| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2000: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥4,300,000 (Direct Cost: ¥4,300,000)
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| Research Abstract |
Autoimmune disease is a consequence of abrogated self-tolerance of immune system, the mechanism of which is not fully understood. Self-tolerance is established mainly by clonal deletion or anergy of lymphocytes that recognizes self antigen. Therefore, abnormal antigen receptor signaling will result in unsuccessful self-tolerance and eventually in the autoimmune disease. Engagement of B cell antigen receptor (BCR) induces activation of tyrosine kinases such as Lyn and Syk, which are responsible for phosphorylation and activation of multiple signaling components. In Lyn-knockout mice, BCR-mediated B cell responses are up-regulated, and the animal produces more abundant antibodies and also anti-self antibodies, and frequently suffers from autoimmune diseases like nephritis. These results suggest that Lyn negatively regulates BCR signal transduction. We have studied the mechanism of Lyn-mediated regulation using chicken B cell line, DT40, deficient for Lyn. We have found that BCR-mediated
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induction of c-myc promoter activity and of PKC activity, but not the expression level of functional PKC, was markedly augmented in Lyn-deficient chicken B cells. This enhancement was reversed to the level of wild-type cells by the expression of exogenous Lyn of kinase-inactive form. These results indicate that Lyn inhibits BCR-mediated activation of a large portion of PKC isozymes in a kinase-independent fashion. This finding reveals a novel role of Lyn in negative regulation of BCR-signaling. Further analyses revealed that, among PKC isotypes expressing in DT40 cells, the activity of PKCα was more potently upregulated by BCR-ligation as well as PMA treatment than others. However, direct interaction between Lyn and PKCα was not observed in DT40 cells. Furthermore, mutant forms of Lyn carrying non-functional SH2 or SH3 domains, respectively, suppressed the exaggerated BCR-signaling observed in Lyn-deficient DT40 cells. Therefore, the remaining N-terminal domain of Lyn may indirectly interact with PKCα and interfere its activation. Less
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