Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7
Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7
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DOI：
10.1038/sj.emboj.7600217
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发表时间：
2004-05-19
期刊：
影响因子：
11.4
通讯作者：
Nakayama, KI
中科院分区：
文献类型：
--
作者：
Yada, M;Hatakeyama, S;Nakayama, KI
F-box蛋白Skp 2通过结合MB 2结构域介导c-Myc泛素化。然而，c-Myc的周转在很大程度上依赖于MB 1中苏氨酸-58和丝氨酸-62的磷酸化，这些残基在癌症中经常发生突变。我们现在表明，F-box蛋白Fbw 7与c-Myc相互作用，从而以依赖于MB 1磷酸化的方式使c-Myc不稳定。然而野生型Fbw 7促进细胞中c-Myc的周转，缺乏F-box结构域的Fbw 7突变体延迟了它。此外，通过RNA干扰去除Fbw 7增加了c-Myc的丰度和反式激活活性。在小鼠Fbw 7（-/-）胚胎干细胞中c-Myc的积累也很明显。这些观察结果表明，两个F-box蛋白，Fbw 7和Skp 2，分别通过靶向MB 1和MB 2差异调节c-Myc稳定性。
The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7(-/-) embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.