| Co-Investigator(Kenkyū-buntansha) |
YABUNAKA Noriyuki Hokkaido University, School of Medicine, Associate, 医学部, 助手 (70240637)
ISHII Atsushi Hokkaido University, School of Medicine, Associate, 医学部, 助手 (20232225)
OHTA Masatsugu Hokkaido University, School of Medicine, Associate Professor, 医学部, 助教授 (90160514)
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| Budget Amount *help |
¥7,800,000 (Direct Cost : ¥7,800,000)
Fiscal Year 1997 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1996 : ¥6,400,000 (Direct Cost : ¥6,400,000)
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| Research Abstract |
During the period from 1996 to 1997, the following new findings were obtained, and most of them were presented in some of the international conferences, and published in the specialized journals : (1) The interaction of the extracellular matrix glycoprotein, fibronectin, with the integrin VLA-5 was shown to be intimately related with the apoptotic phenomena of hematopoietic cells. (2) A significant enhancement of the expression of VLA-5 mRNA was observed only in the monocytic, but not granulocytic, differentiation of human myelogenous leukemia HL-60 cells. (3) The expression of integrin VLA-5 on the cell surface was enhanced exclusively in the process of monocytic differentiation, and the most prominent expression was observed on the surface of peripheral mature monocytes. (4) The sensitivity of fibronectin-induced apoptosis was remarkably increased during monocytic differentiation, and the anti-VLA-5 monoclonal antibody or the RGD peptide completely abolished it. (5) Apoptosis of the
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normal monocytes, but not granulocytes, from peripheral blood was significantly increased by the extracellular matrix fibronectin, and the anti-fibronectin monoclonal antibody suppressed the apoptosis and increased the survival time of normal monocytes. (6) Expression of the extracellular matrix glycoprotein, tenascin, was restricted spatially and temporally during the formation of tumor tissues, depending upon the stromal-epithelial interactions, and the de novo synthesis of tenascins was induced by the soluble growth factor EGF,being also dependent on the stromal-epithelial interactions. Human tenascin C is shown to have the EGF-like domain, but this domain and its derivative peptide could not induce the expression of tenascin. (7) With all the current data taken together, it is concluded that the ECM glycoprotein fibronectin might play an important role as the negative regulator for the survival of monocytes in collaboration with the integrin VLA-5, which characteristically increases during the process of monocytic differentiation.
In the latter part of the present research projects, the following novel findings were demonstrated : (8) Using the elaborately-devised expression cloning method, we have succeeded for the first time in isolating and molecularly characterizing a new and relevant gene (cDNA and its genome) which encodes a key glycosyltransferase, ganglioside GM3 synthase (sialyltransferase-1) , responsible for the biosynthesis of a ubiquitous but intriguing membraneous molecule of the simplest structure, ganglioside GM3. GM3 was previously demonstrated to exhibit a variety of biological functions intimately related to the cell growth control, malignant transformations, the cell-to-cell recognitions, and the differentiation-induction of human myelogenousleukemia cells. Less
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