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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{alpha} and 3ß Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1{triangledown}

Yuxing Zhao,1 Brian J. Altman,1 Jonathan L. Coloff,1 Catherine E. Herman,1,2 Sarah R. Jacobs,1 Heather L. Wieman,1 Jessica A. Wofford,1 Leah N. Dimascio,1 Olga Ilkayeva,1,2 Ameeta Kelekar,3 Tannishtha Reya,1 and Jeffrey C. Rathmell1,2,4*

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

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, DUMC Box 3813, Durham, NC 27710. Phone: (919) 681-1084. Fax: (919) 668-6044. E-mail: jeff.rathmell{at}duke.edu

{triangledown} Published ahead of print on 19 March 2007.

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.



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