Fbxw7β resides in the endoplasmic reticulum membrane and protects cells from oxidative stress
Fbxw7β resides in the endoplasmic reticulum membrane and protects cells from oxidative stress
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DOI：
10.1111/j.1349-7006.2011.01851.x
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发表时间：
2011-04-01
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：
Matsumoto, Akinobu;Tateishi, Yuki;Nakayama, Keiichi I.
氧化应激与癌症的发生和发展有关。Fbxw 7（也称为Fbw 7、SEL-10、hCdc 4或hAgo）是Skp 1-Cul 1-F-box（SCF）型泛素连接酶复合物的F-box蛋白亚基，在癌蛋白（如c-Myc、c-Jun、Notch和细胞周期蛋白E）的降解中发挥核心作用。因此，Fbxw 7被认为是一种肿瘤抑制因子，事实上，Fbxw 7基因在许多人类恶性肿瘤中经常发生突变。Fbxw 7基因座编码三种蛋白质同种型：Fbxw 7 α、Fbxw 7 β和Fbxw 7 γ。Fbxw 7 α和Fbxw 7 γ存在于细胞核中，而Fbxw 7 β显示出细胞质分布，表明定位于内质网（ER）。然而，Fbxw 7 beta的具体功能仍然未知。我们现在表明，Fbxw 7 β含有一个假定的跨膜结构域附近的NH 2-末端，拓扑分析表明，Fbxw 7 β插入在ER膜。Fbxw 7 β与Skp 1、Cul 1和Rbx 1组装形成SCF复合物，尽管该过程的效率似乎低于Fbxw 7 α或Fbxw 7 γ。为了探索Fbxw 7 β的生理作用，我们产生了特异性缺乏Fbxw 7这种亚型的小鼠。虽然这些动物在发育中没有表现出任何明显的异常，但从突变小鼠制备的神经元原代培养物比从野生型小鼠制备的神经元更容易受到氧化应激的影响。相反，Fbxw 7 β的过表达使细胞对氧化应激具有抗性，而不影响对ER应激或其他凋亡诱导剂的敏感性。因此，我们的研究结果表明，Fbxw 7 β有助于保护细胞免受氧化应激。（Cancer Sci 2011; 102：749-755）
Oxidative stress has been implicated in cancer initiation and progression. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of oncoproteins such as c-Myc, c-Jun, Notch, and cyclin E. Fbxw7 is therefore thought to function as a tumor suppressor, and indeed the Fbxw7 gene is frequently mutated in many human malignancies. The Fbxw7 gene locus encodes three protein isoforms: Fbxw7 alpha, Fbxw7 beta, and Fbxw7 gamma. Whereas Fbxw7 alpha and Fbxw7 gamma are resident in the nucleus, Fbxw7 beta shows a cytoplasmic distribution suggestive of localization to the endoplasmic reticulum (ER). The specific function of Fbxw7 beta has remained unknown, however. We now show that Fbxw7 beta contains a putative transmembrane domain near its NH2-terminus, and topological analysis revealed that Fbxw7 beta is inserted in the ER membrane. Fbxw7 beta assembled with Skp1, Cul1, and Rbx1 to form an SCF complex, although the efficiency of this process appeared lower than that for Fbxw7 alpha or Fbxw7 gamma. To explore the physiological role of Fbxw7 beta, we generated mice specifically lacking this isoform of Fbxw7. Although these animals did not exhibit any apparent abnormalities in development, primary cultures of neurons prepared from the mutant mice were more vulnerable to oxidative stress than were those prepared from wild-type mice. Conversely, overexpression of Fbxw7 beta rendered cells resistant to oxidative stress, without affecting sensitivity to ER stress or other apoptosis-inducing agents. Our results thus suggest that Fbxw7 beta contributes to the protection of cells from oxidative stress. (Cancer Sci 2011; 102: 749-755)