Role of Polycomb-group genes in adult stem cells and their expansion

多梳族基因在成体干细胞及其扩增中的作用

基本信息

批准号：
16390080
负责人：
TAKIHARA Yoshihiro
金额：
$ 9.54万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390080/
关键词：
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

项目摘要

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 … More 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

现在，造血干细胞（HSC）在临床印刷中常规，用于骨髓衰竭，并开发出HSC的新策略。调节HSC的分子机制仍然不清楚。在这项研究中，我们试图揭示果蝇遗传学的基因，作为支持蜂窝记忆系统的基因，可以揭示潜在的尾矿。编码P16CDKI和P19ARF G娱乐性支撑脏，我们发现DNA复制的障碍在缺乏PCG的小鼠中受损，DNA复制者是通过PCG的cdtl的ct。基于哺乳动物的保守蛋白结构，我们还发现了hoxb4 eminin.furthermore，使用脱粒病毒介导的基因转移方法，我们详细检查了效果的Gemininininininininininininininininininininininininininin shsc。双子素素素ESI和HSC调节表明，持续的HSC活性中的DNA。