MCB Accepts, published online ahead of print on 19 March 2007
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Mol. Cell. Biol. doi:10.1128/MCB.00153-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

GSK-3{alpha}/{beta} Mediate a Glucose-Sensitive Anti-Apoptotic SignalingPathway to Stabilize Mcl-1

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

Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center, Department of Immunology, Duke University Medical Center, Durham, NC 27710; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis MN 55455

* To whom correspondence should be addressed. Email: jeff.rathmell{at}duke.edu.


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Abstract

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 pro-apoptotic Bcl-2 family protein Bim and attenuated degradation of the anti-apoptotic 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 GSK-3{alpha}/{beta}, which otherwise promoted Mcl-1 degradation. While a number of kinases can phosphorylate and inhibit GSK-3{alpha}/{beta}, we provide evidence that PKCs 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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