Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling
Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling
复制标题
多种机制参与活性氧对 mTORC1 信号传导的调节
DOI：
10.1016/j.cellsig.2010.05.015
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发表时间：
2010-10-01
影响因子：
4.8
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
--
作者：
Li, Ming;Zhao, Li;Bai, Xiaochun
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）整合多种信号以控制细胞生长、增殖、存活和代谢。活性氧（ROS）对mTORC 1信号转导的作用仍然不清楚，ROS调节mTORC 1的机制也不清楚。我们证明，低剂量的ROS暴露刺激mTORC 1，而高浓度或长期的ROS治疗降低mTORC 1在体内和各种细胞系中的活性。抑制或激活所需的剂量/时间取决于细胞类型。在HEK 293细胞中，过氧化氢（H2 O2）刺激AMP激活的激酶（AMPK）（T172）和Raptor（S792）的磷酸化，增强活化的AMPK与Raptor的缔合。此外，AMPK抑制剂化合物c抑制H2 O2诱导的Raptor（5792）磷酸化并逆转mTORC 1下游靶点p70-S6 K1（T389）、S6（S235/236）和4 E-BP 1（T37/46）的H2 O2诱导的去磷酸化。H2 O2还刺激内源性蛋白磷酸酶2A催化亚基（PP 2Ac）与p70-S6 K1的结合。与化合物c（PP 2A抑制剂）一样，冈田酸部分逆转了H2 O2诱导的mTORC 1底物失活。此外，PP 2A和AMPK的抑制部分挽救了H2 O2诱导的细胞死亡。在TSC 2（-/-）P53（-/-）和TSC 2（+/+）P53（-/-）MEF中，高剂量H2 O2抑制而低剂量H2 O2激活mTORC 1。这些数据表明，PP 2A和AMPK介导的Raptor磷酸化介导H2 O2诱导的mTORC 1信号转导抑制。(C)2010年爱思唯尔公司All rights reserved.
The mammalian target of rapamycin complex 1(mTORC1) integrates diverse signals to control cell growth, proliferation, survival, and metabolism. Role of reactive oxygen species (ROS) on mTORC1 signaling remains obscure and mechanisms through which ROS modulate mTORC1 are not known. We demonstrate that low doses ROS exposure stimulate mTORC1 while high concentrations or long-term ROS treatment decrease mTORC1 activity in vivo and in a variety of cell lines. The dose/time needed for inhibition or activation are cell type-dependent. In HEK293 cells hydrogen peroxide (H2O2) stimulates phosphorylation of AMP-activated kinase (AMPK) (T172) and Raptor (S792), enhances association of activated AMPK with Raptor. Furthermore, AMPK inhibitor compound c inhibits H2O2-induced Raptor (5792) phosphorylation and reverses H2O2-induced dephosphorylation of mTORC1 downstream targets p70-S6K1 (T389), S6 (S235/236) and 4E-BP1 (T37/46). H2O2 also stimulates association of endogenous protein phosphatase 2A catalytic subunit (PP2Ac) with p70-S6K1. Like compound c, inhibitor of PP2A, okadaic acid partially reverses inactivation of mTORC1 substrates induced by H2O2. Moreover, inhibition of PP2A and AMPK partially rescued cells from H2O2-induced cell death. High doses of H2O2 inhibit while low doses of H2O2 activate mTORC1 both in TSC2(-/-)P53(-/-) and TSC2(+/+)P53(-/-) MEFs. These data suggest that PP2A and AMPK-mediated phosphorylation of Raptor mediate H2O2-induced inhibition of mTORC1 signaling. (C) 2010 Elsevier Inc. All rights reserved.