Intronic polymorphisms within TFAP2B regulate transcriptional activity and affect adipocytokine gene expression in differentiated adipocytes.
We have identified a gene encoding transcription factor activating enhancer binding protein-2beta (TFAP2B) as a candidate for conferring susceptibility to type 2 diabetes. Although we have also found that TFAP2B was preferentially expressed in adipose cells in a differentiation-dependent manner, the mechanisms by which the gene and gene polymorphisms contribute to conferring susceptibility to the disease have not yet been elucidated. The aim of this study was to evaluate the impact of the polymorphisms within the TFAP2B gene on conferring susceptibility to type 2 diabetes. We identified that a 300-bp DNA fragment in intron 1 of TFAP2B had significant enhancer activity, and the variations of this region affected this enhancer activity in differentiated adipocytes. In an experiment using adenovirus vectors encoding TFAP2B, the expression of TNF-alpha gene was shown to be elevated in the TFAP2B overexpressing cells compared with those in control cells. Furthermore, we demonstrated that the expression of TFAP2B was increased in the adipose tissues of subjects with the disease-susceptibility allele, and the plasma levels of TNF-alpha and high sensitivity C-reactive peptide were significantly elevated in the patients with the disease-susceptibility allele. These results suggest that TFAP2B may contribute to the pathogenesis of type 2 diabetes through regulation of adipocytokine gene expression, and that TFAP2B may be a promising target for treatment or prevention of this disease.
Tsukada
Shuichi
S
Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Tanaka
Yasushi
Y
Maegawa
Hiroshi
H
Kashiwagi
Atsunori
A
Kawamori
Ryuzo
R
Maeda
Shiro
S
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C493677:TFAP2B protein, human; D050656:Transcription Factor AP-2; D014409:Tumor Necrosis Factor-alpha