The Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
Cancer Res. 2010 Jun 1;70(11):4728-38. doi: 10.1158/0008-5472.CAN-10-0040. Epub 2010 May 18.
Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes breast cell proliferation and tumorigenesis through upregulating FGF-BP. The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF(Fbw7)) targets KLF5 for ubiquitin-mediated degradation in a GSK3beta-mediated KLF5 phosphorylation-dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ((303)SPPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and breast cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits breast cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers.
Fbw7 是一种常见的肿瘤抑制因子，在癌症中经常失活。KLF5 转录因子通过上调 FGF-BP 促进乳腺细胞增殖和肿瘤发生。KLF5 蛋白通过泛素蛋白酶体途径迅速降解。在这里，我们表明 Skp1-CUL1-Fbw7 E3 泛素连接酶复合物（SCF（Fbw7））以 GSK3β 介导的 KLF5 磷酸化依赖性方式将 KLF5 作为泛素介导的降解的靶标。KLF5 Cdc4 磷酸化降解基序（（303）SPPSS）中的关键 S303 残基的突变消除了 Fbw7 的蛋白相互作用、泛素化和降解。内源性 Fbw7 的失活显着增加了内源性 KLF5 蛋白丰度。内源性 Fbw7 通过靶向 KLF5 进行降解来抑制 FGF-BP 基因表达和乳腺细胞增殖。这些发现表明，Fbw7 通过靶向 KLF5 进行蛋白水解至少部分抑制乳腺细胞增殖。KLF5 降解的这种新调节机制可能为乳腺癌和其他癌症提供有用的诊断和治疗靶点。
