(taken from the application) The long term goal of this research is to define the roles of MAP kinase cascades in the regulation and function of insulin-secreting cells. MAP kinase have provided a focal point for rapid advances in understanding of intracellular signal transduction. In the insulinoma cell line INS-1, a model system for glucose regulated insulin secretion, as well as in rat islets, the MAP kinases ERK1 and ERK2 are activated by glucose and agents that induce and potentiate insulin secretion. In the presence of glucose, ERKs are translocate to nuclei of INS-1 cells. Norther blot and reporter assays using a construct containing the rat insulin gene promoter suggest that ERK activity is required for glucose-dependent insulin transcription. An elevation of circulating free fatty acids often precedes the onset of non-insulin transcription. An elevation of circulating free fatty acids often precedes the onset of non-insulin-dependent diabetes and may be involved in the development of insulin resistances. Long term exposure of INS-1 cells to free fatty acids caused a marked increase in ERK activity, as much as 10-fold after 7 days. Thus, our goals are to define the mechanisms use by ERKs to regulate insulin transcription, to assess their importance relative to other mechanisms that regulate insulin transcription, and to define the relationship between RK activity and the actions of elevated fatty acids on beta cells. The stress-responsive MAP kinase pathways, containing p38 MAP kinases and c-Jun-N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), have been implicated in the actions of cytokines and other agents that induce inflammatory responses. These pathways may be involved in the normal and impaired functions of islets. Given the effects of ERKs on transcription, our goals are to determine if activation of the stress-sensitive MAP kinase pathways by glucose, cytokines, and other stimuli alter the biosynthesis of insulin.
| Kalwat, Michael A; Hwang, In Hyun; Macho, Jocelyn et al. (2018) Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic ? cells. J Gen Physiol 150:1747-1757 |
| Guerra, Marcy L; Kalwat, Michael A; McGlynn, Kathleen et al. (2017) Sucralose activates an ERK1/2-ribosomal protein S6 signaling axis. FEBS Open Bio 7:174-186 |
| Kalwat, Michael A; Cobb, Melanie H (2017) Mechanisms of the amplifying pathway of insulin secretion in the ? cell. Pharmacol Ther 179:17-30 |
| Kalwat, Michael A; Wichaidit, Chonlarat; Nava Garcia, Alejandra Y et al. (2016) Insulin promoter-driven Gaussia luciferase-based insulin secretion biosensor assay for discovery of ?-cell glucose-sensing pathways. ACS Sens 1:1208-1212 |
| Kalwat, Michael A; Huang, Zhimin; Wichaidit, Chonlarat et al. (2016) Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in ?-Cells. ACS Chem Biol 11:1128-36 |
| Wauson, Eric M; Guerra, Marcy L; Dyachok, Julia et al. (2015) Differential Regulation of ERK1/2 and mTORC1 Through T1R1/T1R3 in MIN6 Cells. Mol Endocrinol 29:1114-22 |
| Lawrence, Michael C; Borenstein-Auerbach, Nofit; McGlynn, Kathleen et al. (2015) NFAT targets signaling molecules to gene promoters in pancreatic ?-cells. Mol Endocrinol 29:274-88 |
| Wauson, Eric M; Dbouk, Hashem A; Ghosh, Anwesha B et al. (2014) G protein-coupled receptors and the regulation of autophagy. Trends Endocrinol Metab 25:274-82 |
| Guerra, Marcy L; Wauson, Eric M; McGlynn, Kathleen et al. (2014) Muscarinic control of MIN6 pancreatic ? cells is enhanced by impaired amino acid signaling. J Biol Chem 289:14370-9 |
| Chamberlain, Chester E; Scheel, David W; McGlynn, Kathleen et al. (2014) Menin determines K-RAS proliferative outputs in endocrine cells. J Clin Invest 124:4093-101 |
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