REGULATION OF IMMUNOGLOBULIN LAMBDA

描述(改编自调查者摘要)：此应用程序 建议：1)分析一种新的淋巴特异性转录因子， PIP是lambda基因表达所必需的，它与 Lambda增强子依赖于与编码的原癌基因的相互作用 蛋白质PU.l。Pip的基因组组织和表达将是 经过分析，将产生PIP缺陷小鼠。2)检查 轻链基因表达与干扰素的关系《管子》 蛋白质序列分析表明，它是干扰素反应的新成员 因子(IRF)家族。与PiP关系最密切的IRF基因是ICSBP，一种 其他IRF的抑制剂。ICSBP可能会在与Pip的互动中与Pip竞争 Lambda增强子，在这样做的过程中，调节lambda基因的表达。3) 编码与λA相互作用蛋白的基因(S)的克隆 拉姆达增强剂的主题。其中两个增强剂LEI和LE2是 类似于在Ig kappa和重链增强剂中发现的DNA基序。一个 第三个是Lb，现在我们已经证明它可以结合PU.1和Pip。这些基因 与基本LA基序相互作用的编码因子将被克隆。 当结合所有四个基序的因素都已知时，这应该是可能的 了解lambda的表达是如何被控制的，尤其是如何 克服了V lambda启动子的沉默活性。4)分析 SJL小鼠的Lambda-1缺陷。低水平的Lambda-1 在SJL小鼠品系中含有lgs很可能是由于效率低下 B细胞被激活。已获得初步证据表明， 缺陷是由Lambda-1恒定区的点突变引起的 将野生型甘氨酸转变为缬氨酸。转基因小鼠携带 带有Gly或Val密码子的SJL基因将被用来证实 这个假说。未来的研究将调查这种变化是如何 单一残基会干扰B细胞的激活。

DESCRIPTION (Adapted from the Investigator's abstract): This application proposes to: 1) Analyze of a novel lymphoid specific transcription factor, Pip which is required for lambda gene expression and whose binding to the lambda enhancers depends on the interaction with the proto-oncogene encoded protein PU.l. The genomic organization and expression of Pip will be analyzed and Pip deficient mice will be generated. 2) Examine the relationship between light chain gene expression and interferons. The Pip protein sequence shows that it is a new member of the interferon response factor (IRF) family. The IRF gene most closely related to Pip is ICSBP, an inhibitor of other IRFs. ICSBP may compete with Pip in the interaction with the lambda enhancers and in so doing, regulate lambda gene expression. 3) To clone of the gene(s) encoding proteins that interact with the lambda A motif of the lambda enhancers. Two of the enhancers, LEI and LE2, are similar to DNA motifs found in the Ig kappa and heavy chain- enhancers. A third one, LB, has now been shown by us to bind PU.1 and Pip. The genes that encode factors that interact with the essential LA motif will be cloned. When the factors binding to all four motifs are known, it should be possible to understand how the expression of lambda is controlled and especially, how the silencing activity of the V lambda promoter is overcome. 4) analyze the lambda-1 defect int he SJL mouse strain. The low level of Lambda-1 containing lgs in the SJL mouse strain is most likely due to inefficient B-cell activation. Preliminary evidence has been obtained showing that the defect is caused by a point mutation in the constant region of Lambda-1 which changes a wildtype glycine to a valine. Transgenic mice that carry the SJL gene with either the gly or the val codon will be made to confirm this hypothesis. Future studies will investigate how this change of a single residue interferes with B-cell activation.