Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β
Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β
复制标题
DOI：
10.1016/s0960-9822(98)70226-x
复制
发表时间：
1998-05-07
期刊：
影响因子：
9.2
通讯作者：
Polakis, P
中科院分区：
文献类型：
--
作者：
Hart, MJ;de los Santos, R;Polakis, P
背景：腺瘤性息肉病基因（APC）肿瘤抑制蛋白的失活与遗传性和散发性结肠癌均有关。APC对生长的控制可能与其在翻译后下调β -连环蛋白的能力有关。在癌症中，APC的突变使其丧失调节β -连环蛋白的能力，而β -连环蛋白的突变使其不能被野生型APC下调。此外，原癌基因wnt - 1的蛋白产物的信号传导会上调β -连环蛋白并促进小鼠肿瘤发生。在非洲爪蟾发育系统中，Wnt - 1信号传导被鼠融合基因的产物Axin所抑制。这表明Axin、Wnt - 1信号传导成分β -连环蛋白和糖原合成酶激酶3β（GSK3β）以及APC之间可能存在联系。
结果：人Axin（hAxin）在体外可直接与β -连环蛋白、GSK3β和APC结合，并且在细胞中内源性蛋白形成复合物。Axin的结合位点被定位到APC的一个区域，该区域由于APC基因中与癌症相关的突变通常会缺失。hAxin的过表达强烈促进结肠癌细胞中野生型β -连环蛋白的下调，而突变的致癌性β -连环蛋白则不受影响。通过从Axin中缺失APC结合结构域，这种下调作用增强，这表明APC可能起到解除Axin活性抑制的作用。此外，hAxin在体外显著促进GSK3β对APC和β -连环蛋白的磷酸化。
结论：Axin作为一种支架，APC、β -连环蛋白和GSK3β在其上组装以协调β -连环蛋白信号传导的调节。（C）当代生物学有限公司，国际标准连续出版物编号0960 - 9822
Background: Inactivation of the adenomatous polyposis coil (APC) tumor suppressor protein is responsible for both inherited and sporadic forms of colon cancer. Growth control by APC may relate to its ability to downregulate beta-catenin post-translationally. In cancer, mutations in APC ablate its ability to regulate beta-catenin, and mutations in beta-catenin prevent its downregulation by wild-type APC. Moreover, signaling by the protein product of the wnt-1 proto-oncogene upregulates beta-catenin and promotes tumorigenesis in mice. In a Xenopus developmental system, Wnt-1 signaling was inhibited by Axin, the product of the murine fused gene. This suggests a possible link between Axin, the Wnt-1 signaling components beta-catenin and glycogen synthase kinase 3 beta (GSK3 beta), and APC.Results: Human Axin (hAxin) binds directly to beta-catenin, GSK3 beta, and APC in vitro, and the endogenous proteins are found in a complex in cells. Binding sites for Axin were mapped to a region of APC that is typically deleted due to cancer-associated mutations in the APC gene. Overexpression of hAxin strongly promoted the downregulation of wild-type beta-catenin in colon cancer cells, whereas mutant oncogenic beta-catenin was unaffected. The downregulation was increased by deletion of the APC-binding domain from Axin, suggesting that APC may function to derepress Axin activity. In addition, hAxin dramatically facilitated the phosphorylation of APC and beta-catenin by GSK3 beta in vitro.Conclusions: Axin acts as a scaffold upon which APC, beta-catenin and GSK3 beta assemble to coordinate the regulation of beta-catenin signaling. (C) Current Biology Ltd ISSN 0960-9822.