| Project/Area Number |
16390080
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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 |
General medical chemistry
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
TAKIHARA Yoshihiro Hiroshima University, Research Institute for Radiation Biology and Medicine, Professor, 原爆放射線医科学研究所, 教授 (60226967)
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| Co-Investigator(Kenkyū-buntansha) |
OHTSUBO Motoaki Hiroshima University, Research Institute for Radiation Biology and Medicine, Research Associate, 原爆放射線医科学研究所, 助手 (10211799)
YASUNAGA Shin'ichiro Hiroshima University, Research Institute for Radiation Biology and Medicine, Research Associate, 原爆放射線医科学研究所, 助手 (50336111)
NISHITANI Hideo Kyushu University, Graduate School of Medical Science, Research Associate, 大学院・医学研究院, 助手 (40253455)
TAKIHARA Keiko Osaka University, Health Care Center, Associate Professor, 保健センター, 助教授 (70252640)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2004: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | Polycomb-group genes / stem cells / stemness / molecular basis / genetically engineered mice / retrovirus vector / 成体幹細胞 / 造血幹細胞 / DNA複製制御 / Geminin / Cdt1 |
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| Research Abstract |
Hematopoietic stem cell (HSC) transplantation is now routinely performed in clinical practice for the treatment of patients with hematological malignancies and bone marrow failure. And new strategies with HSCs are developed for the treatment of patients with the other malignancies and vascular failure including myocardial infarction, attracting further attention to HSCs. However, molecular mechanisms regulating HSCs still remain unclear.
In this study, focusing on Polycomb-group genes we attempted to uncover the role underlying sternness.
Polycomb-group genes (PcG) were uncovered by Drosophila genetics as genes supporting the cellular memory system during development. We for the first time reported that PcG are required for sustaining HSC activity. Although PcG are recently reported to support sternness through the repression activity to ink4A locus encoding p16CDKI and p19ARF, so far the molecular bases underlying PcG functions supporting sternness are not fully understood. We found tha
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t licensing of DNA replication was impaired in mice lacking PcG. And PcG complexes interact with Geminin, an inhibitor of a DNA replication licensing factor Cdtl through Scmhl, a member of PcG, which we originally identified based on the conserved protein structure in mammals. We also found Hoxb4, a well known factor regulating HSCs, also interacts with Geminin.
Furthermore, by using retrovirus-mediated gene transfer method, we examined in detail the effect of affected Geminin regulation on HSCs. And we showed that PcG complexes regulate Geminin at the level of protein through ubiquitination and that Geminin regulation is pivotal in hematopoiesis and HSC regulation.
These results indicate that DNA replication licensing is pivotal in sustaining HSC activity. And PcG complexes play a crucial role in regulation of Geminin. Now by using in vitro reconstituting system further detailed analysis of PcG complexes are in progress. These findings may help future progress in regenerative medicine with stem cells. Less
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