Adrian G S, Bowman B H, Herbert D C, Weaker F J, Adrian E K, Robinson L K, Walter C A, Eddy C A, Riehl R, Pauerstein C J
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78284.
J Biol Chem. 1990 Aug 5;265(22):13344-50.
Transferrin (TF) is a plasma protein that transports and is regulated by iron. The aim of this study was to characterize human TF gene sequences that respond in vivo to cellular signals affecting expression in various tissues and to iron administration. Chimeric genes were constructed containing 152, 622, and 1152 base pairs (bp) of the human TF5'-flanking region with the coding region of a reporter gene, CAT (chloramphenicol acetyltransferase), and introduced into the germ line of mice. Transgenes containing TF 5'-flanking sequences to -152 bp were expressed poorly in all tissues examined. In contrast, transgenes containing TF sequences to -622 or -1152 bp were expressed at high levels in brain and liver, greater than or equal to 1000-fold higher than tissues such as heart and testes. Liver and brain are major sites of endogenous TF mRNA synthesis, but liver mRNA levels are 10-fold higher than brain. A significant diminution of CAT enzymatic activity in liver accompanied iron administration in both TF(0.67) and TF(1.2)CAT transgenic mice, mimicking the decrease of transferrin in humans following iron overload. Levels of endogenous plasma transferrin also decreased in iron-treated transgenic mice. Transgenic mouse lines carrying human TF chimeric genes will be useful models for analyzing the regulation of human transferrin by iron and for determining the molecular basis of transferrin regulation throughout mammalian development into the aging process.
转铁蛋白（TF）是一种血浆蛋白，负责转运铁并受铁调节。本研究的目的是鉴定人类TF基因序列，这些序列在体内对影响各种组织中表达的细胞信号以及铁给药有反应。构建了嵌合基因，其包含人类TF 5'侧翼区的152、622和1152个碱基对（bp）以及报告基因氯霉素乙酰转移酶（CAT）的编码区，并将其导入小鼠生殖系。含有TF 5'侧翼序列至 -152 bp的转基因在所有检测的组织中表达较差。相比之下，含有TF序列至 -622或 -1152 bp的转基因在脑和肝中高水平表达，比心脏和睾丸等组织高1000倍以上。肝和脑是内源性TF mRNA合成的主要部位，但肝mRNA水平比脑高10倍。在TF(0.67)和TF(1.2)CAT转基因小鼠中，铁给药均伴随着肝中CAT酶活性的显著降低，这与人类铁过载后转铁蛋白的减少相似。铁处理的转基因小鼠中内源性血浆转铁蛋白水平也降低。携带人类TF嵌合基因的转基因小鼠品系将成为分析铁对人类转铁蛋白调节以及确定整个哺乳动物发育至衰老过程中转铁蛋白调节分子基础的有用模型。
