| Project/Area Number |
13043003
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | RIKEN (2004-2005)
Chiba University (2001-2003) |
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Principal Investigator |
KOSEKI Haruhiko RIKEN, Developmental Genetics Group, Group Director, 免疫器官形成研究グループ, グループディレクター (40225446)
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| Co-Investigator(Kenkyū-buntansha) |
KAMII Takehiko Shinshu University, Hospital, Lecturer, 医学部附属病院, 講師 (90262708)
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| Project Period (FY) |
2001 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥72,600,000 (Direct Cost: ¥72,600,000)
Fiscal Year 2005: ¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 2004: ¥19,500,000 (Direct Cost: ¥19,500,000)
Fiscal Year 2003: ¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2002: ¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2001: ¥13,200,000 (Direct Cost: ¥13,200,000)
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| Keywords | Polycomb / knockout / cellular senescence / translational regulation / Pc12 / ポリコーム群 / Hox / Ink4a / 胎児性繊維芽細胞 / マウス / Ring1B / X染色体 / ヒストンH2A / ユビキチン化 / MBLR / E2F6複合体 / ホメオプロテインインターラクティングキナーゼ / プログラム細胞死 / ノックアウトマウス / クロマチン / Mel-18 / 細胞死制御 / p53 |
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| Research Abstract |
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.
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