The FBXW7 β-form is suppressed in human glioma cells
The FBXW7 β-form is suppressed in human glioma cells
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DOI：
10.1016/j.bbrc.2007.01.080
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发表时间：
2007-03-23
影响因子：
3.1
通讯作者：
Horii, Akira
中科院分区：
文献类型：
--
作者：
Gu, Zhaodi;Inomata, Kenichi;Horii, Akira
FBXW7（F-box 和 WD40 结构域蛋白 7）是一种具有 7 个串联 WD（色氨酸-天冬氨酸）的 F-box 蛋白，作为 SCF（Skp1-Cull-F-box 蛋白）泛素连接酶的磷酸表位特异性底物识别组件，并催化促进细胞增殖的蛋白的泛素化，例如 CCNE1、MYC、AURKA、 NOTCH1 和 JUN 在多种人类癌症中经常被激活。 FBXW7 是一种候选肿瘤抑制因子，在一些人类肿瘤中已报道有突变。在这项研究中，我们分析了 84 个人类肿瘤细胞系，以寻找 FBXW7 的遗传改变以及 mRNA 和蛋白质表达变化，并将它们与 CCNE1、MYC 和 AURKA 蛋白的表达水平进行比较。我们在结肠癌细胞系 SCC 中发现了一种新的无义突变，并证实了卵巢癌细胞系 SKOV3 和结肠癌细胞系 LoVo 中的错义突变。此外，在卵巢癌、结肠癌、子宫内膜癌、胃癌和前列腺癌中观察到 FBXW7 表达受到抑制，并伴随着靶蛋白的激活。值得注意的是，在所有分析的人神经胶质瘤细胞系中都发现了高度抑制的 FBXW7 β 型 mRNA 表达；在这些细胞中观察到 CCNE1、MYC 和 AURKA 的表达增强。我们目前的结果表明，FBXW7 通过控制细胞周期启动子蛋白的数量在许多组织中发挥着关键作用，并且该蛋白的功能障碍是多个器官癌发生的重要步骤之一。 (c) 2007 Elsevier Inc. 保留所有权利。
FBXW7 (F-box and WD40 domain protein 7) is an F-box protein with 7 tandem WDs (tryptophan-aspartic acid) that functions as a phosphoepitope-specific substrate recognition component of SCF (Skp1-Cull-F-box protein) ubiquitin ligases and catalyzes the ubiquitination of proteins promoting cell proliferation, such as CCNE1, MYC, AURKA, NOTCH1, and JUN, which are frequently activated in a wide range of human cancers. FBXW7 is a candidate tumor suppressor, and mutations have been reported in some human tumors. In this study, we analyzed 84 human tumor cell lines in search for genetic alterations of FBXW7, as well as mRNA and protein expressional changes, and compared them with expression levels of the CCNE1, MYC, and AURKA proteins. We found a novel nonsense mutation in a colon cancer cell line SCC and confirmed the missense mutations in SKOV3, an ovarian cancer cell line, and LoVo, a colon cancer cell line. Moreover, suppressed expression of FBXW7 accompanied by activation of the target proteins were observed in ovarian, colon, endometrial, gastric, and prostate cancers. It is notable that highly suppressed mRNA expression of the FBXW7 beta-form was found in all the human glioma cell lines analyzed; enhanced expressions of CCNE1, MYC, and AURKA were observed in these cells. Our present results imply that FBXW7 plays a pivotal role in many tissues by controlling the amount of cell cycle promoter proteins and that dysfunction of this protein is one of the essential steps in carcinogenesis in multiple organs. (c) 2007 Elsevier Inc. All rights reserved.