Research on Gene Expression Network via Coactivator CBP

基于共激活子CBP的基因表达网络研究

• 批准号: 09470037
• 负责人: ISHII Shunsuke
• 金额: $ 8.13万
• 依托单位: The Institute of Physical and Chemical Research (RIKEN)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470037/
• 关键词: transcriptional mediators; coactivator; CBP; Drosophila mutant; mouse mutant; コアクティベータ-; 仲介因子; 転写制御; 形態形成

Mutations in the human CBP gene appear to be associated with the Rubinstein-Taybi syndrome (RTS), a haploinsufficiency disorder characterized by abnormal pattern formation. However, the mechanism by which decreased CBP levels affect pattern formation is unclear. The hedgehog (hh) signaling pathway is an important determinant of pattern formation. cubitus interruptus (ci), a component of hh signaling, encodes a transcription factor homologous to the Gli family of proteins, and is required for induction of the hh-dependent expression of patched (ptc), decapentaplegic (dpp) and wingless (wg). Interestingly, a haploinsufficiency for the ci-related transcription factor Gli3 causes phenotypic changes in mice (known as "extra-toes") and humans (Greig's cephalopolysyndactyly syndrome) that have similarities to RTS.Our molecular and genetic studies indicated that Drosophila CBP (dCBP) functions as a co-activator of Ci. Thus, the dCBP-Ci interaction may provide clues for understanding the contribution of CBP to pattern formation in mammals. In addition, we showed that dCBP mutants fail to express the twist (twi) gene and generate twisted embryo. This is explained by results showing that dCBP is necessary for dl-mediated activation of the twi gene promoter. Furthermore, We showed that various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice resulting from a C57BL/6-CBA x BALB/c cross. In support of a conserved signaling pathway for pattern formation in insects and mammals, the expression of Bmp7 was found to be reduced in the heterozygous mutants.

人类CBP基因突变似乎与Rubinstein-Taybi综合征（RTS）相关，RTS是一种以异常模式形成为特征的单倍不足疾病。然而，CBP水平降低影响模式形成的机制尚不清楚。刺猬（hh）信号通路是模式形成的重要决定因素。中断肘肌（cubitusinterruptus，CI）是HH信号传导的组分，编码与Gli蛋白家族同源的转录因子，并且是诱导patched（ptc）、decapentaplegic（DPP）和wingless（wg）的HH依赖性表达所必需的。有趣的是，ci相关转录因子Gli 3的单倍不足导致小鼠（称为“外趾”）和人类（格雷格的头多并指综合征）的表型变化，具有与RTS的相似性。我们的分子和遗传学研究表明，果蝇CBP（dCBP）作为Ci的共激活因子。因此，dCBP-Ci相互作用可能为理解CBP对哺乳动物模式形成的贡献提供线索。此外，我们发现dCBP突变体不能表达扭曲（twi）基因，并产生扭曲胚胎。这是解释的结果表明，dCBP是必要的dl介导的激活twi基因启动子。此外，我们还发现，C57 BL/6-CBA × BALB/c杂交产生的杂合型Cbp缺陷小鼠的骨骼系统中发生各种异常的频率很高。为了支持昆虫和哺乳动物中模式形成的保守信号传导途径，发现Bmp 7的表达在杂合突变体中减少。

项目成果

Akimaru,H.et al.: "Drosophila CBP mutations generate twisted embryo : requirement of CBP for dorsal-dependent twist gene expression." Nature Genetics. 17. 211-214 (1997)

Akimaru,H.等人：“果蝇 CBP 突变产生扭曲的胚胎：CBP 是背侧依赖性扭曲基因表达的必要条件。”

Tokitou, F.et al.: "Viral-Ski inhibits retinoblastoma protein(Rb)-mediated transcriptional repression in a dominant negative fashion." J.Biol.Chem.274. 4485-4488 (1999)

Tokitou, F.等人：“Viral-Ski 以显性负向方式抑制视网膜母细胞瘤蛋白 (Rb) 介导的转录抑制。”

Teruaki NOMURA et al.: "Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor" Genes Dev.13. 412-423 (1999)

Teruaki NOMURA 等人：“Ski 是 Mad 和甲状腺激素受体转录抑制所需的组蛋白脱乙酰酶复合物的组成部分”Genes Dev.13。

Kanei-Ishii,C.et al.: "Activation of heat shock transcription factor 3 by c-Myb in the absence of cellular stress." Science. 277. 246-248 (1997)

Kanei-Ishii,C.et al.：“在没有细胞应激的情况下，c-Myb 激活热休克转录因子 3。”

野村照明 他: "Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor." Genes Dev.13. 412-423 (1999)

Shomei Nomura 等人：“Ski 是 Mad 和甲状腺激素受体转录抑制所需的组蛋白脱乙酰酶复合物的组成部分。”Genes Dev.13 (1999)。