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.
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