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Regulation of the cell type-specific expression of the gene encoding glial fibrillary acidic protein.

机译：调节编码胶质纤维酸性蛋白的基因的细胞类型特异性表达。

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摘要

Glial fibrillary acidic protein (GFAP) is a specific marker in the development of the central nervous system, where its presence distinguishes astrocytes from other glial cell types. Cell type-specific expression of the gene encoding GFAP is regulated principally at the level of transcription. The regulation of cell type-specific expression of this gene was examined by introducing various deletion mutants of the gene into GFAP expressing (U251 human astrocytoma) and non-expressing (HeLa) cell lines and measuring their transcriptional activity in a RNase protection assay. When the intact GFAP gene with 2 Kb of 5{dollar}spprime{dollar} flanking sequence and 2 Kb of 3{dollar}spprime{dollar} untranslated and 3{dollar}spprime{dollar} flanking sequences was transfected into U251 and HeLa cells, the GFAP specific mRNA was detected only in U251. Replacing sequences downstream from the GFAP transcriptional start site by a heterologous cDNA led to the expression of this chimeric gene in cells that are either permissive or nonpermissive for the expression of GFAP, implying the existence of an intragenic regulatory element. Analysis of the GFAP gene truncated at its 3{dollar}spprime{dollar} end showed the existence of negative regulatory elements located in the first and third introns.; Two positive regulatory elements were identified: the proximal element (located between nucleotide {dollar}-{dollar}94 and {dollar}-{dollar}78) and the distal element (located 1.5kb upstream from the GFAP transcriptional start site). The distal element can confer cell type specificity on a heterologous promoter. Gel retardation assays and DNaseI footprinting showed that an ubiquitous protein factor binds to sequences {dollar}-{dollar}96 to {dollar}-{dollar}80. Deletion of this sequence abolished the expression of GFAP in vivo. An AP-1 site was identified within the distal element which contributed to the cell type-specific expression of GFAP. Thus, the cell type-specific expression of the GFAP gene is regulated by the concerted action of multiple regulatory elements located both upstream and downstream from the transcriptional start site.
机译：胶质原纤维酸性蛋白（GFAP）是中枢神经系统发育中的一种特殊标记物，它的存在将星形胶质细胞与其他胶质细胞类型区分开。编码GFAP的基因的细胞类型特异性表达主要在转录水平上调节。通过将基因的各种缺失突变体引入表达GFAP的（U251人星形细胞瘤）和不表达的（HeLa）细胞系并在RNase保护试验中测量其转录活性，来检查该基因的细胞类型特异性表达的调控。当完整的GFAP基因具有2 Kb的5 {dollar} spprime {dollar}侧翼序列和2 Kb的3 {dollar} spprime {dollar}侧翼序列未翻译和3 {dollar} spprime {dollar}侧翼序列被转染到U251和HeLa细胞中时，仅在U251中检测到GFAP特异性mRNA。用异源cDNA替换GFAP转录起始位点下游的序列，导致该嵌合基因在允许或不允许GFAP表达的细胞中表达，这意味着存在基因内调控元件。 GFAP基因在其3 {sp}}末端被截短的分析表明，负调控元件存在于第一和第三内含子中。确定了两个阳性调控元件：近端元件（位于核苷酸{dollar}-{dollar} 94和{dollar}-{dollar} 78之间）和远端元件（位于GFAP转录起始位点上游1.5kb）。远端元件可以赋予异源启动子细胞类型特异性。凝胶阻滞测定和DNaseI足迹显示，普遍存在的蛋白质因子结合序列{美元}-{美元} 96至{美元}-{美元} 80。该序列的删除消除了体内GFAP的表达。在远侧元件中鉴定出AP-1位点，其有助于GFAP的细胞类型特异性表达。因此，GFAP基因的细胞类型特异性表达由位于转录起始位点上游和下游的多个调节元件的协同作用调节。

著录项

  • 作者

    Sarkar, Srijata.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 1990
  • 页码 105 p.
  • 总页数 105
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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