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Molecular and Cellular Biology, June 2007, p. 4328-4339, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00153-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3 and 3ß Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1

Department of Pharmacology and Cancer Biology,¹ Sarah W. Stedman Nutrition and Metabolism Center,² Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710,⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455³

Received 26 January 2007/ Returned for modification 2 March 2007/ Accepted 9 March 2007

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 and 3ß (GSK-3/ß), which otherwise promoted Mcl-1 degradation. While a number of kinases can phosphorylate and inhibit GSK-3/ß, we provide evidence that protein kinase C may be stimulated by glucose-induced alterations in diacylglycerol levels or distribution to phosphorylate GSK-3/ß, 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.

Published ahead of print on 19 March 2007.

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