Inhibition of Human T-Cell Proliferation by Mammalian Target of Rapamycin (mTOR) Antagonists Requires Noncoding RNA Growth-Arrest-Specific Transcript 5 (GAS5)
Inhibition of Human T-Cell Proliferation by Mammalian Target of Rapamycin (mTOR) Antagonists Requires Noncoding RNA Growth-Arrest-Specific Transcript 5 (GAS5)
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DOI：
10.1124/mol.110.064055
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发表时间：
2010-07-01
影响因子：
3.6
通讯作者：
Williams, Gwyn T.
中科院分区：
文献类型：
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作者：
Mourtada-Maarabouni, Mirna;Hasan, Anwar M.;Williams, Gwyn T.
丝氨酸/苏氨酸蛋白激酶mTOR（哺乳动物雷帕霉素靶蛋白）在控制细胞生长和增殖中的核心重要性已得到充分证实。然而，我们对控制mTOR活性的上游途径和介导这些影响的下游事件的了解仍然严重不完整。我们报道了一种以前未被怀疑的非蛋白编码RNA GAS5在抑制mTOR拮抗剂如雷帕霉素产生的t细胞增殖中的作用。GAS5转录本在生长停滞期间和雷帕霉素治疗后上调，GAS5最近被证明是正常t细胞生长停滞的必要和充分条件。使用RNA干扰下调GAS5可保护白血病和原代人T细胞免受mTOR拮抗剂产生的增殖抑制。GAS5转录物是5′端寡聚嘧啶类rna的一员，在翻译水平上受mTOR通路的特异性控制，GAS5对细胞周期的影响为细胞增殖控制提供了新的重要环节。这些观察结果表明，我们对mTOR抑制剂的作用机制的理解取得了重大进展，这可能会导致免疫抑制和癌症治疗的改进。
The central importance of the serine/threonine protein kinase mTOR (mammalian Target of Rapamycin) in the control of cell growth and proliferation is well established. However, our knowledge both of the upstream pathways controlling mTOR activity and of the downstream events mediating these effects is still seriously incomplete. We report a previously unsuspected role for the nonprotein-coding RNA GAS5 in the inhibition of T-cell proliferation produced by mTOR antagonists such as rapamycin. GAS5 transcripts are up-regulated during growth arrest and after rapamycin treatment, and GAS5 has recently been shown to be necessary and sufficient for normal T-cell growth arrest. Down-regulation of GAS5 using RNA interference protects both leukemic and primary human T cells from the inhibition of proliferation produced by mTOR antagonists. The GAS5 transcript is a member of the 5' terminal oligopyrimidine class of RNAs, which is specifically controlled at the level of translation by the mTOR pathway, and the effects of GAS5 on the cell cycle provide a novel and important link to the control of proliferation. These observations point to a significant advance in our understanding of the mechanism of action of mTOR inhibitors, which is likely to lead to improvements in immunosuppressive and cancer therapy.