Liu Jun, Stevens Jeffery, Matsunami Nori, White Raymond L
Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA 94608, USA.
Biochem Biophys Res Commun. 2004 Jan 23;313(4):1023-9. doi: 10.1016/j.bbrc.2003.12.035.
Adenomatous polyposis coli (APC) tumor suppressor protein, together with Axin and glycogen synthase kinase 3beta (GSK-3beta), forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of cytoplasmic beta-catenin by ubiquitin-dependent proteolysis. Degradation of phosphorylated beta-catenin is initiated by interaction through the WD40-repeat of a F-box protein beta-TrCP, a component of SCF ubiquitin ligase complex. Mutations in APC, Axin, and beta-catenin that prevent down-regulation of cytoplasmic beta-catenin are found in various types of cancers. In the search for efficient treatment and prevention of malignancies associated with increased levels of cytoplasmic beta-catenin, we created chimeric F-box fusion proteins by replacing the WD40-repeat of beta-TrCP with the beta-catenin-binding domains of Tcf4 and E-cadherin. Expression of chimeric F-box fusion proteins successfully promotes degradation of beta-catenin independently of GSK-3beta-mediated phosphorylation. More importantly, this degradation does not require intact APC protein (pAPC).
腺瘤性结肠息肉病蛋白（APC）肿瘤抑制蛋白与Axin以及糖原合酶激酶3β（GSK-3β）共同形成一种Wnt调节的信号复合物，该复合物通过泛素依赖性蛋白水解介导细胞质β-连环蛋白的磷酸化依赖性降解。磷酸化β-连环蛋白的降解是通过F-box蛋白β-TrCP（SCF泛素连接酶复合物的一个组分）的WD40重复序列相互作用启动的。在各种类型的癌症中都发现了APC、Axin和β-连环蛋白的突变，这些突变会阻止细胞质β-连环蛋白的下调。在寻找与细胞质β-连环蛋白水平升高相关的恶性肿瘤的有效治疗和预防方法时，我们通过用Tcf4和E-钙黏蛋白的β-连环蛋白结合结构域替换β-TrCP的WD40重复序列，构建了嵌合F-box融合蛋白。嵌合F-box融合蛋白的表达成功地促进了β-连环蛋白的降解，且不依赖于GSK-3β介导的磷酸化。更重要的是，这种降解不需要完整的APC蛋白（pAPC）。
