Intronic polymorphisms within TFAP2B regulate transcriptional activity and affect adipocytokine gene expression in differentiated adipocytes
Intronic polymorphisms within TFAP2B regulate transcriptional activity and affect adipocytokine gene expression in differentiated adipocytes
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DOI：
10.1210/me.2005-0311
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发表时间：
2006-05-01
影响因子：
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通讯作者：
Maeda, S
中科院分区：
文献类型：
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作者：
Tsukada, S;Tanaka, Y;Maeda, S
我们已经确定了一个基因编码转录因子激活增强子结合蛋白-2 β（TFAP 2B）作为一个候选人赋予2型糖尿病的易感性。虽然我们也发现TFAP 2B以分化依赖的方式优先在脂肪细胞中表达，但该基因和基因多态性有助于赋予对该疾病的易感性的机制尚未阐明。本研究的目的是评估TFAP 2B基因多态性对2型糖尿病易感性的影响。我们发现TFAP 2B内含子1中的一个300 bp的DNA片段具有显著的增强子活性，并且该区域的变化影响分化脂肪细胞中该增强子的活性。在使用编码TFAP 2B的腺病毒载体的实验中，与对照细胞相比，在TFAP 2B过表达细胞中显示TNF-α基因的表达升高。此外，我们证明了TFAP 2B的表达增加的受试者的脂肪组织中的疾病易感性等位基因，和TNF-α和高敏C-反应肽的血浆水平显着升高的患者的疾病易感性等位基因。这些结果表明，TFAP 2B可能有助于通过调节脂肪细胞因子基因表达的2型糖尿病的发病机制，TFAP 2B可能是一个有前途的治疗或预防这种疾病的目标。
We have identified a gene encoding transcription factor activating enhancer binding protein-2 beta (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.