| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Protein-tyrosine kinases play essential roles in intracellular signaling events regulating a wide range of important functions of multi-cellular organisms. Dok-family of proteins are thought to work as a docking protein because they consist of N-terminal PH and PTB domains followed by C-terminal part carrying multiple SH2-target sites like IRS-family of docking proteins. As an initial step to understand physiological roles of Dok-family proteins, we established the Dok/Dok-2-deficient mice. The mice showed increased numbers of granulocytes and monocytes in peripheral blood and of their precursor cells in bone marrow and spleen. Then, we investigated numbers of hematopoietic stem cells in bone marrow and spleen to find out that Dok/Dok-2-deficient mice have increased number of stem cells for granulocytes and monocytes in both of the organs. In addition, hamatopoietic cells derived from the double-deficient mice showed augmented responses to stimulation with cytokines important for such stem cells. In the kidney of the Dok/Dok-2 deficient mice, we often found glomerulonephritis with immunoglobulin deposition, suggesting autoimmunity. Moerover, we crossed the Dok/Dok-2 deficient mice with chronic myelogenous leukemia (CML)model mice having bcr-abl transgene and found that Dok and Dok-2 protect those mice from blast crisislike disease. Together, these results indicate that Dok and Dok-2 are negative regulator of hematopoietic cells in terms of proliferation and malignancy and probably of immune response. On the other hand, we identified several tyrosine-phosphorylated Dok-binding novel proteins among other known ones and cloned a novel dok-family cDNA.
Based on the above results, we are investigating physiological roles and biochemical mechanisms of Dok-family proteins in regulating immune response, cellular proliferation, malignancies and so forth.
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