Molecular mechanisms that integrate 'cell death and cell cycle progression.

整合“细胞死亡和细胞周期进展”的分子机制。

基本信息

批准号：
13043003
负责人：
KOSEKI Haruhiko
金额：
$ 46.46万
依托单位：
RIKEN (2004-2005)Chiba University (2001-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

项目摘要

We have newly identified Polycomblike 2 (Pc12) gene product as a component of Polycomb Repressive Complex-1 (PRC 1) although Pc12 had been identified as a PRC2 component previously. We have generated Pc12 deficient mice and revealed its novel role to link PRC1 and PRC2. Although PRC1 mutant MEFs (mouse embryonic fibroblasts) are shown to undergo premature senescence, Pc12-deficient MEFs cancelled senescence and subsequently transformed. This suggests Pc12 acts as a tumor suppressor. Indeed, biochemical analysis revealed that Pc12 deficiency results in stable repression of Ink4a gene through the stabilization of PRC1. Concordantly, Phc2/Pc12 doubly deficient MEFs eventually cancelled senescence, which was accompanied by genomic loss of Ink4a gene. Since stabilization of PRC1 in Pcl2 deficient MEFs was not associated with increase of transcription of mRNA encoding PRC1 components, this stabilization was expected to be mediated either by translational regulation or protein stability. To address this issue, we have first identified binding proteins for Pc12 by pull-down of TAP-tagged Pcl2 upon overexpression in 293T cells, where proteins involved in translational regulation was overrepresented such as Ribosomal proteins, RNA helicases, and RNA binding proteins. In addition, mRNA encoding PRC1 components were overrepresented within untranslated fractions of polysomes in Pc12 deficient MEFs. Together with presence of Tudor domain, which may contributes to RNA binding, Pc12 is likely involved in translational regulation of PRC1 components.

尽管PC12先前已被鉴定为PC12，但我们已将新鉴定的PolyComblike 2（PC12）基因产物作为PolyComb抑制复合物1（PRC 1）的组成部分。我们已经产生了PC12不足的小鼠，并揭示了其在链接PRC1和PRC2方面的新作用。尽管PRC1突变体MEF（小鼠胚胎成纤维细胞）已显示出过早的衰老，但PC12缺陷型MEF取消了衰老并随后转化。这表明PC12充当肿瘤抑制器。实际上，生化分析表明，PC12缺乏通过PRC1的稳定而稳定地抑制了Ink4a基因。一致的是，PHC2/PC12双重缺陷的MEF最终取消了衰老，并伴随着Ink4a基因的基因组丧失。由于PCL2缺乏MEF中PRC1的稳定与编码PRC1成分的mRNA转录的增加无关，因此预期该稳定性是通过转化调节或蛋白质稳定性介导的。为了解决这个问题，我们首先通过在293T细胞中过表达后通过Tapged PCL2的下拉鉴定了PC12的结合蛋白，其中参与转化调节的蛋白质的蛋白质过多，例如核糖体蛋白质，RNA Helicase和RNA结合蛋白。此外，在PC12缺陷MEF中，在未翻译的多个部分中，编码PRC1组件的mRNA编码过多。加上可能有助于RNA结合的Tudor结构域的存在，PC12可能参与了PRC1成分的翻译调节。

项目成果

期刊论文数量（96）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mice doubly deficient for the Polycomb-Groupe genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiaticn of Hox gene exuression.

Polycomb-Groupe 基因 Mel18 和 Bmi1 双重缺陷的小鼠揭示了协同作用和维持的需要，但不是 Hox 基因表达的启动。

DOI：
发表时间：
2001
期刊：
Development 128
影响因子：
0
作者：
Suzuki;M.;Mizutani-Koseki;Y.;Fujimura;Y.;Miyagishima;H.Kaneko;T.;Takada;Y.;Akasaka;T.;Tanzawa;H.;Taldhara;Y.;Nakano;M.;Masumoto;H.;Vidal;M.;Isono K.Koseki;H.;Koizumi K;Akasaka T
通讯作者：
Akasaka T

Yamamoto K.: "The KDEL receptor mediates a retrieval mechanism that contributes to quality control at the endoplasmic reticulum"The EMBO Journal. 20. 3082-3091 (2001)

Yamamoto K.：“KDEL 受体介导一种有助于内质网质量控制的恢复机制”EMBO 杂志。