mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition
mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition
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DOI：
10.1128/mcb.01946-08
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发表时间：
2009-09-15
影响因子：
5.3
通讯作者：
Hay, Nissim
中科院分区：
文献类型：
--
作者：
Bhaskar, Prashanth T.;Nogueira, Veronique;Hay, Nissim
目前的概念是，TSC缺陷细胞通过高活性的mTORC1诱导的负反馈机制抑制Akt活性，从而对细胞凋亡敏感。然而，出乎意料的是，我们发现TSC1/2缺陷细胞对血清剥夺诱导的细胞凋亡表现出更强的抵抗力。在缺乏血清的TSC1/2缺陷细胞中，mTORC1的过度活性部分通过增加生长因子非依赖的己糖激酶II(HKII)和GLUT1的表达而参与了对TSC1/2缺陷细胞的凋亡抵抗。MTORC1介导的缺氧诱导因子1α(HIF1α)丰度的增加是导致这些变化的原因之一，这种增加发生在正常缺氧的TSC2缺陷细胞中，在没有血清的情况下发生。这些细胞中HIF1α丰度的增加归因于HIF1αmRNA水平的增加和持续翻译。持续的糖原合成酶激酶3α抑制和Mcl-1的表达也有助于TSC2缺陷细胞对血清剥夺的凋亡抵抗。雷帕霉素或Raptor基因敲除对mTORC1活性的抑制不能使这些细胞对血清剥夺诱导的细胞凋亡重新敏感，因为Akt活性升高，这是mTORC1抑制的间接结果。然而，在去血清的TSC2(-/-)细胞中，HIF1α丰度的增加和Mcl-1蛋白表达的维持在很大程度上依赖于这些细胞中过度活跃的eIF4E。一直以来，eIF4E水平的降低消除了TSC2(-/-)细胞对血清剥夺诱导的凋亡的抵抗力。
The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1 alpha (HIF1 alpha) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1 alpha abundance in these cells is attributed to both an increased level and the sustained translation of HIF1 alpha mRNA. Sustained glycogen synthase kinase 3 alpha inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1 alpha abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2(-/-) cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2(-/-) cells to serum deprivation-induced apoptosis.