Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population
Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population
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DOI：
10.1016/s0014-5793(03)01225-0
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发表时间：
2003-11-20
期刊：
影响因子：
3.5
通讯作者：
Kobayashi, M
中科院分区：
文献类型：
--
作者：
Ishihara, H;Sasaoka, T;Kobayashi, M
已知10号染色体上缺失的磷酸酶和张力素同源物（PTEN）作为脂质磷酸酶水解磷脂酰肌醇（PI）（3,4,5）P-3到PI(4,5)P-2。由于pi3激酶产物PI(3,4,5)P3是导致胰岛素代谢作用的重要第二信使，PTEN作为胰岛素信号的有效负调节因子，其基因可能是参与2型（非胰岛素依赖型）糖尿病易感性发展的候选基因之一。在本研究中，我们研究了日本2型糖尿病患者和非糖尿病对照组的PTEN基因多态性。我们在2型糖尿病患者中发现了三种基因突变。在这些突变中，位于外显子1非翻译区-9位（-9C—>G） （SNP1）的C被G取代的频率在2型糖尿病患者中显著高于对照组。此外，SNP1转染PTEN基因后，在Cos1和Rat1细胞中，PTEN蛋白的表达水平明显高于野生型PTEN基因。此外，转染SNP1 PTEN基因后，HIRc细胞中胰岛素诱导的Akt磷酸化水平明显低于转染野生型PTEN基因。这些发现表明，PTEN基因-9位C到G的变化可能与2型糖尿病的胰岛素抵抗有关，这可能是由于pi3激酶产物的水解增强。(C) 2003年欧洲生化学会联合会。Elsevier B.V.版权所有。
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known to act as a lipid phosphatase hydrolyzing phosphatidylinositol (PI)(3,4,5)P-3 to PI(4,5)P-2. Since the PI3-kinase product, PI(3,4,5)P3, is an important second messenger leading to the metabolic action of insulin, PTEN functions as a potent negative regulator of insulin signaling and its gene is one of the possible candidates involved in susceptibility to the development of type 2 (non-insulin-dependent) diabetes. In the present study, we investigated the polymorphisms of the PTEN gene in Japanese patients with type 2 diabetes and nondiabetic control subjects. We identified three mutations of the gene in the type 2 diabetes patients. Among these mutations, the frequency of the substitution of C with G at position -9 (-9C-->G) (SNP1), located in the untranslated region of exon 1, was significantly higher in type 2 diabetic patients than in control subjects. In addition, transfection of the PTEN gene with SNP1 resulted in a significantly higher expression level of PTEN protein compared with that of the wild-type PTEN gene in Cos1 and Rat1 cells. Furthermore, insulin-induced phosphorylation of Akt in HIRc cells was decreased more greatly by transfection of SNP1 PTEN gene than that of wild-type PTEN gene. These findings suggest that the change of C to G at position -9 of the PTEN gene is associated with the insulin resistance of type 2 diabetes due possibly to a potentiated hydrolysis of the PI3-kinase product. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.