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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.

我们新鉴定了Polycomblike 2（Pc 12）基因产物作为Polycomb Repressive Complex-1（PRC 1）的组分，尽管Pc 12先前已被鉴定为PRC 2组分。我们已经产生了Pc 12缺陷小鼠，并揭示了其新的作用，以连接PRC 1和PRC 2。虽然PRC 1突变MEFs（小鼠胚胎成纤维细胞）显示经历过早衰老，Pc 12缺陷MEFs取消衰老，随后转化。这表明Pc 12是一种肿瘤抑制因子。事实上，生化分析表明，Pc 12缺陷导致通过稳定PRC 1的Ink 4a基因的稳定阻遏。Phc 2/Pc 12双缺陷MEFs最终取消衰老，这伴随着Ink 4a基因的基因组丢失。由于PRC 1在Pcl 2缺陷MEFs中的稳定化与编码PRC 1组分的mRNA转录的增加无关，因此预期这种稳定化通过翻译调节或蛋白质稳定性介导。为了解决这个问题，我们首先通过在293 T细胞中过表达时下拉TAP标记的Pcl 2来鉴定Pcl 2的结合蛋白，其中参与翻译调控的蛋白质如核糖体蛋白、RNA解旋酶和RNA结合蛋白质被过度表达。此外，在Pc 12缺陷的MEFs中，编码PRC 1组分的mRNA在多核糖体的非翻译组分中过度表达。连同Tudor结构域的存在，这可能有助于RNA结合，Pc 12可能参与PRC 1组件的翻译调控。

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）

Miki, T: "Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1"Nature Med. 8. 466-472 (2002)

Miki, T：“通过破坏内向整流器 Kir6.1 建立 Prinzmetal 心绞痛小鼠模型”Nature Med。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

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。