Akt Requires Glucose Metabolism to Suppress Puma Expression and Prevent Apoptosis of Leukemic T Cells
Akt Requires Glucose Metabolism to Suppress Puma Expression and Prevent Apoptosis of Leukemic T Cells
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DOI：
10.1074/jbc.m110.179101
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发表时间：
2011-02-18
影响因子：
4.8
通讯作者：
Rathmell, Jeffrey C.
中科院分区：
文献类型：
--
作者：
Coloff, Jonathan L.;Mason, Emily F.;Rathmell, Jeffrey C.
PI 3 K/Akt通路在刺激的细胞和许多癌症中被激活，以促进葡萄糖代谢并防止细胞死亡。虽然抑制Akt介导的细胞存活可能提供消除癌细胞的手段，但这种存活途径仍然不完全清楚。特别是，与不依赖于葡萄糖的抗凋亡Bcl-2家族蛋白防止凋亡不同，Akt需要葡萄糖代谢来抑制细胞死亡。这种葡萄糖依赖性可能部分通过促凋亡Bcl-2家族蛋白的代谢调节而发生。在这里，我们发现激活的Akt依赖于糖酵解来抑制Puma的诱导，Puma对促凋亡Bcl-2家族成员的代谢状态非常敏感，并且在葡萄糖缺乏的条件下迅速上调。重要的是，阻止Puma表达对于Akt介导的细胞存活至关重要，因为Puma缺陷保护细胞免于葡萄糖剥夺，而Akt不能容易地阻断Puma介导的细胞凋亡。与此相反，促凋亡Bcl-2家族蛋白Bim正常诱导，即使当组成型活性Akt的表达，但Akt可以提供保护Bim细胞毒性。Puma的上调似乎是由线粒体代谢物的可用性降低介导的，而不是糖酵解本身，因为替代线粒体燃料可以抑制葡萄糖剥夺后的Puma诱导和凋亡。Puma的代谢调节是通过p53依赖的转录诱导和Puma蛋白稳定性的控制来介导的，Puma在营养充足的条件下降解，而在营养缺乏的条件下寿命较长。总之，这些数据确定了Bcl-2家族蛋白在Akt介导的细胞存活中的关键作用，这在正常免疫和癌症中可能是至关重要的，通过Akt依赖性糖酵解刺激来抑制Puma表达。
The PI3K/Akt pathway is activated in stimulated cells and in many cancers to promote glucose metabolism and prevent cell death. Although inhibition of Akt-mediated cell survival may provide a means to eliminate cancer cells, this survival pathway remains incompletely understood. In particular, unlike anti-apoptotic Bcl-2 family proteins that prevent apoptosis independent of glucose, Akt requires glucose metabolism to inhibit cell death. This glucose dependence may occur in part through metabolic regulation of pro-apoptotic Bcl-2 family proteins. Here, we show that activated Akt relies on glycolysis to inhibit induction of Puma, which was uniquely sensitive to metabolic status among pro-apoptotic Bcl-2 family members and was rapidly up-regulated in glucose-deficient conditions. Importantly, preventing Puma expression was critical for Akt-mediated cell survival, as Puma deficiency protected cells from glucose deprivation and Akt could not readily block Puma-mediated apoptosis. In contrast, the pro-apoptotic Bcl-2 family protein Bim was induced normally even when constitutively active Akt was expressed, yet Akt could provide protection from Bim cytotoxicity. Up-regulation of Puma appeared mediated by decreased availability of mitochondrial metabolites rather than glycolysis itself, as alternative mitochondrial fuels could suppress Puma induction and apoptosis upon glucose deprivation. Metabolic regulation of Puma was mediated through combined p53-dependent transcriptional induction and control of Puma protein stability, with Puma degraded in nutrient-replete conditions and long lived in nutrient deficiency. Together, these data identify a key role for Bcl-2 family proteins in Akt-mediated cell survival that may be critical in normal immunity and in cancer through Akt-dependent stimulation of glycolysis to suppress Puma expression.