期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 27, 期 12, 页码 4328-4339出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00153-07
关键词
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资金
- NATIONAL CANCER INSTITUTE [R01CA123350] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI063345] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA123350, R01 CA123350-01A1] Funding Source: Medline
- NIAID NIH HHS [R01 AI063345-02, R01 AI063345] Funding Source: Medline
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.
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