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 基因突变似乎与鲁宾斯坦-泰比综合征 (RTS) 有关，这是一种以异常模式形成为特征的单倍体不足性疾病。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。 cubitus Interruptus (ci) 是 hh 信号传导的一个组成部分，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 Gli3 的单倍体不足会导致小鼠（称为“额外脚趾”）和人类（格雷格头多指并指综合征）发生与 RTS 相似的表型变化。我们的分子和遗传学研究表明，果蝇 CBP (dCBP) ) 作为 Ci 的共激活剂发挥作用。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，我们还发现 dCBP 突变体无法表达扭曲（twi）基因并产生扭曲的胚胎。这可以通过显示 dCBP 对于 dl 介导的 twi 基因启动子激活所必需的结果来解释。此外，我们发现，由 C57BL/6-CBA x BALB/c 杂交产生的杂合 Cbp 缺陷小鼠的骨骼系统中高频率发生各种异常。为了支持昆虫和哺乳动物模式形成的保守信号通路，发现杂合突变体中 Bmp7 的表达减少。

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。”

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。”

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。

Sano, Y.et al.: "ATF-2 is a common nuclear target of Smad and TAK1 pathways in TGF-b signaling" J.Biol.Chem.274(印刷中). (1999)

Sano, Y. 等人：“ATF-2 是 TGF-b 信号传导中 Smad 和 TAK1 途径的常见核靶点”J.Biol.Chem.274（出版中）。