摘要:肿瘤抑制基因 FBW7突变体在多种肿瘤中高表达。FBW7通过靶向降解多种原癌蛋白如 Brg1、Cyclin E、C-myc、Notch、c-Jun、Mcl-1和SREBP等调控细胞增殖、凋亡及能量代谢等多种生物学过程中的关键分子而发挥肿瘤抑制作用。本文将从 FBW7靶向降解底物抑制肿瘤生长和 FBW7突变、FBW7靶向降解底物突变和的FBW7自身紊乱三方面探究FBW7抑癌作用的消失进行综述。
图1 FBW7 底物示意图
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[1]王新安,徐成党,吴登龙.FBW7抑制肿瘤生长的机制及其研究进展[J].泌尿外科杂志(电子版),2022,14(02):39-44.DOI:10.20020/j.CNKI.1674-7410.2022.02.09.
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肿瘤抑制基因 (F-box/WD repeat- containingprotein 7,FBW7)亦称为FBXW7、AGO、CDC4[1],1973 年由 Hartwell首次在酵母中发现并被鉴定为细胞周期相关蛋白的调节剂,并命名为 CDC4[2]。人类FBW7基因定位于染色体 4q32位点,为 200 kb的碱基序列。FBW7 基 因 属 于 SCF 类 (SKP1- CUL1- F-box,SKP1,CUL1,F- box 蛋白) 泛素连接酶 E3复合物中特异性识别底物的关键因子,在泛素-蛋白酶体系统 (UPS) 介导的快速蛋白降解途径可以调节不同的细胞进程[3]。泛素化通过泛素-蛋白酶体系统 (UPS) 进行的蛋白酶体降解关键真核蛋白水解机制涉及 80%以上细胞周期,细胞生长和凋亡。底物的蛋白磷酸化结构域 (CPD:Cdc4 phosphodegron) 被 FBW7 识别并通过泛素激活酶 E1、泛素结合蛋白 E2和泛素连接酶 E3的一系列泛素化作用,然后由 26S 蛋白酶体对底物进行快速降解,其底物主要 包括细胞周期蛋白 E (cyclin E)、Myc 原癌基因 蛋白 (c-myc)、神经源性基因位点缺口同源蛋白 (notch) 等众多癌蛋白,因此 FBW7被认为是一种广泛的抑癌基因。FBW7 本身表现为单倍型肿瘤抑制基因即一个功能性等位基因的缺失足以促进肿瘤的生长,其已在小鼠模型中得到证明[4]。
4 展望
诸多研究证实,FBW7 作为一种抑癌基因在肿瘤的发生、发展中有重要作用,不同的底物加深了我们对 FBW7 调控的多种致癌途径的了解。FBW7的缺失或突变使得在底物结合中受损,肿瘤细胞得到进一步增殖,因此通过 FBW7 结合底物可能提供抑制肿瘤生长的合理方法,另外一种切实可行的方法是直接抑制 FBW7致癌靶标的活性。
在前列腺癌中,发现 FBW7 的表达水平与疾病状态和复发相关,使其成为确定蛋白酶体靶标疗法疗效的重要生物标志物。FBW7 导致极光激酶 A 的上调,从而调控癌细胞的增殖。在前列腺小细胞神经内分泌癌中,p53突变引起 miR-25的过度表达并抑制 FBW7[57]。有报道称酪氨酸激酶抑制剂 TKI 会增加 Mcl-1 的降解,并与 Bcl-XL/Bcl-2 抑制剂一起驱动前列腺癌细胞的凋亡,给笔者研究前列腺癌提供了新的观点。研究者课题组发现 FBW7 靶向降解 ERG,抑制了前列腺癌的发生发展。
尽管针对 FBW7 的研究报道逐年增加,但对FBW7 及其底物的认识还存在许多空白亟待填补,如在实体瘤中 FBW7 除了以往证实的底物外还存在哪些新的靶分子,以此来更全面地了解 FBW7 在肿瘤中的作用及其调控。更好地了解 FBW7 的结构和功能及其在癌症进展中的作用应有助于开发针对FBW7或其底物的新抗癌疗法。
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