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首页> 外文期刊>Molecular and Cellular Biology >Glycogen Synthase Kinase 3α and 3β Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1
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Glycogen Synthase Kinase 3α and 3β Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1

机译：糖原合酶激酶3α和3β介导葡萄糖敏感性抗凋亡信号通路稳定Mcl-1。

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Glucose uptake and utilization are growth factor-stimulated processes that are frequently upregulated in cancer cells and that correlate with enhanced cell survival. The mechanism of metabolic protection from apoptosis, however, has been unclear. Here we identify a novel signaling pathway initiated by glucose catabolism that inhibited apoptotic death of growth factor-deprived cells. We show that increased glucose metabolism protected cells against the proapoptotic Bcl-2 family protein Bim and attenuated degradation of the antiapoptotic Bcl-2 family protein Mcl-1. Maintenance of Mcl-1 was critical for this protection, as glucose metabolism failed to protect Mcl-1-deficient cells from apoptosis. Increased glucose metabolism stabilized Mcl-1 in both cell lines and primary lymphocytes via inhibitory phosphorylation of glycogen synthase kinase 3α and 3β (GSK-3α/β), which otherwise promoted Mcl-1 degradation. While a number of kinases can phosphorylate and inhibit GSK-3α/β, we provide evidence that protein kinase C may be stimulated by glucose-induced alterations in diacylglycerol levels or distribution to phosphorylate GSK-3α/β, maintain Mcl-1 levels, and inhibit cell death. These data provide a novel nutrient-sensitive mechanism linking glucose metabolism and Bcl-2 family proteins via GSK-3 that may promote survival of cells with high rates of glucose utilization, such as growth factor-stimulated or cancerous cells.
机译：葡萄糖的摄取和利用是生长因子刺激的过程，在癌细胞中经常被上调，并且与细胞存活率提高相关。然而，尚不清楚细胞凋亡的代谢保护机制。在这里，我们确定了由葡萄糖分解代谢启动的新型信号通路，该通路抑制了生长因子缺乏细胞的凋亡死亡。我们显示增加的葡萄糖代谢保护细胞免受促凋亡的Bcl-2家族蛋白Bim和减弱的抗凋亡Bcl-2家族蛋白Mcl-1的降解。 Mcl-1的维持对于这种保护至关重要，因为葡萄糖代谢无法保护Mcl-1缺陷细胞免于凋亡。葡萄糖代谢的增加通过糖原合酶激酶3α和3β（GSK-3α/β）的抑制性磷酸化而稳定了细胞系和原代淋巴细胞中的Mcl-1，否则会促进Mcl-1的降解。尽管许多激酶可以磷酸化并抑制GSK-3α/β，但我们提供的证据表明，蛋白激酶C可能受到葡萄糖诱导的二酰基甘油水平改变或磷酸化GSK-3α/β，维持Mcl-1水平和磷酸分布的刺激。抑制细胞死亡。这些数据提供了通过GSK-3连接葡萄糖代谢和Bcl-2家族蛋白的新型营养敏感机制，该机制可促进具有高葡萄糖利用率的细胞（例如生长因子刺激的或癌细胞）的存活。

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