Analysis of c-Myb dependent transcriptional repression mechanism by Ski

在本研究中，我们获得了有关c-Myb转录活性调控的几个重要数据。TIF1DNA直接与c-Myb的C端负调控区结合，其他3个辅阻遏子Ski、N-COR和mSin3A与c-MybDNA结合区结合。这些辅抑制子将组蛋白脱乙酰酶招募到c-Myb，并负向调节c-Myb依赖的反式激活。果蝇TIF1β同源物Bonus与果蝇Myb在体内存在遗传互作。辅阻遏子Ski与辅活化子CBP竞争结合c-Myb，提示Ski在c-Myb正负转录活性的转换机制中起着重要作用。与c-Myb相比，v-Myb与辅阻遏子的亲和力降低，转录活性增强。研究还发现，c-Myb与Hipk2(同源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Frizzled型受体结合后，Tak1(转化生长因子β激活的蛋白1)、Hipk2和NLk(Nemo样蛋白)被激活，导致c-Myb在多个位点的磷酸化。它诱导c-Myb的泛素化和蛋白酶体依赖的降解。V-Myb相对抵抗Wnt-1诱导的蛋白质降解，提示v-Myb具有较高的致癌活性。

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.