title: Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1.
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 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 3alpha and 3beta (GSK-3alpha/beta), which otherwise promoted Mcl-1 degradation. While a number of kinases can phosphorylate and inhibit GSK-3alpha/beta, we provide evidence that protein kinase C may be stimulated by glucose-induced alterations in diacylglycerol levels or distribution to phosphorylate GSK-3alpha/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.
authors: Department of Pharmacology and Cancer Biology, DUMC Box 3813, Durham, NC 27710, USA.
authors: Yuxing
authors: Y
authors: Zhao
authors: Brian J
authors: BJ
authors: Altman
authors: Jonathan L
authors: JL
authors: Coloff
authors: Catherine E
authors: CE
authors: Herman
authors: Sarah R
authors: SR
authors: Jacobs
authors: Heather L
authors: HL
authors: Wieman
authors: Jessica A
authors: JA
authors: Wofford
authors: Leah N
authors: LN
authors: Dimascio
authors: Olga
authors: O
authors: Ilkayeva
authors: Ameeta
authors: A
authors: Kelekar
authors: Tannishtha
authors: T
authors: Reya
authors: Jeffrey C
authors: JC
authors: Rathmell
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000145:classification / Q000502:physiology*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D038362:Glycogen Synthase Kinase 3; D005947:Glucose