The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc
The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc
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DOI：
10.1038/emboj.2008.279
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发表时间：
2009-03-04
期刊：
影响因子：
11.4
通讯作者：
Sears, Rosalie C.
中科院分区：
文献类型：
--
作者：
Arnold, Hugh K.;Zhang, Xiaoli;Sears, Rosalie C.
c-Myc原癌蛋白的表达在正常细胞中受到严格调控。在两个保守残基，苏氨酸58（T58）和丝氨酸62（S62）的磷酸化，调节c-Myc蛋白的稳定性。在癌细胞中，c-Myc可以变得异常稳定，与改变的T58和S62磷酸化相关。涉及GSK 3b激酶、Pin 1脯氨酰异构酶和PP 2A-B56 a磷酸酶的复杂信号级联控制这些位点的磷酸化。我们在这里报告了一个新的作用，肿瘤抑制支架蛋白Axin 1促进c-Myc含有GSK 3b，Pin 1和PP 2A-B56 a的降解复合物的形成。虽然Axin 1的敲低降低了c-Myc与这些蛋白的结合，减少了T58和增强了S62磷酸化，并增加了c-Myc的稳定性，但Axin 1的急性表达降低了c-Myc水平并抑制了c-Myc的转录活性。此外，Axin 1对c-Myc的调节在几种测试的癌细胞系中受损，已知c-Myc稳定或Axin 1缺失。这项研究为c-Myc表达的调控提供了重要的见解，这在三种癌症类型中是如何被破坏的，并增加了我们对Axin 1肿瘤抑制活性的了解。
Expression of the c-Myc proto-oncoprotein is tightly regulated in normal cells. Phosphorylation at two conserved residues, threonine58 (T58) and serine62 (S62), regulates c-Myc protein stability. In cancer cells, c-Myc can become aberrantly stabilized associated with altered T58 and S62 phosphorylation. A complex signalling cascade involving GSK3b kinase, the Pin1 prolyl isomerase, and the PP2A-B56a phosphatase controls phosphorylation at these sites. We report here a novel role for the tumour suppressor scaffold protein Axin1 in facilitating the formation of a degradation complex for c-Myc containing GSK3b, Pin1, and PP2A-B56a. Although knockdown of Axin1 decreases the association of c-Myc with these proteins, reduces T58 and enhances S62 phosphorylation, and increases c-Myc stability, acute expression of Axin1 reduces c-Myc levels and suppresses c-Myc transcriptional activity. Moreover, the regulation of c-Myc by Axin1 is impaired in several tested cancer cell lines with known stabilization of c-Myc or loss of Axin1. This study provides critical insight into the regulation of c-Myc expression, how this can be disrupted in three cancer types, and adds to our knowledge of the tumour suppressor activity of Axin1.