| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
Development of erythrocytes is a comlex process governed by multiple cytokines. Colony assay revealed the physiologic importance of each of the cytokines. However, biochemical studies of highly purified human colony forming unit-erythroid (CFU-E) generated in vitro from CD34+ cells have only recently begun. Studies from our groups and others suggested that signal transduction in the primary erythroid cells may differ considerably from that in cell lines or the primary cells from other species. We have developed a method to generate purified erythroid progenitors, which are expanded from CD34+ cells in human peripheral blood in a sufficient number to allow for examination of early signaling by EPO or apoptosis. Using these cells, we have found that SCF protected purified human glycophorin A-positive (GPA^+)/c-kit^+ cells from apoptosis, and suggeswted that mediated Src kinase activation is involved in Akt activation and cell survival. Further, we have suggested that SCF prevents Fas-med
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iated apoptosis of erythroid progenitor cells in a manner dependent on the activity of Src-family tyrosine kinases. We also identified active Lyn in erythroid cells. These data suggest the presence of a novel Src-family/AKT dependent function of SCF in the development of erythrocytes. At the same time, we identified a novel Kruppel associated box (KRAB) zinc finger gene, ZNF317. ZNF317 encoded a protein comprised of thirteen Kruppel-like zinc fingers and a KRAB domain. RT-PCR analysis revealed four alternatively splicing products (ZNF317-1 through ZNF317-4). The ZNF317 gene has seven exons and is located in human chromosome 19p13. ZNF317-1 and ZNF317-2 transcripts were ubiquitously expressed, whereas ZNF317-3 and ZNF317-4 transcripts were detected only in lymphocytes, spleen and lung. The expression of ZNF317 mRNA significantly decreased during erythroid maturation. In lymphocytes, ZNF317 expression was reduced in response to mitogenic stimulation. We propose that ZNF317 may play an important role in erythroid maturation and lymphoid proliferation. Less
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