Glycogen synthase kinase 3α and 3β mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1
Glycogen synthase kinase 3α and 3β mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1
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DOI：
10.1128/mcb.00153-07
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发表时间：
2007-06-01
影响因子：
5.3
通讯作者：
Rathmell, Jeffrey C.
中科院分区：
文献类型：
--
作者：
Zhao, Yuxing;Altman, Brian J.;Rathmell, Jeffrey C.
葡萄糖的摄取和利用是生长因子刺激的过程，在癌细胞中经常上调，并且与增强的细胞存活率相关。然而，代谢保护免受细胞凋亡的机制尚不清楚。在这里，我们发现了一种由葡萄糖分解代谢启动的新信号通路，可抑制生长因子剥夺细胞的凋亡。我们发现，葡萄糖代谢的增加可以保护细胞免受促凋亡 Bcl-2 家族蛋白 Bim 的侵害，并减弱抗凋亡 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成酶激酶 3 α 和 30 (GSK-3 α/β) 的抑制性磷酸化稳定了细胞系和原代淋巴细胞中的 Mcl-1，否则会促进 Mcl-1 降解。虽然许多激酶可以磷酸化和抑制 GSK-3 α/β，但我们提供的证据表明，蛋白激酶 C 可能会受到葡萄糖诱导的二酰甘油水平或分布变化的刺激，从而磷酸化 GSK-3 α/β、维持 Mcl-1 水平并抑制细胞死亡。这些数据提供了一种通过 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，可以促进葡萄糖利用率高的细胞（例如生长因子刺激的细胞或癌细胞）的存活。
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 3 alpha and 30 (GSK-3 alpha/beta), which otherwise promoted Mcl-1 degradation. While a number of kinases can phosphoryllate and inhibit GSK-3 alpha/beta, we provide evidence that protein kinase C may be stimulated by glucose-induced alterations in diacylglycerol levels or distribution to phosphorylate GSK-3 alpha/beta, 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.