1998 Fiscal Year Final Research Report Summary
Signal transduction mediated by hematopoietic factors and TGF-β in p53-deficient mice
| Project/Area Number |
08457079
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
INOUE Tohru National Institute of Health Sciences, Biological Safety Researchi Center, Cellular & Molecular Toxicology Division, Chairperson, 安全性生物試験研究センター・毒性部, 部長 (50100110)
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| Co-Investigator(Kenkyū-buntansha) |
HIRABAYASHI Yoko National Institute of Health Sciences, Biological Safety Reaearch Center, Cellular & Molecular Toxicology Division, Senior Researcher, 安全性生物試験研究センター・毒性部, 主任研究官 (30291115)
TAKAGI Atsuya National Institute of Health Sciences, Biological Safety Reaearch Center, Cellular & Molecular Toxicology Division, Senior Researcher, 安全性生物試験研究センター・毒性部, 主任研究官 (00179417)
HIROSE Akihiko National Institute of Health Sciences, Biological Safety Reaearch Center, Division of Risk Assessment, Senior Researcher, 安全性生物試験研究センター・総合評価研究室, 主任研究官 (90228833)
SASAKI Hideki Yokohama City Unversity School of Mdicine, Department of Pediatrics, Associate Professor, 医学部・小児科, 助教授 (50106316)
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| Project Period (FY) |
1996 – 1998
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| Keywords | p53-deficient mice / sytokine / TGF-β / hematopoietic progenitor cells |
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| Research Abstract |
We investigated the effect of hematopoietic factors and transforming growth factor-P (TGF-β)on hematopoietic progressions in p53-deficient mice to clarify whether p53 plays a role in TGF-p-induced growth inhibition in the hematopoietic system. TGF-p has been found to block the progression of the cell-cycle by up-regulating a Cdk inhibitor, p 15, only in epithelial cells ; on the other hand, wild-type p53 was shown to activate transcriptionally the gene for another Cdk inhibitor, p21. The regulatory effects of TGF-β on hematopoietic tissues is poorly understood. Hence, we investigated the effect of TGF-β on hematopoietic progenitor cells in p53-deficient mice to determine whether an inhibitory signal from TGF-β is linked to p53 in hematopoietic regulation. We found that the proliferation of megakaryocyte-progenitors (CFU-Mk) in our wild-type mice was markedly inhibited by TGF-β. Contrary to an earlier report an elytroid and a granulocyte-macrophage progenitor, stimulated by IL-3, were not significantly inhibited, whereas TGF-β also completely inhibited the growth of high-proliferative potential progenitor cells (HPP-CFC) in the marrow of mice with 5-fluorouracil (5FU), as reported. It is interesting that in the p53-deficient mice, the inhibitory action of TGF- p on the HPP-CFC was incompletely abolished. The response curve we obtained for graded doses of TGF-β suggests that there is, at least, a subpopulation of HPP-CFC which is less sensitive to the regulation by TGF-β. In contrast to HPP-CFC, the CFU-Mk, which TGF-β inhibited only in wild-type mice not treated with 5FU, remained inhibited in the p53-deficient strain. Thus, HPP-CFC might be regulated by TGF-β through their signal pathways which are linked to p53.
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