Article

p38 MAPK is a major regulator of MafA protein stability under oxidative stress.

Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Molecular Endocrinology (impact factor: 4.54). 05/2009; 23(8):1281-90. DOI:10.1210/me.2008-0482 pp.1281-90
Source: PubMed

ABSTRACT Mammalian MafA/RIPE3b1 is an important glucose-responsive transcription factor that regulates function, maturation, and survival of beta-cells. Increased expression of MafA results in improved glucose-stimulated insulin secretion and beta-cell function. Because MafA is a highly phosphorylated protein, we examined whether regulating activity of protein kinases can increase MafA expression by enhancing its stability. We demonstrate that MafA protein stability in MIN6 cells and isolated mouse islets is regulated by both p38 MAPK and glycogen synthase kinase 3. Inhibiting p38 MAPK enhanced MafA stability in cells grown under both low and high concentrations of glucose. We also show that the N-terminal domain of MafA plays a major role in p38 MAPK-mediated degradation; simultaneous mutation of both threonines 57 and 134 into alanines in MafA was sufficient to prevent this degradation. Under oxidative stress, a condition detrimental to beta-cell function, a decrease in MafA stability was associated with a concomitant increase in active p38 MAPK. Interestingly, inhibiting p38 MAPK but not glycogen synthase kinase 3 prevented oxidative stress-dependent degradation of MafA. These results suggest that the p38 MAPK pathway may represent a common mechanism for regulating MafA levels under oxidative stress and basal and stimulatory glucose concentrations. Therefore, preventing p38 MAPK-mediated degradation of MafA represents a novel approach to improve beta-cell function.

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Keywords

active p38 MAPK
 
common mechanism
 
glucose-responsive transcription factor
 
glucose-stimulated insulin secretion
 
glycogen synthase kinase 3
 
glycogen synthase kinase 3. Inhibiting p38 MAPK
 
inhibiting p38 MAPK
 
MafA protein stability
 
MafA results
 
MafA stability
 
major role
 
Mammalian MafA/RIPE3b1
 
mouse islets
 
N-terminal domain
 
oxidative stress-dependent degradation
 
p38 MAPK pathway
 
p38 MAPK-mediated degradation
 
protein kinases
 
regulates function
 
regulating MafA levels