p38 MAPK Is a Major Regulator of MafA Protein Stability under Oxidative Stress
p38 MAPK Is a Major Regulator of MafA Protein Stability under Oxidative Stress
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DOI：
10.1210/me.2008-0482
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发表时间：
2009-08-01
影响因子：
--
通讯作者：
Sharma, Arun
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文献类型：
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作者：
Kondo, Takuma;El Khattabi, Ilham;Sharma, Arun
哺乳动物MafA/RIPE 3b 1是一种重要的葡萄糖响应性转录因子，调节β细胞的功能、成熟和存活。MafA的表达增加导致葡萄糖刺激的胰岛素分泌和β细胞功能改善。由于MafA是一种高度磷酸化的蛋白质，我们研究了调节蛋白激酶的活性是否可以通过增强其稳定性来增加MafA的表达。我们证明，MafA蛋白在MIN 6细胞和分离的小鼠胰岛中的稳定性受到p38 MAPK和糖原合成酶激酶3的调节。抑制p38 MAPK增强了在低和高浓度葡萄糖下生长的细胞中MafA的稳定性。我们还表明，MafA的N-末端结构域在p38 MAPK介导的降解中起着重要作用;同时将MafA中的苏氨酸57和134突变为丙氨酸足以防止这种降解。在氧化应激（一种对β细胞功能有害的条件）下，MafA稳定性的降低与活性p38 MAPK的伴随增加相关。有趣的是，抑制p38 MAPK而不是糖原合成酶激酶3阻止了MafA的氧化应激依赖性降解。这些结果表明，p38 MAPK途径可能代表了一个共同的机制，在氧化应激和基础和刺激性葡萄糖浓度下调节MafA水平。因此，防止p38 MAPK介导的MafA降解代表了改善β细胞功能的新方法。（分子内分泌学23：1281-1290，2009）
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. (Molecular Endocrinology 23: 1281-1290, 2009)