| Co-Investigator(Kenkyū-buntansha) |
DE VRIES Jan Novortis Research Institute, Novartis Forschungs institut, Head Scientis, 主任研究員
SHLOMAI Jose ヘブライ大学, 医学部, 教授
ARAI Naoko DNAX Research Institute, Chief Scientist, 細胞シグナリング研究所, 副部長
SATO Noriko University of Tokyo, Institute of Medical Science, Research Associate, 医科学研究所, 助手 (70280956)
WATANABE Sumio University of Tokyo, Institute of Medical Science, Research Associate, 医科学研究所, 助手 (60240735)
JOSEPH Sholomai The Hebrew University, Professor
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| Research Abstract |
In this collaborative project, we are studying on the mechanisms of induction of DNA replication, gene expression and other various cellular responses in growth factor-mediated proliferation and differentiation of mammalian cells.
This year, we have obtained the following results.
1) We have isolated a putative regulatory subunit for fission yeast Hsk1 kinase. Among several S.pombe clones encoding Hsk1-interacting molecules, Him1 (H__-sk1 i__-nteracting m__-olecule 1) forms a complex with Hsk1, stimulates its kinase activity and is specifically phosphorylated by Hsk1. him1^+ is essential for viability of fission yeast cells and its transcription is cell cycle-regulated, reaching maximum at the G1/S boundary, although it is not under the control of cdc10^+.
2) We have also isolated a novel human cDNA,H37, encoding a huCdc7-interacting molecule. H37 and huCdc7, when coexpressed with huCdc7 in COS7 cells or in insect cells, forms a complex and the complex formation activates huCdc kinase, re
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sulting in extensive phosphorylation of both huCdc and H37. This indicates that H37 is a regulatory subunit for huCdc kinase. Microinjection of antibodies against H37 protein inhibited DNA synthesis in primary fibroblast cells, indicating that the function of H37-huCdc7 is required for S phase initiation.
3) We have mapped replication origins in the GM-CSF/IL-3 locus of the human 5q region by using the competitive PCR method. Our preliminary results indicate the presence of an active replication origin near the inducible DNaseI-hypersensitive site within the intergenic region.
4) We have mapped tyrosine residues of the cytoplasmic region of beta-chain of GM-CSF receptore whose phosphorylation is required for DNA replication, induction of early response genes, prevention of apoptosis, and so on.
5) We have shown that dimerization of Jak2 alone can induce induction of c-myc, STAT5 activation and cytokine-independent proliferation.
6) We have isolated novel clones whish are induced by cytokine stimulation of mutant GM-CSF receptors capable specifically of promoting proliferaton.
6) Administration of human GM-CSF to human GM-CSF receptor transgenic mice stimulated myelopoiesis as well as erythropoiesis and megakaryopoiesis in mice. it also affected the development of natural killer cells in the transgenic mice. Less
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