Glycogen Synthase Kinase 3alpha and 3beta Mediate a Glucose-sensitive Antiapoptotic Signaling Pathway to Stabilize Mcl-1.
From: Department of Pharmacology and Cancer Biology, DUMC Box 3813, Durham, NC 27710, USA.
Molecular and cellular biology
- Publish Date: Jun 2007
- ISSN: 0270-7306
- Volume: 27
- Issue: 12
- Pages: 4328-39
- Medium: Print
- Language: English
- Citation (JAMA): Zhao Yuxing, Altman Brian J, Coloff Jonathan L, et al. Glycogen Synthase Kinase 3alpha and 3beta Mediate a Glucose-sensitive Antiapoptotic Signaling Pathway to Stabilize Mcl-1.. Mol. Cell. Biol. Jun 2007;27:4328-39
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.
Mesh Headings (Keywords): Animals, Apoptosis, Cell Line, Glucose, Glycogen Synthase Kinase 3, Mice, Neoplasm Proteins, Proto-Oncogene Proteins c-bcl-2, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 17371841
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