proliferation, which was associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs). Although Akt was activated by mTORC1 inactivation, FoxO3a was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, which resulted in its nuclear accumulation. Consistently, mTORC1 inactivation induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), the kinase responsible for Ser314 phosphorylation. Expression of FoxO3a mutated at Ser314 suppressed cell proliferation by inducing CDKI expression. SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation. These results suggest that mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314.
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DOI：
10.1126/science.1199498
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hsu PP;Kang SA;Rameseder J;Zhang Y;Ottina KA;Lim D;Peterson TR;Choi Y;Gray NS;Yaffe MB;Marto JA;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
5.3
作者：
Brunet, A;Park, J;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
3.3
作者：
Arteaga, Maria Francisca;de la Rosa, Diego Alvarez;Canessa, Cecilia M.
通讯作者：
Canessa, Cecilia M.
影响因子：
11.4
作者：
Nada, Shigeyki;Hondo, Akihiro;Okada, Masato
通讯作者：
Okada, Masato
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME