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p38 MAPK Signaling Pathway Regulates MafA Protein Stability.
- Source :
-
Diabetes . Jun2007 Supplement 1, Vol. 56, pA444-A445. 2p. - Publication Year :
- 2007
-
Abstract
- MafA/RIPE3b1 is an important glucose-responsive insulin gene transcription factor; its expression is differentially regulated by acute and chronic hyperglycemic conditions. Our understanding of the molecular mechanisms regulating MafA expression is still limited. Using RT-PCR and Western blot analyses; we demonstrate that the induction of MafA expression in response to acute increases in the glucose level requires both new RNA and protein synthesis. Furthermore, chronic hyperglycemia, as observed in diabetic rats, inhibited expression of both MafA mRNA and protein in pancreatic islets. Normalizing hyperglycemia with Phlorizin treatment reversed this reduction in MafA expression. These observations demonstrate a direct correlation between loss of MafA and β-cell dysfunction. We show that mammalian MafA, like its avian counterpart, is a phospho-protein and that phosphorylation affects its stability and migration. Increased phosphorylation of MafA reduces its stability. Consistent with these observations, specific inhibition of ERK or p38 MAPK increased MafA protein stability. Chronic hyperglycemia can trigger oxidative stress; treatment of MIN6 cells with tea-Butyl hydroperoxide, an inducer of oxidative stress, reduces MafA stability by increasing p38 MAPK activity. Interestingly, even under conditions of reduced oxidative stress such as low glucose concentrations, inhibiting p38 MAPK pathway enhanced the MafA protein stability. These results suggest that p38 MAPK pathway represents a common mechanism for regulating MafA levels under basal, acute and chronic hyperglycemic conditions. Results demonstrate that p38 MAPK mediated phosphorylation of MafA is important for its activity, this would suggest that the active MafA will be rapidly degraded in a cell, possibly to prevent any detrimental action of its uncontrolled activity. Thus identifying mechanisms that will permit regulation of p38 MAPK mediated activation of MafA without increasing its degradation may provide novel approaches to improve β-cell dysfunction. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 56
- Database :
- Academic Search Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 25822048