Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function
Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function
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DOI：
10.1073/pnas.0409177102
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发表时间：
2005-03-29
影响因子：
11.1
通讯作者：
Froguel, P
中科院分区：
文献类型：
--
作者：
Neve, B;Fernandez-Zapico, ME;Froguel, P
KLF11 (TIEG2) 是一种富含胰腺的转录因子，因其在体外和体内作为外分泌细胞生长负调节因子的作用而引起了广泛关注。然而，其在内分泌胰腺中的功能作用仍有待确定。在这里，据我们所知，我们首次报告了 KLF11 作为胰岛素基因的葡萄糖诱导调节剂的特征。随机寡核苷酸结合、EMSA、荧光素酶报告基因和染色质免疫沉淀测定的组合表明，KLF11 与胰岛素启动子结合并调节其在 β 细胞中的活性。 KLF11 基因的遗传分析揭示了两种罕见的变异（Ala347Ser 和 Thr220Met），它们与早发 2 型糖尿病家族中的糖尿病分离，并显着损害其转录活性。此外，对 1,696 名 2 型糖尿病患者和 1,776 名血糖正常受试者的分析显示，Gln62Arg 常见的多态性变异与北欧人群的 2 型糖尿病显着相关（OR = 1.29，P = 0.00033）。此外，该变体改变了 KLF11 的辅阻遏物 mSin3A 结合活性，损害胰岛素启动子的激活，并显示胰腺 β 细胞中胰岛素表达水平较低。此外，携带 Gln62Arg 等位基因的受试者在口服葡萄糖挑战后表现出血浆胰岛素下降。有趣的是，所有三个非同义的 KLF11 变体都显示出对过氧化氢酶 1 启动子的抑制增加，表明其在自由基清除中的作用，可能使 β 细胞对氧化应激更加敏感。因此，功能和遗传分析表明，KLF11 在胰腺 β 细胞生理学的调节中发挥作用，其变异体可能有助于糖尿病的发生。
KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.