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Alternative Variants of Pax4 Human Transcription Factor: Comparative Transcriptional Activity
Molecular Biology ( IF 1.2 ) Pub Date : 2020-10-19 , DOI: 10.1134/s0026893320050076
A. I. Melnikova , T. S. Krasnova , N. A. Zubkova , A. N. Tiulpakov , P. M. Rubtsov

Abstract

MODY is a group of genetically and clinically heterogeneous forms of diabetes characterized by autosomal dominant inheritance and is subdivided in 13 subtypes dependent on the gene involved. The subtype MODY9 is a very rare form caused by mutations in the gene encoding the PAX4 transcription factor which is engaged in differentiation of pancreatic beta-cells. PAX4 contains two DNA-binding domains—Paired and Homeo. Expression of the human PAX4 gene is tissue-specific. The alternatively spliced mRNA variants encode for protein isoforms which differ within their N- and C-terminal regions. In this study, the transcriptional activities of the human PAX4 variants, both known and new ones, were determined. The full-length PAX4 containing intact DNA-binding domains was found to have maximal activity in transient expression system of the firefly luciferase reporter gene under control of the insulin promoter in HEK293 cells. The transcriptional activity is significantly reduced in the variants lacking eight N-terminal amino acid residues and/or variants whose Homeo domain is truncated from the C-terminus. Similar data were obtained with the glucagon promoter reporter system. The aberrant PAX4 variants were shown to retain stability and nuclear localization.



中文翻译:

Pax4人类转录因子的替代变体:比较转录活性。

摘要

MODY是一组具有常染色体显性遗传特征的遗传和临床异质性糖尿病,根据所涉及的基因分为13种亚型。MODY9亚型是一种非常罕见的形式,是由参与胰腺β细胞分化的编码PAX4转录因子的基因突变引起的。PAX4包含两个DNA结合域-Paired和Homeo。人PAX4基因的表达具有组织特异性。交替剪接的mRNA变体编码在其N端和C端区域不同的蛋白质同工型。在这项研究中,确定了人类PAX4变体(已知的和新的)的转录活性。发现在HEK293细胞中,在胰岛素启动子的控制下,含有完整DNA结合域的全长PAX4在萤火虫荧光素酶报道基因的瞬时表达系统中具有最大活性。在缺少八个N末端氨基酸残基的变体和/或Homeo结构域从C端被截断的变体中,转录活性显着降低。用胰高血糖素启动子报告系统获得了相似的数据。异常PAX4变体显示保留稳定性和核定位。用胰高血糖素启动子报告系统获得了相似的数据。异常PAX4变体显示保留稳定性和核定位。用胰高血糖素启动子报告系统获得了相似的数据。异常PAX4变体显示保留稳定性和核定位。

更新日期:2020-10-19
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