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Analysis on switching of alternative exons 1 causing aberrant expression of estrogen synthetase

替代外显子1转换引起雌激素合成酶表达异常的分析

基本信息

批准号：
07671163
负责人：
NOBUHIRO Harada
金额：
$ 1.54万
依托单位：
Fujita Health University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671163/
关键词：
estrogen cytochrome P-450 multiple exons 1 alternative splicing osteoporosis hormone-dependent cancer arterial sclerosis

项目摘要

We have shown that elevation of aromatase expression in the proximal regions to breast cancer tissues was significantly correlated with switching of tissue-specific exons 1 of human aromatase gene in these regions. To further investigate what causes elevation of the aromatase mRNA and switching from exon 1b to exon 1c in the transcription factors of the aromatase gene in human breast cancer tissues, the effects of various on the exoression levels and preference of alternative expns 1 were examined in cultured adipose stromal cells from breast tissues. The aromatase mRNA was transcribed from exon 1b in the stromal cells cultured in the presence of calf serum. However, deprivation of the serum induced rapid elevation of aromatase mRNA and switching of aromatase transcripts to exon 1c the cells. Aromatase mRNA in HepG2 cells as well as in non-malignant breast tissues was also transcribed from exon 1b.Then, the promoter region responsible for the exon 1b-specific utilization in HepG2 cells was examined by fluorometric promoter assay using a new reporter containing 4 major alternative exons 1 and promoters. The results suggested that transcriptional elements determining preferential utilization of exon 1b in the cells was located on the promoter region of exon 1b form -255 to -1145. We have also observed significant levels of immunoreactive aromatase proteins and aromatase mRNA in the bone and vascular tissues. As decreased levels of estrogen in these tissues are paid attention in connecion with causes of osteoporosis in bone tissues and arterial sclerosis in vascular tissues and aromatase mRNA in these tissues is transcribed from exon 1b, switching of alternative exons 1 of the aromatase gene might contribute to a part of causes in these diseases.

我们已经表明，芳香化酶在乳腺癌组织近端区域的表达升高与这些区域中人类芳香化酶基因的组织特异性外显子1的转换显著相关。为了进一步研究是什么导致了人乳腺癌组织中芳香酶mRNA的升高以及芳香酶基因的转录因子从外显子1b转换到外显子1c，在来自乳腺组织的培养的脂肪基质细胞中检查了各种对替代性expns 1的表达水平和偏好的影响。在小牛血清存在下培养的基质细胞中，芳香化酶mRNA从外显子1b转录。然而，剥夺血清诱导芳香化酶mRNA的快速升高和转换的芳香化酶转录外显子1c的细胞。在HepG 2细胞和非恶性乳腺组织中，芳香化酶mRNA也从外显子1b转录，然后用荧光启动子分析法检测HepG 2细胞中负责外显子1b特异性利用的启动子区域，该区域包含4个主要的替代外显子1和启动子。结果表明，决定细胞优先利用外显子1b的转录元件位于外显子1b启动子区-255 ~-1145。我们还观察到显着水平的免疫反应芳香化酶蛋白和芳香化酶mRNA的骨和血管组织。由于这些组织中雌激素水平的降低与骨组织中的骨质疏松症和血管组织中的动脉硬化的原因有关，并且这些组织中的芳香化酶mRNA是从外显子1b转录的，因此芳香化酶基因的替代外显子1的转换可能有助于这些疾病的部分原因。