Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population

• Published in: FEBS letters 2003-11, Vol.554 (3), p.450-454
• Main Authors: Ishihara, Hajime, Sasaoka, Toshiyasu, Kagawa, Syota, Murakami, Shihou, Fukui, Kazuhito, Kawagishi, Yukio, Yamazaki, Katsuya, Sato, Akira, Iwata, Minoru, Urakaze, Masaharu, Ishiki, Manabu, Wada, Tsutomu, Yaguchi, Saori, Tsuneki, Hiroshi, Kimura, Ikuko, Kobayashi, Masashi
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions - genetics; Akt; Animals; Cell Line; COS Cells; Diabetes Mellitus, Type 2 - genetics; DNA Primers - chemistry; DNA Primers - genetics; Exons - genetics; Female; Gene Frequency - genetics; Humans; Insulin - pharmacology; Introns - genetics; Japan; Male; Middle Aged; Phosphatase and tensin homolog deleted on chromosome 10; Phosphatidylinositol 3-kinase; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Polymorphism; Polymorphism, Single Nucleotide - genetics; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Transfection; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Type 2 diabetes
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(03)01225-0

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)P 3, 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 non-diabetic 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.