| Research Abstract |
G-CSF is known to play an important role in the proliferation, differentiation and functional activation of neutrophilic lineage cells. We tried analysis of G-CSF signal transduction pathway including the cloning of new molecules using the hematopoietic cells form neutrophil disorders.
First, we found the abnormal structure at the juxtamembrane intracellular part of G-CFS receptor, which is important for proliferation signal transduction, in one case with severe congenital neutropenia. This mutated cDNA-transfected cells can not proliferate well in response to G-CSF. On the other hand, we also found another case carrying a mutation at the C-terminal cytoplasmic region, which is important for differentiation signal transduction. Therefore, we can now examine the cells possessing the two types of mutated G-CSF receptor, which can not transduce the proliferation signal or differentiation signal, respectively. Using this method, we may find new molecules to relate the specific function of G
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-CSF.
In addition, we found a new type of soluble G-CSF receptor, which misses the transmembrane part completely. When we tried to compare the function of the new type and common type of soluble G-CSF receptor, there was no difference between the inhibitory effect on the activity of G-CSF. However, the chimeric protein consisting of the extracellular part of the G-CSF receptor and the Fc region of IgG, which is considered to be a good model for new type of soluble G-CSF receptor, could completely inhibit the function of G-CSF.
On the other hand, G-CSF could stimulate the proliferation of AML cells vigorously without functional maturation. Therefore, we analysed the structure of the G-CSF receptor and Jak kinases in many cases with myelogenous leukemia. We found a polymorphism, but no significant pathogenic mutations in any patients. However, we found the unbalanced gene expression of Stat 3 isoform in AML cells. These analysis may be a help to clarify not only the pathogenesis of hematopoietic disorders but also the regulating system of normal hematopoiesis. Less
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