Analysis of c-Myb dependent transcriptional repression mechanism by Ski

Ski分析c-Myb依赖性转录抑制机制

• 批准号: 15570151
• 负责人: NOMURA Teruaki
• 金额: $ 2.37万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15570151/
• 关键词: Myb; Ski; Corepressor

In this study, we got the several important data about the regulation of transcriptional activities of c-Myb. TIF1β directly binds to the C-terminus negative regulatory domain and other three corepressors, Ski, N-CoR and mSin3A bind to the DNA binding domain of c-Myb. These corepressors recruit the histon deacetylase to c-Myb and negatively regulate c-Myb dependent trans-activation. Furthermore there was the genetic interaction between the Drosophila TIF1β homologue, Bonus and Drosophila Myb in vivo. The corepressor Ski competes with the coactivator CBP for binding to c-Myb, suggesting the role of Ski in the switching mechanism of positive and negative transcriptional activities of c-Myb. V-Myb has the reduced affinities with the corepressors and the enhanced transcriptional activities compare to the c-Myb. It was also found that c-Myb bound to Hipk2(homeodomain-interacting protein kinase 2). Hipk2 is regulated by Wnt-1 signaling pathway. When Wnt-1bind to Frizzled receptors, TAK1(TGFβ-activated-kinase 1), Hipk2,and NLK(nemo-like kinase) are activated, which results in the phosphorylation of c-Myb at multiple sites. It induces ubiquitination and proteasome-dependent degradation of c-Myb. V-Myb was relatively resistant to Wnt-1 induced protein degradation, which is suggesting the higher oncogenic activity of v-Myb.

在本研究中，我们获得了关于c-Myb转录活性调控的几个重要数据。TIF1β直接与c端负调控域结合，而Ski、N-CoR和mSin3A等3个辅抑制因子与c-Myb的DNA结合域结合。这些辅抑制因子募集c-Myb的组蛋白去乙酰化酶并负性调节c-Myb依赖性反式激活。此外，果蝇TIF1β同系物、Bonus和果蝇Myb在体内存在遗传互作。协同抑制因子Ski与协同激活因子CBP竞争c-Myb的结合，提示Ski在c-Myb阳性和阴性转录活性的转换机制中发挥作用。与c-Myb相比，V-Myb与辅抑制因子的亲和力降低，转录活性增强。还发现c-Myb与Hipk2（同源结构域相互作用蛋白激酶2）结合。Hipk2受Wnt-1信号通路调控。当wnt -1与卷曲受体结合时，TAK1（tgf β活化激酶1）、Hipk2和NLK（nemo样激酶）被激活，导致c-Myb在多个位点磷酸化。它诱导泛素化和蛋白酶体依赖的c-Myb降解。V-Myb相对抵抗Wnt-1诱导的蛋白质降解，这表明V-Myb具有更高的致癌活性。

项目成果

Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1β and Ski

• DOI: 10.1074/jbc.m313069200
• 发表时间: 2004-04-16
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Nomura, T;Tanikawa, J;Ishii, S
• 通讯作者: Ishii, S

Requirement of the co-repressor homeodomain-interacting protein kinase 2 for Ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation

• DOI: 10.1074/jbc.m307112200
• 发表时间: 2003-10-03
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Harada, J;Kokura, K;Ishii, S
• 通讯作者: Ishii, S

The Ski-binding protein C184M negatively regulate TGF-βsignaling 〔by sequestering the Smad proteins in the cytoplasm.

Ski 结合蛋白 C184M [通过将 Smad 蛋白隔离在细胞质中，对 TGF-β 信号传导产生负调节。

• 发表时间: 2003
• 期刊: J.Biol.Chem. 278
• 作者: 石井 知恵;石井 知恵;古倉 健嗣
• 通讯作者: 古倉 健嗣

Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein degradation

• DOI: 10.1074/jbc.m407831200
• 发表时间: 2004-10-22
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Kanei-Ishii, C;Nomura, T;Ishii, S
• 通讯作者: Ishii, S

Requirement of the co-repressor homeodomain-interacting protein kinase 2 for Ski- mediated inhibition of Bone morphogenetic protein-induced transcrip

Ski 介导的骨形态发生蛋白诱导转录抑制需要共阻遏物同源域相互作用蛋白激酶 2

• 发表时间: 2003
• 期刊: J.Biol.Chem. 278
• 作者: 石井 知恵;石井 知恵;古倉 健嗣;原田 純
• 通讯作者: 原田 純