Functional analysis of a novel family of inhibitor of differentiation

新型分化抑制剂家族的功能分析

• 批准号: 13670153
• 负责人: MIYAKE Satoshi
• 金额: $ 2.37万
• 依托单位: Tohoku University (2003)Tokyo Medical and Dental University (2001-2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670153/
• 关键词: EID-1; EID-2; histone acetyltransferase; histone deacetylase; differentiation; pRB

We recently identified E1A-like inhibitor of differentiation-1 (EID-1) as a pRB-binding protein. EID-1 inhibited differentiation via blocking histone acetyltransferase (HAT) activity of p300, a transcriptional coactivator which promotes differentiation. In addition to p300, EID-1 bound to core histones and this binding inhibited histone acetylation (histone masking). pRB promoted differentiation when it bound and helped degradation of EID-1.We also identified EID-2 and EID-3 as family proteins of EID-1. When overexpressed in the cells, EID-2 and -3 inhibited differentiation like ED-1. Surprisingly, EID-1 did not block HAT activity of p300 rather it bound to histone deacetylases (HDAC). EID-2 also interacted with Smads and inhibited transcription.These results shows that EIDs belong to a new protein family which functions as repressors of transcription involved in differentiation. We are now generating knock out mice of EID family genes and investigating their involvement to human diseases.

我们最近发现E1 A样分化抑制因子-1（EID-1）是一种pRB结合蛋白。EID-1通过阻断组蛋白乙酰转移酶（HAT）活性的p300，一个转录辅激活因子，促进分化抑制分化。除了p300，EID-1结合核心组蛋白，这种结合抑制组蛋白乙酰化（组蛋白掩蔽）。pRB与EID-1结合后促进其分化并促进其降解。我们还鉴定了EID-2和EID-3为EID-1的家族蛋白。当在细胞中过表达时，EID-2和EID-3像艾德-1一样抑制分化。令人惊讶的是，EID-1没有阻断p300的HAT活性，而是与组蛋白脱乙酰酶（HDAC）结合。EID-2也与Smads相互作用并抑制其转录，这些结果表明EID属于一个新的蛋白家族，其功能是参与分化的转录抑制因子。我们现在正在产生EID家族基因的敲除小鼠，并研究它们与人类疾病的关系。

项目成果

Sakai H, Eishi Y, Li X-L, Akiyama Y, Miyake S, Takizawa T, Konishi N, Tatematsu M, Koike M, Yuasa Y: "PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas]"Gut. 53. 323-330 (2004)

Sakai H、Eishi Y、Li X-L、Akiyama Y、Miyake S、Takizawa T、Konishi N、Tatematsu M、Koike M、Yuasa Y：“假幽门腺和胃癌中的 PDX1 同源盒蛋白表达]”肠道。

Nakajima Y et al.: "The Expressions of p21 and pRB may be Good Indicators for Sensitivity of Esophageal Squamous Cell Cancers to CPT-11 : Cell Proliferation Activity Correlates with the Effect of CPT-11"Cancer Science. (in press). (2004)

Nakajima Y 等人：“p21 和 pRB 的表达可能是食管鳞状细胞癌对 CP​​T-11 敏感性的良好指标：细胞增殖活性与 CPT-11 的作用相关”《癌症科学》。

Miyake S, Yanagisawa Y, Yuasa Y: "novel EID-1 family member, EID-2, associates with histone deacetylases and inhibits muscle differentiation"J Biol Chem. 278. 17061-17065 (2003)

Miyake S、Yanagisawa Y、Yuasa Y：“新的 EID-1 家族成员 EID-2 与组蛋白脱乙酰酶相关并抑制肌肉分化”J Biol Chem。

Nakajima, Y, et al.: "CPT-II May Provide Therapeutic Efficacy for Esophageal Squamous Cell Cancer and the Effects Correlate with the Level of DNA Topoisomerase I Protein"Jpn J Cancer Res. 92(12). 1335-1341 (2001)

Nakajima, Y, et al.：“CPT-II 可能为食管鳞状细胞癌提供治疗效果，其效果与 DNA 拓扑异构酶 I 蛋白的水平相关”Jpn J Cancer Res。

Bai Y et al.: "CDX2, a homeobox transcription factor, up-regulates transcription of the p21/WAF1/CIP1 gene."Oncogene. 22. 5998-6005 (2003)

Bai Y 等人：“CDX2 是一种同源框转录因子，上调 p21/WAF1/CIP1 基因的转录。”癌基因。