GENETICS OF HUMAN METAL BINDING PROTEINS

转铁蛋白（Transferrin，TF）是铁缺乏症患者血浆中主要的铁结合蛋白， 脊椎动物，在铁代谢中起着至关重要的作用。 它是一种生长因子， 恶性细胞 由于其对铁的高亲和力，TF 限制了金属对微生物入侵者的可用性， 因此形成了抑菌活性的重要部分， 等离子体 肝脏是TF合成的主要场所。 研究 我们的实验室在过去的两年里已经证明了 T淋巴细胞的T4“诱导物”亚群合成TF， 确定了一个迄今未知的转铁蛋白自分泌作用 淋巴细胞增殖所必需的。 TF合成也已 在骨形成细胞中检测到。 TF启动子是一种相对较强的真核生物启动子， 发起人研究。 影响TF的主要因素 铁储存水平和类固醇激素。 与 人TF基因组DNA的分离和表征，我们 与调控序列相同或同源的保守序列 5'区重金属和类固醇受体的元素 TF基因。 T淋巴细胞所需的序列- 在TF启动子中也发现了特异性基因表达 地区 因此，人TF基因是一个有前途的模型， 研究基因调控。 在这项拟议的研究中，涉及的分子机制， 转铁蛋白基因调控将被分析。 的性质和 由T细胞特异性产生的62 kD TF蛋白的来源将 被定性。 本研究采用的程序， 研究调节TF生物合成的分子事件， 对铁缺乏和雌激素诱导的反应包括在体外 诱变、小基因转染、Southwestern印迹和 基因组足迹 体内TF表达将在 转基因小鼠 本文所述研究的结果将提供一种分子 调节细胞增殖所需基因的基础。

Transferrin (TF), the major iron-binding protein in plasma of vertebrates, plays a vital and central role in iron metabolism. It is a growth factor required for proliferating normal and malignant cells. By virtue of its high affinity for iron, TF limits the availability of the metal to microbial invaders, and thus forms an important part of the bacteriostatic activity of plasma. The liver is the major site of TF synthesis. Research in our laboratory during the past two years has demonstrated the synthesis of TF by the T4 "inducer" subset of T lymphocytes and identified a heretofore unknown autocrine role of transferrin required for lymphocyte proliferation. TF synthesis has also been detected in bone-forming cells. The TF promoter is one of the relatively strong eukaryotic promoters studied. The most important factors which influence TF synthesis are iron storage levels and steroid hormones. With the isolation and characterization of human TF genomic DNA, we have located conserved sequences identical or homologous to regulatory elements for heavy metals and steroid receptors in the 5' region of TF gene. A sequence proposed to be required for T lymphocyte- specific gene expression was also identified in the TF promoter region. The human TF gene is therefore a promising model for the study of gene regulation. In this proposed study, molecular mechanisms involved in the transferrin gene regulation will be analyzed. The nature and the origin of a 62 kD TF protein specifically produced by T cells will be characterized. The procedures to be employed in this study to investigate the molecular events that regulate TF biosynthesis in response to iron deficiency and estrogen induction include in vitro mutagenesis, minigene transfection, Southwestern blotting and genomic footprinting. TF expression in vivo will be analyzed in transgenic mice. Results from the study described here will provide a molecular basis for the regulation of a gene required for cell proliferation.