Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Patent
1992-09-22
1996-11-12
Allen, Marianne P.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
536 231, 536 235, 435 691, 530351, C12N 1512, C07K 14705, C07K 14715
Patent
active
055741363
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to an isolated DNA encoding granulocyte colony-stimulating factor receptor. More particularly, it relates to an isolated DNA encoding a receptor peptide capable of specifically binding to a colony-stimulating factor (hereinafter, referred to as G-CSF), an expression vector containing said DNA, a transformant transformed by said vector, and a process for the production of said receptor by culturing said transformant. The present invention also relates to a recombinant G-CSF receptor prepared according to the present process.
BACKGROUND OF THE INVENTION
Proliferation and differentiation of hematopoietic cells are regulated by hormone-like growth and differentiation factors designated as colony-stimulating factors (CSF) (Metcalf, D. Nature 339, 27-30 (1989)). CSF can be classified into several factors according to the stage of the hematopoietic cells to be stimulated and the surrounding conditions as follows: granulocyte colony-stimulation factor (G-CSF), granulocyte-macrophage colony-stimulation factor (GM-CSF), macrophage colony-stimulation factor (M-CSF), and interleukin 3 (IL-3). G-CSF participates greatly in the differentiation and growth of neutrophilic granulocytes and plays an important role in the regulation or blood levels of neutrophils and the activation of mature neutrophils (Nagata, S., "Handbook of Experimental Pharmacology", volume "Peptide Growth Factors and Their Receptors", eds. Sporn, M. B. and Roberts, A. B., Spring-Verlag, Heidelberg, Vol.95/1, pp.699-722 (1990); Nicola, N. A. et al., Annu.Rev.Biochem. 58, pp.45-77 (1989)). Thus, G-CSF stimulates the growth and differentiation of neutrophilic granulocytes through the interaction between cell-surface receptors on precursors of neutrophilic granulocytes to give mainly the neutrophilic granulocytes (Nicola, N. A. & Metcalf, D., Proc. Natl. Acad., Sci. USA, 81, 3765-3769 (1984)).
G-CSF has various biological activities in addition to those mentioned above. For example, G-CSF prepared by recombinant DNA technology has proven to be a potent regulator of neutrophils in vivo using animal model systems (Tsuchiya et al., EMBO J. 6 611-616 (1987); and Nicola et al., Annu. Rev. Biochem. 58, 45-77 (1989)). Recent clinical trials in patients suffering from a variety of hemopoietic disorders have shown that the administration of G-CSF is beneficial in chemotherapy and bone marrow transplantation therapy (Morstyn et al., Trends Pharmacol. Sci. 10, 154-159 (1989)). It is also reported that G-CSF stimulates the growth of tumor cells such as myeloid leukemia cells.
Despite the biological and clinical importance of G-CSF, little is known about the mechanism through which G-CSF exerts its effects. Therefore, it has been needed to elucidate such mechanism to establish more effective treatment and diagnosis for G-CSF-related disorders. For this purpose, the biochemical characterization of specific cell-surface receptors for G-CSF and the evaluation of interaction between G-CSF and the receptor must be performed.
Several reports suggested that the target cells of G-CSF is restricted to progenitor and mature neutrophils and various myeloid leukemia cells (Nicola and Metcalf, Proc. Natl. Acad. Sci. USA, 81, 3765-3769 (1984); Begley et al., Leukemia, 1, 1-8 (1987); and Park et al., Blood 74, 56-65 (1989)). Human G-CSF is a 174 amino acid polypeptide while murine G-CSF consists of 178 amino acids. Human and mouse G-CSFs are highly homologous (72.6%) at the amino acid sequence level, in agreement with the lack of species-specificity between them (Nicola et al, Nature 314, 626-628 (1985)). What makes the research in G-CSF more interesting is that G-CSF receptor has also recently been found in non hemopoietic cells such as human endothelial cells (Bussolino et al., Nature 337, 471-473 (1989)) and placenta (Uzumaki et al., Proc. Natl. Acad. Sci. USA, 86, 9323-9326 (1989)).
As can be seen from the above, the elucidation of the interaction between G-CSF and its receptor should greatly contribute to the development of the
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Yamasaki et al, Science, 241, 1988, pp. 825-828.
Sims et al, Science, 241, 1988, pp. 585-589.
Uzumaki et al, PNAS, 86, 1989, pp. 9323-9326.
Cosman et al, 1990, vol 2(1) pp. 1-31.
Larsen, A. et al., J. Exp. Med., The Rockefeller Univ. Press. vol. 172 "Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains", pp. 1559-1570 (Dec. 1990).
Park, L. S. et al., Blood, vol. 74, No. 1, "Interleukin-3, GM-CSF, and G-CSF, receptor expression on cell lines and primary leukemia cells: receptor heterogeneity and relationship to growth factor responsiveness" pp. 56-65, (Jul. 1989).
Fukunaga Rikiro
Nagata Shigekazu
Allen Marianne P.
Osaka Bioscience Institute
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