收稿日期：2023-02-10 接受日期：2023-02-10 出版日期：2023-02-10 发布日期：2023-02-10
通讯作者： 吴登龙,主任医师,教授,上海市同济医院泌尿外科主任,同济大学附属同济医院 泌尿外科，上海 200065
作者简介： 王新安,同济大学附属同济医院 泌尿外科，上海 . 徐成党,同济大学附属同济医院 泌尿外科，上海 . 吴登龙,男,同济大学附属同济医院 泌尿外科，上海 200065,主任医师,教授,同济大学附属同济医院 党委副书记；上海市优秀学术带头人；中国医师协会男科与性医学分会常委；中国医师协会泌尿外科学分会委员；中国抗癌协会泌尿生殖肿瘤分会常委；世界华人泌尿外科医师分会常委；上海市医师协会男科分会副会长；上海抗癌协会泌尿生殖肿瘤分会副会长；中西医结合学会上海泌尿男科分会副主任委员 .
基金资助：，项目负责人： 吴登龙
中图分类号：R37
文献标识码：A
文章编号：1674-7410(2022)02-0039-06
DOI：10.20020/j.CNKI.1674-7410.2022.02.09
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
[1]
[1] NAKAYAMA K I, NAKAYAMA K. Ubiquitin ligases: cellcycle control and cancer [J]. Nat Rev Cancer, 2006, 6(5):369-381.
[2] HARTWELL L H, CULOTTI J, PRINGLE J R, et al.Genetic control of the cell division cycle in yeast [J]. Science, 1974, 183(4120): 46-51.
[3] KRAMER H B, NICHOLSON B, KESSLER B M, etal. Detection of ubiquitin- proteasome enzymatic activitiesin cells: application of activity- based probes to inhibitordevelopment [J]. Biochim Biophys Acta, 2012, 1823(11):2029-2037.
[4] MAO J H, PEREZ- LOSADA J, WU D, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene [J]. Nature, 2004, 432(7018): 775-779.
[5] HAO B, OEHLMANN S, SOWA M E, et al. Structureof a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases [J]. MolCell, 2007, 26(1): 131-143.
[6] BAI C, SEN P, HOFMANN K, et al. SKP1 connectscell cycle regulators to the ubiquitin proteolysis machinerythrough a novel motif,the F- box [J]. Cell, 1996, 86(2):263-274.
[7] DAVIS R J,WELCKER M,CLURMAN B E. Tumorsuppression by the Fbw7 ubiquitin ligase: mechanisms andopportunities [J]. Cancer Cell, 2014, 26(4): 455-464.
[8] ORLICKY S, TANG X, WILLEMS A, et al. Structural basis for phosphodependent substrate selection and orientationby the SCFCdc4 ubiquitin ligase [J]. Cell, 2003, 112(2):243-256.
[9] GRIM J E, GUSTAFSON M P, HIRATA R K, et al.Isoform- and cell cycle- dependent substrate degradation bythe Fbw7 ubiquitin ligase [J]. J Cell Biol, 2008, 181(6):913-920.
[10] STROHMAIER H, SPRUCK CH, KAISER P, et al.Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line [J]. Nature,2001, 413(6853): 316-322.
[11] LI M, OUYANG L, ZHENG Z, et al. E3 ubiquitin ligaseFBW7 α inhibits cholangiocarcinoma cell proliferation bydownregulating c-Myc and cyclin E [J]. Oncol Rep, 2017,37(3): 1627-1636.
[12] EKHOLM- REED S, GOLDBERG MS, SCHLOSSMACHER M G, et al. Parkin- dependent degradation of theF- box protein Fbw7β promotes neuronal survival in response to oxidative stress by stabilizing Mcl- 1 [J]. MolCell Biol, 2013, 33(18): 3627-3643.
[13] TAN Y, SANGFELT O, SPRUCK C. The Fbxw7/hCdc4 tumor suppressor in human cancer [J]. Cancer Lett,2008, 271(1): 1-12.
[14] SPRUCK C H, STROHMAIER H, SANGFELT O, etal. hCDC4 gene mutations in endometrial cancer [J]. CancerRes, 2002, 62(16): 4535-4539.
[15] RAJAGOPALAN H, JALLEPALLI PV, RAGO C, etal. Inactivation of hCDC4 can cause chromosomal instability [J]. Nature, 2004, 428(6978): 77-81.
[16] LEE J W, SOUNG Y H, KIM H J, et al. Mutationalanalysis of the hCDC4 gene in gastric carcinomas [J]. EurJ Cancer, 2006, 42(14): 2369-2373.
[17] YOKOBORI T, MIMORI K, IWATSUKI M, et al. p53-Altered FBXW7 expression determines poor prognosis in gastriccancer cases [J]. Cancer Res, 2009, 69(9): 3788-3794.
[18] GUANGWEI W, YUNSHAN W, PENGJU Z, et al. Evaluating the prognostic significance of FBXW7 expressionlevel in human breast cancer by a meta- analysis of transcriptional profiles [J]. Journal of cancer science & therapy,2012, 4(9): 299-305.
[19] CANCER GENOME ATLAS NETWORK. Comprehensive molecular characterization of human colon and rectalcancer [J]. Nature, 2012, 487(7407): 330-337.
[20] KIMURA T, GOTOH M, NAKAMURA Y, et al.hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53 [J]. Cancer Sci, 2003, 94(5): 431-436.
[21] CAO J, GE M H, LING Z Q. Fbxw7 Tumor Suppressor:A Vital Regulator Contributes to Human Tumorigenesis [J].Medicine (Baltimore), 2016, 95(7): e2496.
[22] DAVIS H, LEWIS A, BEHRENS A, et al. Investigation of the atypical FBXW7 mutation spectrum in humantumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines [J]. Gut, 2014,63(5): 792-799.
[23] CALCAGNO D Q, FREITAS V M, LEAL M F, et al.MYC, FBXW7 and TP53 copy number variation and expression in gastric cancer [J]. BMC Gastroenterol, 2013,13: 141.
[24] WELCKER M, LARIMORE E A, SWANGER J, et al.Fbw7 dimerization determines the specificity and robustness of substrate degradation [J]. Genes Dev, 2013, 27(23):2531-2536.
[25] HEMANN M T, BRIC A, TERUYA- FELDSTEIN J,et al. Evasion of the p53 tumour surveillance network by tumour- derived MYC mutants [J]. Nature, 2005, 436(7052):807-811.
[26] HAGEDORN M, DELUGIN M, ABRALDES I, et al.FBXW7/hCDC4 controls glioma cell proliferation in vitroand is a prognostic marker for survival in glioblastoma patients [J]. Cell Div, 2007, 2: 9.
[27] DAVIS R J, GONEN M, MARGINEANTU D H, et al.Pan- cancer transcriptional signatures predictive of oncogenicmutations reveal that Fbw7 regulates cancer cell oxidativemetabolism [J]. Proc Natl Acad Sci U S A, 2018, 115(21):5462-5467.
[28] EKHOLM- REED S, GOLDBERG M S, SCHLOSSMACHER M G, et al. Parkin- dependent degradation of theF- box protein Fbw7β promotes neuronal survival in response to oxidative stress by stabilizing Mcl- 1 [J]. MolCell Biol, 2013, 33(18): 3627-3643.
[29] OIKE T, OGIWARA H, TOMINAGA Y, et al. A synthetic lethality- based strategy to treat cancers harboring agenetic deficiency in the chromatin remodeling factor BRG1[J]. Cancer Res, 2013, 73(17): 5508-5518.
[30] JUBIERRE L, SORIANO A, PLANELLS- FERRER L,et al. BRG1/SMARCA4 is essential for neuroblastoma cellviability through modulation of cell death and survival pathways [J]. Oncogene, 2016, 35(39): 5179-5190.
[31] HUANG L Y, ZHAO J, CHEN H, et al. SCF(FBW7)-mediated degradation of Brg1 suppresses gastric cancer metastasis [J]. Nat Commun, 2018, 9(1): 3569.
[32] BERTOLI C, SKOTHEIM J M, DE BRUIN R A. Control of cell cycle transcription during G1 and S phases [J].Nat Rev Mol Cell Biol, 2013, 14(8): 518-528.
[33] HWANG H C, CLURMAN B E. Cyclin E in normal andneoplastic cell cycles [J]. Oncogene, 2005, 24(17): 2776-2786.
[34] OHTSUBO M, ROBERTS J M. Cyclin-dependent regulation of G1 in mammalian fibroblasts [J]. Science, 1993,259(5103): 1908-1912.
[35] SPRUCK C H, WON K A, REED S I. Deregulated cyclin E induces chromosome instability [J]. Nature, 1999,401(6750): 297-300.
[36] SCHRAML P, BUCHER C, BISSIG H, et al. Cyclin Eoverexpression and amplification in human tumours [J]. JPathol, 2003, 200(3): 375-382.
[37] TEIXEIRA L K, WANG X, LI Y, et al. Cyclin E deregulation promotes loss of specific genomic regions [J]. CurrBiol, 2015, 25(10): 1327-1333.
[38] KEYOMARSI K, TUCKER S L, BUCHHOLZ T A, etal. Cyclin E and survival in patients with breast cancer [J].N Engl J Med, 2002, 347(20): 1566-1575.
[39] KOEPP D M, SCHAEFER L K, YE X, et al. Phosphorylation- dependent ubiquitination of cyclin E by the SCFFbw7ubiquitin ligase [J]. Science, 2001, 294(5540): 173-177.
[40] TAKADA M, ZHANG W, SUZUKI A, et al. FBW7 losspromotes chromosomal instability and tumorigenesis via cyclin E1/CDK2- Mediated phosphorylation of CENP- A [J].Cancer Res, 2017, 77(18): 4881-4893.
[41] PALOMERO T, ODOM DT, O'NEIL J, et al. Transcriptional regulatory networks downstream of TAL1/SCLin T- cell acute lymphoblastic leukemia [J]. Blood, 2006,108(3): 986-992.
[42] ALLEN-PETERSEN B L, SEARS R C. Mission Possible: Advances in MYC Therapeutic Targeting in Cancer [J].BioDrugs, 2019, 33(5): 539-553.
[43] 高海燕, 钟立厚, 胡克. Skp2蛋白在非小细胞肺癌中的表达及其与 c- myc 蛋白表达的关系[J]. 中国肺癌杂志, 2004, (6):493-496.
[44] WELCKER M, ORIAN A, JIN J, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation- dependent c- Myc protein degradation [J]. ProcNatl Acad Sci U S A, 2004, 101(24): 9085-9090.
[45] POPOV N, HEROLD S, LLAMAZARES M, et al. Fbw7and Usp28 regulate myc protein stability in response to DNAdamage [J]. Cell Cycle, 2007, 6(19):2327-2331.
[46] YADA M, HATAKEYAMA S, KAMURA T, et al. Phosphorylation- dependent degradation of c- Myc is mediatedby the F- box protein Fbw7 [J]. Embo j, 2004, 23(10):2116-2125.
[47] MOJSA B, LASSOT I, DESAGHER S. Mcl-1 ubiquitination: unique regulation of an essential survival protein [J].Cells, 2014, 3(2): 418-437.
[48] THOMAS L W,LAM C,EDWARDS S W. Mcl- 1; themolecular regulation of protein function [J]. FEBS Lett,2010, 584(14): 2981-2989.
[49] WERTZ I E, KUSAM S, LAM C, et al. Sensitivity toantitubulin chemotherapeutics is regulated by MCL1 andFBW7 [J]. Nature, 2011, 471(7336): 110-114.
[50] TONG J, WANG P, TAN S, et al. Mcl- 1 degradationis required for targeted therapeutics to eradicate colon cancer cells [J]. Cancer Res, 2017, 77(9): 2512-2521.
[51] TONG J, TAN S, NIKOLOVSKA- COLESKA Z, et al.FBW7- Dependent Mcl- 1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors [J]. Mol Cancer Ther,2017, 16(9): 1979-1988.
[52] WANG Z, INUZUKA H, ZHONG J, et al. Tumor suppressor functions of FBW7 in cancer development and progression [J]. FEBS Lett, 2012, 586(10): 1409-1418.
[53] LIN L, DING D, XIAO X, et al. Trametinib potentiatesTRAIL- induced apoptosis via FBW7- dependent Mcl- 1degradation in colorectal cancer cells [J]. Mol Med, 2020,24(12): 6822-6832.
[54] ZHU J, CUI G, CHEN M, et al. Expression of R132Hmutational IDH1 in human U87 glioblastoma cells affectsthe SREBP1a pathway and induces cellular proliferation [J].J Mol Neurosci, 2013, 50(1): 165-171.
[55] ZHENG Z G, ZHANG X, LIU X X, et al. Inhibition ofHSP90beta improves lipid disorders by promoting matureSREBPs degradation via the ubiquitin- proteasome system [J].Theranostics, 2019, 9(20): 5769-5783.
[56] SUNDQVIST A, BENGOECHEA- ALONSO M T, YEX, et al. Control of lipid metabolism by phosphorylationdependent degradation of the SREBP family of transcription factors by SCF (Fbw7) [J]. Cell Metab, 2005, 1(6):379-391.
[57] SAILO B L, BANIK K, GIRISA S, et al. FBXW7 incancer: What has been unraveled thus far? [J]. Cancers (Basel), 2019, 11(2):246.
OECHEA- ALONSO M T, YEX, et al. Control of lipid metabolism by phosphorylationdependent degradation of the SREBP family of transcription factors by SCF (Fbw7) [J]. Cell Metab, 2005, 1(6):379-391.
[57] SAILO B L, BANIK K, GIRISA S, et al. FBXW7 incancer: What has been unraveled thus far? [J]. Cancers (Basel), 2019, 11(2):246.
[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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