Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation
Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation
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DOI：
10.1016/j.bbrc.2012.08.032
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发表时间：
2012-09-14
影响因子：
3.1
通讯作者：
Ishii, Shunsuke
中科院分区：
文献类型：
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作者：
Kanei-Ishii, Chie;Nomura, Teruaki;Ishii, Shunsuke
C-myb原癌基因产物(c-Myb)在Wnt-1信号转导过程中降解。在这个过程中。Fbxw7α是SCF复合体的F-box蛋白，通过其C端的WD40结构域与c-Myb结合，诱导c-Myb的泛素化。在这里，我们报告了Fbxw5，另一种F-box蛋白，促进核c-Myb的苏莫化。Fbxw5通过DDB1-Cul4A-Rbx1复合体促进c-Myb求和。由于Fbxw5-DDB1-Cul4A-Rbx1复合体被证明是肿瘤抑制基因TSC2的泛素连接酶，我们的结果表明该复合体可以作为双重相扑/泛素连接酶发挥作用。Fbxw5定位于胞核和胞浆，促进核内c-Myb的苏莫化，并诱导c-Myb定位于核内点状结构域。共表达Fbxw5可抑制野生型c-Myb对c-myc启动子的反式激活，但不能抑制缺乏总酶切位点的v-Myb的反式激活。这些结果表明，多个E3连接酶通过苏莫化或泛素化抑制c-Myb的活性，而v-Myb不再受这些负调控的影响。(C)2012 Elsevier Inc.保留所有权利。
The c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling. In this process. Fbxw7 alpha, the F-box protein of the SCF complex, binds to c-Myb via its C-terminal WD40 domain, and induces the ubiquitination of c-Myb. Here, we report that Fbxw5, another F-box protein, enhances sumoylation of nuclear c-Myb. Fbxw5 enhanced c-Myb sumoylation via the DDB1-Cul4A-Rbx1 complex. Since the Fbxw5-DDB1-Cul4A-Rbx1 complex was shown to act as a ubiquitin ligase for tumor suppressor TSC2, our results suggest that this complex can function as a dual SUMO/ubiquitin ligase. Fbxw5, which is localized to both nucleus and cytosol, enhanced sumoylation of nuclear c-Myb and induced the localization of c-Myb to nuclear dot-like domains. Co-expression of Fbxw5 suppressed the trans-activation of c-myc promoter by wild-type c-Myb, but not by v-Myb, which lacks the sumoylation sites. These results suggest that multiple E3 ligases suppress c-Myb activity through sumoylation or ubiquitination, and that v-Myb is no longer subject to these negative regulations. (C) 2012 Elsevier Inc. All rights reserved.