Cloning and characterization of the 5'-flanking sequence for the human DNA topoisomerase II beta gene.
Cloning and characterization of the 5'-flanking sequence for the human DNA topoisomerase II beta gene.
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人类 DNA 拓扑异构酶 II β 基因 5 侧翼序列的克隆和表征。
DOI：
10.1016/s0378-1119(97)00500-3
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发表时间：
1997
期刊：
影响因子：
3.5
通讯作者：
Schnipper,LE
中科院分区：
文献类型：
--
作者：
Ng,SW;Liu,Y;Schnipper,LE
哺乳动物细胞表达II型DNA拓扑异构酶的两种异构体，其是许多结构不同的抑制剂的细胞内靶点。拓扑异构酶II同工酶的水平是细胞对靶向拓扑异构酶II的药物的细胞毒性的敏感性的重要决定因素。为探讨拓扑异构酶II β亚型在耐药背景下的表达是否协调以及调控其表达的机制，克隆了人拓扑异构酶IIβ亚型基因的5′-侧翼序列并进行了鉴定。5′-侧翼区GC含量很高，不含典型的TATA盒元件。两个独立的转录起始位点分别位于ATG翻译起始密码子上游的腺嘌呤和鸟嘌呤，193和89个核苷酸。拓扑异构酶IIβ基因5′侧翼序列除翻译起始密码子上游的一小段区域外，与已报道的α基因没有明显的同源性。拓扑异构酶IIβ基因5′-侧翼区不同5′-和3′-缺失的瞬时表达测定已描绘出对该基因转录调控重要的区域。有趣的是，第一内含子内的序列也有助于启动子活性。凝胶迁移率变化研究表明，从核提取物的蛋白质因子可以特异性地结合到下游元件，并可能参与转录调控。
Mammalian cells express two isoforms of type II DNA topoisomerase which are the intracellular targets of many structurally diverse antineoplastic agents. The levels of topoisomerase II isozymes are important determinants for the sensitivity of cells to the cytotoxicity of drugs that target topoisomerase II. To investigate whether the expression of topoisomerase II isoforms is coordinated and the mechanisms governing their expression in the context of drug resistance, the 5′-flanking sequence for the gene of human topoisomerase IIβ isoform was cloned and characterized. The 5′-flanking region has a very high GC content and contains no canonical TATA box element. Two separate transcriptional start sites are located to an adenine and a guanine, 193 and 89 nucleotides, respectively, upstream from the ATG translation initiation codon. Except for a small region immediately upstream of the translation initiation codon, there is no obvious sequence homology between the 5′-flanking sequences of human topoisomerase IIβ gene and the previously described α gene. Transient expression assays with different 5′- and 3′-deletions of the 5′-flanking region of the topoisomerase IIβ gene have delineated regions important for transcriptional regulation of the gene. Interestingly, sequences within the first intron also contribute to the promoter activity. Gel mobility shift studies demonstrate that protein factors from the nuclear extracts can bind specifically to the downstream elements and may participate in transcriptional regulation.
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