Breslin Mary B, Zhu Min, Lan Michael S
Research Institute for Children, Children's Hospital, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70118, USA.
J Biol Chem. 2003 Oct 3;278(40):38991-7. doi: 10.1074/jbc.M306795200. Epub 2003 Jul 30.
IA-1 is a novel zinc finger transcription factor with a restricted tissue distribution in the embryonic nervous system and tumors of neuroendocrine origin. The 1.7-kilobase 5'-upstream DNA sequence of the human IA-1 gene directed transgene expression predominantly in the developing nervous system including forebrain, midbrain, hindbrain, spinal cord, retina, olfactory bulb, and cerebellum, which recapitulated the expression patterns of neuroendocrine tissues and childhood brain tumors. The IA-1 promoter deletion reporter gene constructs revealed that the sequence between -426 and -65 bp containing three putative E-boxes (approximately 361 bp) upstream of the transcription start site was sufficient to confer tissue-specific transcriptional activity. Further mutation analysis revealed that the proximal E-box (E3) closest to the start site is critical to confer transcriptional activity. Electrophoretic mobility shift assay and transient transfection studies demonstrated that the NeuroD1 and E47 heterodimer are the key transcription factors that regulate the proximal E-box of the IA-1 promoter. Therefore, we concluded that the IA-1 gene is developmentally expressed in the nervous system and the NeuroD1/E47 transcription factors up-regulate IA-1 gene expression through the proximal E-box element of the IA-1 promoter.
IA-1是一种新型锌指转录因子，在胚胎神经系统和神经内分泌起源的肿瘤中具有受限的组织分布。人类IA-1基因1.7千碱基的5'上游DNA序列主要在发育中的神经系统中指导转基因表达，包括前脑、中脑、后脑、脊髓、视网膜、嗅球和小脑，这重现了神经内分泌组织和儿童脑肿瘤的表达模式。IA-1启动子缺失报告基因构建体显示，转录起始位点上游-426至-65 bp之间包含三个推定E盒（约361 bp）的序列足以赋予组织特异性转录活性。进一步的突变分析表明，最接近起始位点的近端E盒（E3）对于赋予转录活性至关重要。电泳迁移率变动分析和瞬时转染研究表明，NeuroD1和E47异二聚体是调节IA-1启动子近端E盒的关键转录因子。因此，我们得出结论，IA-1基因在神经系统中呈发育性表达，NeuroD1/E47转录因子通过IA-1启动子的近端E盒元件上调IA-1基因表达。
