Bishop T R, Miller M W, Beall J, Zon L I, Dierks P
Department of Pediatric Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Nucleic Acids Res. 1996 Jul 1;24(13):2511-8. doi: 10.1093/nar/24.13.2511.
In an effort to understand how the heme biosynthetic pathway is uniquely regulated in erythroid cells, we examined the structure of the gene encoding murine delta-aminolevulinate dehydratase (ALAD; EC4.2.1.24), which is the second enzyme of the pathway. The gene contains two first exons, named 1A and 1B, which are alternatively spliced to exon 2, where the coding region begins. Each first exon has its own promoter. The promoter driving exon 1A expression is TATA-less and contains many GC boxes. In contrast, the exon 1B promoter bears regulatory sequences similar to those found for beta-globin and other erythroid-specific genes. Tissue distribution studies reveal that ALAD mRNA containing axon 1A is ubiquitous, whereas mRNA containing axon 1B is found only in erythroid tissues. This finding, together with our further observation that GATA-1 mRNA levels increase 3-fold during maturation of murine erythroid progenitor cells, may help explain simultaneous 3-fold increases in exon 1B expression. The unexpected result that axon 1A expression also increases 3-fold during CFU-E maturation may be attributable to the action of NF-E2, since there is a potential binding site in a position analogous to the NF-E2 site in the locus control region of the beta-globin gene cluster.
为了了解血红素生物合成途径在红细胞中是如何被独特调控的，我们研究了编码小鼠δ-氨基-γ-酮戊酸脱水酶（ALAD；EC4.2.1.24）的基因结构，该酶是该途径的第二个酶。该基因包含两个第一外显子，命名为1A和1B，它们可选择性地剪接至外显子2，编码区域从外显子2开始。每个第一外显子都有自己的启动子。驱动外显子1A表达的启动子没有TATA盒，包含许多GC盒。相比之下，外显子1B启动子带有与β-珠蛋白和其他红细胞特异性基因相似的调控序列。组织分布研究表明，含有外显子1A的ALAD mRNA普遍存在，而含有外显子1B的mRNA仅在红细胞组织中发现。这一发现，连同我们进一步观察到的在小鼠红细胞祖细胞成熟过程中GATA-1 mRNA水平增加3倍，可能有助于解释外显子1B表达同时增加3倍的现象。在CFU-E成熟过程中外显子1A表达也增加3倍这一意外结果可能归因于NF-E2的作用，因为在β-珠蛋白基因簇的基因座控制区域中存在一个与NF-E2位点类似位置的潜在结合位点。
