Chase Michael B, Fu Sidong, Haga Susanne B, Davenport Gregory, Stevenson Holly, Do Khanh, Morgan Doris, Mah Alex L, Berg Patricia E
Division of Human Genetics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Mol Cell Biol. 2002 Apr;22(8):2505-14. doi: 10.1128/MCB.22.8.2505-2514.2002.
In earlier studies we identified a putative repressor of the human beta-globin gene, termed beta protein 1 (BP1), which binds to two silencer DNA sequences upstream of the adult human beta-globin gene and to a negative control region upstream of the adult delta-globin gene. Further studies demonstrated an inverse correlation between the binding affinity of the BP1 protein for the distal beta-globin silencer sequence and the severity of sickle cell anemia, suggesting a possible role for BP1 in determining the production of hemoglobin S. We have now cloned a cDNA expressing the BP1 protein. Sequencing revealed that BP1 is a member of the homeobox gene family and belongs to the subfamily called Distal-less (DLX), genes important in early development. Further analysis showed that BP1 is an isoform of DLX4. BP1 protein has repressor function towards the beta-globin promoter, acting through the two beta-globin DNA silencers, demonstrated in transient transfection assays. Strong BP1 expression is restricted to placenta and kidney tissue, with no expression in 48 other human tissues. BP1 exhibits regulated expression in the human erythroid cell line MB-02, where its expression decreases upon induction of the beta-globin gene. BP1 is thus the first member of the DLX family with known DNA binding sites and a function in globin gene regulation.
在早期研究中，我们鉴定出一种假定的人类β-珠蛋白基因阻遏物，称为β蛋白1（BP1），它与成人人类β-珠蛋白基因上游的两个沉默子DNA序列以及成人δ-珠蛋白基因上游的一个负调控区域结合。进一步的研究表明，BP1蛋白与远端β-珠蛋白沉默子序列的结合亲和力与镰状细胞贫血的严重程度呈负相关，这表明BP1在决定血红蛋白S的产生中可能发挥作用。我们现在已经克隆了一个表达BP1蛋白的cDNA。测序显示BP1是同源异型盒基因家族的成员，属于名为无翅型（Distal-less，DLX）的亚家族，这些基因在早期发育中很重要。进一步分析表明BP1是DLX4的一种异构体。在瞬时转染实验中表明，BP1蛋白对β-珠蛋白启动子具有阻遏功能，通过两个β-珠蛋白DNA沉默子起作用。BP1的强表达仅限于胎盘和肾脏组织，在其他48种人类组织中无表达。BP1在人类红系细胞系MB-02中表现出受调控的表达，在该细胞系中，其表达在β-珠蛋白基因诱导后降低。因此，BP1是DLX家族中第一个具有已知DNA结合位点且在珠蛋白基因调控中具有功能的成员。
