Dual role of proapoptotic BAD in insulin secretion and beta cell survival
| Autor: | Sandeep Robert Datta, Gerald I. Shulman, Jude T. Deeney, Joel Morash, Jakob D. Wikstrom, Jill K. Fisher, Chen-Yu Zhang, Barbara E. Corkey, Loren D. Walensky, Orian S. Shirihai, Stanley J. Korsmeyer, Kirsten Robertson, Sheene Kim, Susanne Neschen, Michael E. Greenberg, Nika N. Danial, Cheol Soo Choi, Bradford B. Lowell, Kenneth L. Pitter, Ameya Kulkarni, Gregory H. Bird, Anthony J.A. Molina |
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| Rok vydání: | 2008 |
| Předmět: |
Blood Glucose
medicine.medical_specialty Cell Survival medicine.medical_treatment Molecular Sequence Data Cell Count Biology Article General Biochemistry Genetics and Molecular Biology Mice Phosphoserine Insulin-Secreting Cells Internal medicine Glucokinase Insulin Secretion medicine Animals Humans Insulin Amino Acid Sequence Beta (finance) Death domain Membrane Potential Mitochondrial Models Genetic Physician-scientist General Medicine Hydrocarbons Diet Protein Structure Tertiary Cell biology Transplantation Glucose Endocrinology Phosphorylation Calcium bcl-Associated Death Protein biological phenomena cell phenomena and immunity Beta cell Peptides |
| Zdroj: | Nature Medicine. 14:144-153 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion. |
| Databáze: | OpenAIRE |
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