| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
ARG is a widely expressed tyrosine kinase, while the function is not well understood. In the study, TEL/ARG was used to investigate the function of ARG, and it's role in leukemohenesis
The TEL/ARG oncogene associated with AML is formed by the t (1;2) (q25;p13) reciprocal translocation, fusing part of the TEL gene to the tyrosine kinase, c-ARG. I have demonstrated that the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and was associated with factor-independent proliferation when expressed in the factor-dependent murine hematopoietic cell line Ba/F3. Using the sublines, I also have reported that the ARG kinase activity is inhibited by the ABL kinase inhibitor, STI571. In an effort to determine the biological effects and investigate signaling of the TEL/ARG protein more precisely, multiple sublines of Ba/F3 cells were generated in which a TEL/ARG Cdna was expressed under the control of a tetracyline-inducible promo
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ter. Treatment of these cells with doxycycline, a tetracy cline analogue, rapidly induced expression of the TEL/ARG protein. The Ba/F3 -tet- TEL/ARG cells remained IL-3 dependent without doxycycline, but with doxycycline displayed a marked reduction in cell death in the absence IL-3. TEL/ARG cells also displayed an enhanced proliferative response to IL-3 and to IGF-1. Some of the signaling pathways activated by TEL/ARG were compared to those activated by other TEL-tyrosine kinase oncogenes in Ba/F3 cells, inctuding TEL/ABL, TEL/JAK2 and TEL/PDGFRβ. TEL//ARG was heavily phosphorylated on tyrosine residues, and was also found to induce tyrosine phosphorylation of multiple cellular proteins, including rasGAP, Cbl, STAT5, paxillin and SHC. Most of these substrates are also phosphorylated in Ba/F3 cells transformed by another oncogenes listed above, indicating that this family of activated tyrosine kinase oncogenes share several comon signaling pathways. At least in Ba/F3 cells, however, TEL/ARG appears to be less likely to induce complete factor independence compared to other TEL/kinase oncogenes. Nonetheless, the hyper-responsiveness to growth factors reported in this study is highly likely to contribute to the pathogenesis of leukemia Less
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