Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1β and Ski
Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1β and Ski
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DOI：
10.1074/jbc.m313069200
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发表时间：
2004-04-16
影响因子：
4.8
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Nomura, T;Tanikawa, J;Ishii, S
c-myb原癌基因产物（c-Myb）通过诱导一组靶基因的转录来调节造血细胞的增殖。在c-Myb的C-末端一半中的负调节结构域（NRD）的去除或突变导致反式激活能力增加和致癌激活。在这里，我们报告，TIF 1 β直接结合到NRD和负调控c-Myb依赖的反式激活。此外，三种辅阻遏物（Ski、N-CoR和mSin 3A）与TIF 1 β一起结合到c-Myb的DNA结合结构域，并将组蛋白脱乙酰酶复合物募集到c-Myb。此外，果蝇TIF 1 β同源物Bonus负调控果蝇Myb活性。Ski辅阻遏物与辅激活物CBP竞争结合c-Myb，表明辅激活物和辅阻遏物的选择是c-Myb依赖性转录的关键事件。c-Myb的NRD的突变或缺失以及v-Myb的DNA结合结构域中发现的突变降低了与这些辅阻遏物的相互作用，并削弱了辅阻遏物诱导的Myb活性的负调节。这些观察对于理解核致癌基因是如何被激活的具有概念上的意义。
The c-myb proto-oncogene product (c-Myb) regulates proliferation of hematopoietic cells by inducing the transcription of a group of target genes. Removal or mutations of the negative regulatory domain (NRD) in the C-terminal half of c-Myb leads to increased transactivating capacity and oncogenic activation. Here we report that TIF1beta directly binds to the NRD and negatively regulates the c-Myb-dependent trans-activation. In addition, three corepressors (Ski, N-CoR, and mSin3A) bind to the DNA-binding domain of c-Myb together with TIF1beta and recruit the histone deacetylase complex to c-Myb. Furthermore, the Drosophila TIF1beta homolog, Bonus, negatively regulates Drosophila Myb activity. The Ski corepressor competes with the coactivator CBP for binding to c-Myb, indicating that the selection of coactivators and corepressors is a key event for c-Myb-dependent transcription. Mutations or deletion of the NRD of c-Myb and the mutations found in the DNA-binding domain of v-Myb decrease the interaction with these corepressors and weaken the corepressor-induced negative regulation of Myb activity. These observations have conceptual implications for understanding how the nuclear oncogene is activated.