Fbxw7 contributes to tumor suppression by targeting multiple proteins for ubiquitin-dependent degradation
Fbxw7 contributes to tumor suppression by targeting multiple proteins for ubiquitin-dependent degradation
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DOI：
10.1111/j.1349-7006.2006.00239.x
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发表时间：
2006-08-01
期刊：
影响因子：
5.7
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Fujii, Yo;Yada, Masayoshi;Nakayama, Keiichi I.
Fbxw7(也称为Sel-10、hCdc4或Hago)是Skp1-Cul1-F-box蛋白(SCF)泛素连接酶的F-box蛋白成分。Fbxw7参与泛素介导的细胞周期蛋白E、c-Myc、Aurora-A、Notch和c-Jun的降解，所有这些似乎都是细胞周期启动子和致癌蛋白。Fbxw7的缺失导致其底物表达增加，这可能导致肿瘤的发生。然而，在Fbxw7突变的癌细胞中，哪种积累的底物与癌症的发展最相关，目前仍不清楚。在本研究中，我们检测了七个癌细胞株中细胞周期蛋白E、c-Myc和Aurora-A的丰度，这些癌细胞含有野生型(三株)和突变型(四株)Fbxw7。虽然这三种底物在Fbxw7突变细胞中积累，但这些蛋白的表达增加的程度在每一株系中是不同的。Fbxw7的强制表达降低了Fbxw7突变细胞中细胞周期蛋白E、c-Myc和Aurora-A的水平。相反，通过RNA干扰降低细胞周期蛋白E、c-Myc或Aurora-A的表达，显著抑制Fbxw7-突变细胞的增殖和非贴壁生长。因此，这些发现表明，Fbxw7的缺失导致细胞周期蛋白E、c-Myc和Aurora-A的积聚，所有这些似乎都是促进癌细胞生长所必需的。Fbxw7似乎调节多个靶点的水平，以抑制癌症的发展。
Fbxw7 (also known as Sel-10, hCdc4 or hAgo) is the F-box protein component of a Skp1-Cul1-F-box protein (SCF) ubiquitin ligase. Fbxw7 contributes to the ubiquitin-mediated degradation of cyclin E, c-Myc, Aurora-A, Notch and c-Jun, all of which appear to function as cell-cycle promoters and oncogenic proteins. Loss of Fbxw7 results in elevated expression of its substrates, which may lead to oncogenesis. However, it remains largely unclear which accumulating substrate is most related to cancer development in Fbxw7-mutant cancer cells. In the present study, we examined the abundance of cyclin E, c-Myc and Aurora-A in seven cancer cell lines, which harbor wild-type (three lines) or mutant (four lines) Fbxw7. Although these three substrates accumulated in the Fbxw7-mutant cells, the extent of increase in the expression of these proteins varied in each line. Forced expression of Fbxw7 reduced the levels of cyclin E, c-Myc and Aurora-A in the Fbxw7-mutant cells. In contrast, a decrease in the expression of cyclin E, c-Myc or Aurora-A by RNA interference significantly suppressed the rate of proliferation and anchorage-independent growth of the Fbxw7-mutant cells. These findings thus suggest that the loss of Fbxw7 results in accumulation of cyclin E, c-Myc and Aurora-A, all of which appear to be required for growth promotion of cancer cells. Fbxw7 seems to regulate the levels of multiple targets to suppress cancer development.