TY - JOUR
T1 - Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population
AU - Ishihara, Hajime
AU - Sasaoka, Toshiyasu
AU - Kagawa, Syota
AU - Murakami, Shihou
AU - Fukui, Kazuhito
AU - Kawagishi, Yukio
AU - Yamazaki, Katsuya
AU - Sato, Akira
AU - Iwata, Minoru
AU - Urakaze, Masaharu
AU - Ishiki, Manabu
AU - Wada, Tsutomu
AU - Yaguchi, Saori
AU - Tsuneki, Hiroshi
AU - Kimura, Ikuko
AU - Kobayashi, Masashi
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (to T.S.). We express special thanks to Drs. Mika Kishida and Tatsuhito Uno (Toyama Medical and Pharmaceutical University, Japan) for their help in the enrollment of subjects, and Drs. Mikio Takaishi, Teruhiko Makino, and Yoshimi Takada (Toyama Medical and pharmaceutical University, Japan) for their technical assistance in genetic analyses, and Dr. Hyogo Horiguchi (Jichi Medical School, Japan) for his assistance in statistical analyses.
PY - 2003/11/20
Y1 - 2003/11/20
N2 - 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)P2. 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 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.
AB - 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)P2. 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 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.
KW - Akt
KW - Phosphatase and tensin homolog deleted on chromosome 10
KW - Phosphatidylinositol 3-kinase
KW - Polymorphism
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=0242541686&partnerID=8YFLogxK
U2 - 10.1016/S0014-5793(03)01225-0
DO - 10.1016/S0014-5793(03)01225-0
M3 - 学術論文
C2 - 14623110
AN - SCOPUS:0242541686
SN - 0014-5793
VL - 554
SP - 450
EP - 454
JO - FEBS Letters
JF - FEBS Letters
IS - 3
ER -
