E3连接酶SCF~(β-TRCP)调控MTSS1蛋白在肿瘤细胞增殖与转移中的作用机制
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摘要
MTSS1(肿瘤转移抑制基因-1)首先作为一种肿瘤转移抑制基因被鉴定出来，其在转移性膀胱癌细胞系中不表达。在对MTSS1功能的进一步研究中， MTSS1也可以作为一种支架蛋白，与多个伴侣分子相互作用来调控肌动蛋白动力学。近来的研究显示，MTSS1蛋白与肿瘤的发生发展密切相关，特别是前列腺癌和乳腺癌。前列腺癌中MTSS1的表达下调可以促进肿瘤的发生、发展和转移。而乳腺癌中MTSS1的低表达与乳腺癌的预后呈现出明显的相关性。但是，前列腺癌和乳腺癌细胞内MTSS1蛋白水平下调的机制还不是很清楚。
泛素蛋白酶体系统是真核细胞中主要的蛋白质降解通路，通过细胞周期、DNA复制和修复、凋亡以及一些重要的信号通路相关蛋白的降解，下调细胞内蛋白的表达水平，间接的调控细胞的多种生物学过程。泛素蛋白酶体系统通过E1泛素活化酶，E2泛素结合酶和E3泛素连接酶将泛素分子共价修饰至底物上，蛋白酶体通过识别和降解泛素标记的蛋白对底物进行降解。E3泛素连接酶决定了泛素蛋白酶体系统对于底物蛋白质降解的特异性。
β-TRCP是E3连接酶的一种，其可以识别蛋白质的特异性氨基酸序列，通过与Cullin1、Skp1及Rbx1形成SCFβ-TRCPE3泛素连接酶复合物对底物进行降解。底物被降解之前，首先被细胞内的激酶磷酸化，然后SCFβ-TRCP复合物将其携带的泛素分子转移至底物，底物被泛素化后被蛋白酶体所降解。
我们前期对于MTSS1蛋白结构的观察发现，MTSS1蛋白存在可以被E3泛素连接酶SCFβ-TRCP1识别的氨基酸序列DSG(X)2+nS，提示MTSS1蛋白可能被泛素蛋白酶体途径识别和降解。
基于E3泛素连接酶SCFβ-TRCP1降解底物的特征，我们设计了本实验。首先通过检测MTSS1与E3泛素连接酶SCFβ-TRCP复合物之间的结合，观察抑制E3泛素连接酶SCFβ-TRCP1复合物对底物水平的调节以及寻找磷酸化MTSS1蛋白的激酶及其磷酸化位点，验证了E3泛素连接酶SCFβ-TRCP是否介导了MTSS1蛋白的降解。其次，分别在前列腺癌和乳腺癌中构建了高表达MTSS1野生型和突变了激酶磷酸化位点的细胞系，通过细胞增殖和转移实验，探讨了SCFβ-TRCP1对MTSS1细胞功能的影响。
方法：
（1）免疫共沉淀和免疫印迹的方法探讨MTSS1蛋白与SCFβ-TRCP1E3泛素连接酶复合物之间的结合。
（2）利用shRNA片段连入慢病毒载体，包被病毒，感染目的细胞方法建立稳定基因敲除的细胞系，观察抑制SCFβ-TRCP1E3泛素连接酶复合物中基因的表达对MTSS1蛋白表达水平的影响。
（3）利用半衰期实验检测细胞内不同细胞系MTSS1蛋白降解速度。
（4） RT-PCR检测抑制细胞内β-TRCP对细胞内MTSS1和β-TRCP mRNA水平的影响。
（5）瞬时转染后利用免疫印迹方法检测CKIδ介导的外源性MTSS1的降解。利用点突变的方法突变被CKIδ磷酸化的位点，观察突变位点对于β-TRCP和MTSS1结合以及MTSS1降解的影响。
（6）利用逆转录病毒建立高表达MTSS1野生型以及突变型细胞系。划痕实验观察高表达野生型或者突变型MTSS1基因对细胞迁移速度的影响。
（7） Bromodeoxyuridine (BrdU)实验检测细胞增殖的改变。
（8） Transwell实验检测细胞迁移能力。
结果：
（1）免疫共沉淀结果显示，MTSS1蛋白可以与SCFβ-TRCP1E3泛素连接酶复合物成分β-TRCP1、Cullin1、Skp1及Rbx1相结合。
（2）利用shRNA抑制β-TRCP和Cullin1可以增加细胞内MTSS1蛋白表达水平。蛋白质半衰期实验显示，抑制细胞内β-TRCP水平可以明显的降低MTSS1蛋白的降解速度。
（3）蛋白质降解实验显示，激酶CKIδ参与了SCFβ-TRCP1E3泛素连接酶复合物对于底物蛋白质的降解。
（4）突变MTSS1322位点的丝氨酸可以抑制β-TRCP介导的MTSS1蛋白的泛素化。突变型MTSS1（S322A）可以抑制MTSS1蛋白质与β-TRCP之间的结合以及CKIδ介导的MTSS1蛋白的降解。
（5）构建高表达MTSS1野生型以及突变型细胞系，细胞计数以及BrdU实验结果显示，高表达MTSS1野生型细胞系细胞增殖速度明显的降低，处于S期细胞数目明显减少，而MTSS1突变型细胞系细胞增殖速度进一步被抑制。
（6）划痕和Transwell实验结果显示，高表达MTSS1可以明显的抑制细胞的迁移，而突变了β-TRCP识别区域后，细胞的迁移能力进一步降低。
结论：
E3泛素连接酶SCFβ-TRCP1通过CKIδ对MTSS1蛋白322位点的丝氨酸的磷酸化修饰介导了MTSS1蛋白泛素化降解过程。SCFβ-TRCP1E3泛素连接酶复合物对MTSS1蛋白的降解调控参与了MTSS1蛋白在前列腺癌和乳腺癌细胞生长抑制和转移中的作用。
MTSS1(metastasis suppressor-1) was first identified as a metastasis suppressorissing in metastatic bladder carcinoma cell lines. In the further study of MTSS1unction, MTSS1also acts as a scaffold protein that interacts with multiple partners toegulate actin dynamics. Recent research shows that MTSS1protein is closely relatedo the development of tumor, especially prostate cancer and breast cancer. The downegulation of MTSS1expression in prostate cancer contributes to the occurrence,evelopment and metastasis of tumor. MTSS1low expression is related to therognosis of breast cancer. However, the mechanism of down regulation of MTSS1inrostate and breast cancer cells is not clear.
Ubiquitin proteasome system is the main protein degradation pathway in theukaryotic cells, through degradation of the cell cycle, DNA replication and repair,poptosis, and the degradation of some important signal pathways related proteins,own regulation intracellular protein expression level, indirect regulates a variety ofiological processes of cells. Ubiquitin proteasome system through E1biquitin-activating enzyme, E2ubiquitin-conjugating enzyme, and E3ubiquitinigase enzyme covalently attachs of multiple ubiquitin molecules to a substrate androteasome identifying and degradation of ubiquitin marker proteins for degradationf the substrate. The substrate specificity of ubiquitin proteasome system isetermined by the E3enzymes.
β-TRCP is a kind of E3ligase, it can identify the specificity amino acid sequencef the protein, by combination with Cullin1, Skp1and Rbx1, SCFβ-TRCPcompoundsor degradation of the substrate. Before degradation, the substrate is first phosphorylated by intracellular kinase, then SCFβ-TRCPtransfer ubiquitin molecules tothe substrate and after the ubiquitin the substrate is degradated by proteasome.
Dependent the observation of MTSS1protein structure, we found that theMTSS1protein has the amino acid sequence DSG(X)2+nS, which can be identified byE3ubiquitin ligase SCFβ-TRCP1, and its suggest MTSS1protein may be identificationand degradation by ubiquitin proteasome pathway.
Based on the degradation characteristics of E3ubiquitin ligase SCFβ-TRCP1substrate, we designed this experiment. First, we detect the combination of theMTSS1and E3ubiquitin ligase SCFβ-TRCP1complexes，observe influence of substratelevel by inhibition of E3ubiquitin ligase complex and search phosphorylation MTSS1protein kinase and its phosphorylation site, to verify MTSS1protein degradation byE3ubiquitin ligase SCFβ-TRCP1complexes. Second, we respectively constructedoverexpression of MTSS1wild type and mutant kinase phosphorylation sites of celllines in prostate and breast cancer, to explored the affection of SCFβ-TRCP1on MTSS1cell function through cell proliferation and metastasis the experiment.
Methods:
（1） The combination between MTSS1protein and SCFβ-TRCP1E3ubiquitin ligasecompounds was detected by co-immunoprecipitation and immunoblotting.
（2） We used the method of link shRNA fragments to slow virus vector, packagedvirus, infected cell to establish a stable knockout cell line, to observe theinhibition of the expression of genes within SCFβ-TRCP1E3ubiquitin ligasecompounds for the effect of MTSS1protein expression level.
（3） We used the half-life experimental to detect the degradation rate of MTSS1protein in different cell lines.
（4） The inhibiton of β-TRCP for the effect of MTSS1and β-TRCP mRNA level incell detected by RT-PCR.
（5） We applied immunoblotting to detect exogenous MTSS1degradationmediated by CKIδ after transient transfection. We used the method of pointmutations to mutate the site phosphorylated by CKIδ, to observe the effect ofmutation site for the combination of β-TRCP and MTSS and the degradationof MTSS1.
（6） We used retroviruses to establish the wide-type cell line of MTSS1highexpression and mutant cell line. And applied nick experimental to observe theeffect of wild-type or mutant MTSS1gene for cell migration velocity.
（7） The change of cell proliferation was detected by bromodeoxyuridineexperimental.
（8） The cell migration ability was detected by transwell experimental.
Results:
（1） The results of co-immunoprecipitation showed that MTSS1protein cancombine with Cullin1、β-TRCP1、Skp1and Rbx1Which are the compositionsof SCFβ-TRCP1E3ubiquitin ligase compounds.
（2） The inhibition of Cullin1and β-TRCP by shRNA increased the expression ofMTSS1protein level. The half-life experimental showed that the inhibition ofβ-TRCP level obviously decreased the degradation rate of MTSS1protein.
（3） Protein degradation experimental showed that kinase CKIδ involved in thedegradation of substrates protein by SCFβ-TRCP1E3ubiquitin ligase compounds.Mutate the serine of MTSS1322site inhibited the ubiquitylation of MTSS1protein mediated by β-TRCP.
（4） Mutant-type MTSS1(S322A) inhibited the combination of β-TRCP and MTSSand the degradation of MTSS1mediated by CKIδ.
（5） The wide-type cell line of MTSS1high expression and mutant cell line wereestablished, the results of cell counting and BrdU showed that cellproliferation rate of wide-type cell line of MTSS1high expression be notablydecreased, the cell number in S phase be obviously reduced, however the cell proliferation rate of MTSS1mutant-type cell line further be suppressed.
（6） The results of nick experimental and transwell experimental showed that thehigh expression of MTSS1can obviously inhibite cell migration, and aftermutate the identification domain of β-TRCP, the cell migration ability furtherbe decreased.
Conclusions:
E3ubiquitin ligase SCFβ-TRCP1mediated the MTSS1ubiquitin proteindegradation process through phosphorylate322serine of MTSS1by CKIδ. Thedegradation of regulation MTSS1protein by SCFβ-TRCP1E3ubiquitin ligase involvedin cell growth and metastasis in prostate and breast cancer.
泛素蛋白酶体系统是真核细胞中主要的蛋白质降解通路，通过细胞周期、DNA复制和修复、凋亡以及一些重要的信号通路相关蛋白的降解，下调细胞内蛋白的表达水平，间接的调控细胞的多种生物学过程。泛素蛋白酶体系统通过E1泛素活化酶，E2泛素结合酶和E3泛素连接酶将泛素分子共价修饰至底物上，蛋白酶体通过识别和降解泛素标记的蛋白对底物进行降解。E3泛素连接酶决定了泛素蛋白酶体系统对于底物蛋白质降解的特异性。
β-TRCP是E3连接酶的一种，其可以识别蛋白质的特异性氨基酸序列，通过与Cullin1、Skp1及Rbx1形成SCFβ-TRCPE3泛素连接酶复合物对底物进行降解。底物被降解之前，首先被细胞内的激酶磷酸化，然后SCFβ-TRCP复合物将其携带的泛素分子转移至底物，底物被泛素化后被蛋白酶体所降解。
我们前期对于MTSS1蛋白结构的观察发现，MTSS1蛋白存在可以被E3泛素连接酶SCFβ-TRCP1识别的氨基酸序列DSG(X)2+nS，提示MTSS1蛋白可能被泛素蛋白酶体途径识别和降解。
基于E3泛素连接酶SCFβ-TRCP1降解底物的特征，我们设计了本实验。首先通过检测MTSS1与E3泛素连接酶SCFβ-TRCP复合物之间的结合，观察抑制E3泛素连接酶SCFβ-TRCP1复合物对底物水平的调节以及寻找磷酸化MTSS1蛋白的激酶及其磷酸化位点，验证了E3泛素连接酶SCFβ-TRCP是否介导了MTSS1蛋白的降解。其次，分别在前列腺癌和乳腺癌中构建了高表达MTSS1野生型和突变了激酶磷酸化位点的细胞系，通过细胞增殖和转移实验，探讨了SCFβ-TRCP1对MTSS1细胞功能的影响。
方法：
（1）免疫共沉淀和免疫印迹的方法探讨MTSS1蛋白与SCFβ-TRCP1E3泛素连接酶复合物之间的结合。
（2）利用shRNA片段连入慢病毒载体，包被病毒，感染目的细胞方法建立稳定基因敲除的细胞系，观察抑制SCFβ-TRCP1E3泛素连接酶复合物中基因的表达对MTSS1蛋白表达水平的影响。
（3）利用半衰期实验检测细胞内不同细胞系MTSS1蛋白降解速度。
（4） RT-PCR检测抑制细胞内β-TRCP对细胞内MTSS1和β-TRCP mRNA水平的影响。
（5）瞬时转染后利用免疫印迹方法检测CKIδ介导的外源性MTSS1的降解。利用点突变的方法突变被CKIδ磷酸化的位点，观察突变位点对于β-TRCP和MTSS1结合以及MTSS1降解的影响。
（6）利用逆转录病毒建立高表达MTSS1野生型以及突变型细胞系。划痕实验观察高表达野生型或者突变型MTSS1基因对细胞迁移速度的影响。
（7） Bromodeoxyuridine (BrdU)实验检测细胞增殖的改变。
（8） Transwell实验检测细胞迁移能力。
结果：
（1）免疫共沉淀结果显示，MTSS1蛋白可以与SCFβ-TRCP1E3泛素连接酶复合物成分β-TRCP1、Cullin1、Skp1及Rbx1相结合。
（2）利用shRNA抑制β-TRCP和Cullin1可以增加细胞内MTSS1蛋白表达水平。蛋白质半衰期实验显示，抑制细胞内β-TRCP水平可以明显的降低MTSS1蛋白的降解速度。
（3）蛋白质降解实验显示，激酶CKIδ参与了SCFβ-TRCP1E3泛素连接酶复合物对于底物蛋白质的降解。
（4）突变MTSS1322位点的丝氨酸可以抑制β-TRCP介导的MTSS1蛋白的泛素化。突变型MTSS1（S322A）可以抑制MTSS1蛋白质与β-TRCP之间的结合以及CKIδ介导的MTSS1蛋白的降解。
（5）构建高表达MTSS1野生型以及突变型细胞系，细胞计数以及BrdU实验结果显示，高表达MTSS1野生型细胞系细胞增殖速度明显的降低，处于S期细胞数目明显减少，而MTSS1突变型细胞系细胞增殖速度进一步被抑制。
（6）划痕和Transwell实验结果显示，高表达MTSS1可以明显的抑制细胞的迁移，而突变了β-TRCP识别区域后，细胞的迁移能力进一步降低。
结论：
E3泛素连接酶SCFβ-TRCP1通过CKIδ对MTSS1蛋白322位点的丝氨酸的磷酸化修饰介导了MTSS1蛋白泛素化降解过程。SCFβ-TRCP1E3泛素连接酶复合物对MTSS1蛋白的降解调控参与了MTSS1蛋白在前列腺癌和乳腺癌细胞生长抑制和转移中的作用。
MTSS1(metastasis suppressor-1) was first identified as a metastasis suppressorissing in metastatic bladder carcinoma cell lines. In the further study of MTSS1unction, MTSS1also acts as a scaffold protein that interacts with multiple partners toegulate actin dynamics. Recent research shows that MTSS1protein is closely relatedo the development of tumor, especially prostate cancer and breast cancer. The downegulation of MTSS1expression in prostate cancer contributes to the occurrence,evelopment and metastasis of tumor. MTSS1low expression is related to therognosis of breast cancer. However, the mechanism of down regulation of MTSS1inrostate and breast cancer cells is not clear.
Ubiquitin proteasome system is the main protein degradation pathway in theukaryotic cells, through degradation of the cell cycle, DNA replication and repair,poptosis, and the degradation of some important signal pathways related proteins,own regulation intracellular protein expression level, indirect regulates a variety ofiological processes of cells. Ubiquitin proteasome system through E1biquitin-activating enzyme, E2ubiquitin-conjugating enzyme, and E3ubiquitinigase enzyme covalently attachs of multiple ubiquitin molecules to a substrate androteasome identifying and degradation of ubiquitin marker proteins for degradationf the substrate. The substrate specificity of ubiquitin proteasome system isetermined by the E3enzymes.
β-TRCP is a kind of E3ligase, it can identify the specificity amino acid sequencef the protein, by combination with Cullin1, Skp1and Rbx1, SCFβ-TRCPcompoundsor degradation of the substrate. Before degradation, the substrate is first phosphorylated by intracellular kinase, then SCFβ-TRCPtransfer ubiquitin molecules tothe substrate and after the ubiquitin the substrate is degradated by proteasome.
Dependent the observation of MTSS1protein structure, we found that theMTSS1protein has the amino acid sequence DSG(X)2+nS, which can be identified byE3ubiquitin ligase SCFβ-TRCP1, and its suggest MTSS1protein may be identificationand degradation by ubiquitin proteasome pathway.
Based on the degradation characteristics of E3ubiquitin ligase SCFβ-TRCP1substrate, we designed this experiment. First, we detect the combination of theMTSS1and E3ubiquitin ligase SCFβ-TRCP1complexes，observe influence of substratelevel by inhibition of E3ubiquitin ligase complex and search phosphorylation MTSS1protein kinase and its phosphorylation site, to verify MTSS1protein degradation byE3ubiquitin ligase SCFβ-TRCP1complexes. Second, we respectively constructedoverexpression of MTSS1wild type and mutant kinase phosphorylation sites of celllines in prostate and breast cancer, to explored the affection of SCFβ-TRCP1on MTSS1cell function through cell proliferation and metastasis the experiment.
Methods:
（1） The combination between MTSS1protein and SCFβ-TRCP1E3ubiquitin ligasecompounds was detected by co-immunoprecipitation and immunoblotting.
（2） We used the method of link shRNA fragments to slow virus vector, packagedvirus, infected cell to establish a stable knockout cell line, to observe theinhibition of the expression of genes within SCFβ-TRCP1E3ubiquitin ligasecompounds for the effect of MTSS1protein expression level.
（3） We used the half-life experimental to detect the degradation rate of MTSS1protein in different cell lines.
（4） The inhibiton of β-TRCP for the effect of MTSS1and β-TRCP mRNA level incell detected by RT-PCR.
（5） We applied immunoblotting to detect exogenous MTSS1degradationmediated by CKIδ after transient transfection. We used the method of pointmutations to mutate the site phosphorylated by CKIδ, to observe the effect ofmutation site for the combination of β-TRCP and MTSS and the degradationof MTSS1.
（6） We used retroviruses to establish the wide-type cell line of MTSS1highexpression and mutant cell line. And applied nick experimental to observe theeffect of wild-type or mutant MTSS1gene for cell migration velocity.
（7） The change of cell proliferation was detected by bromodeoxyuridineexperimental.
（8） The cell migration ability was detected by transwell experimental.
Results:
（1） The results of co-immunoprecipitation showed that MTSS1protein cancombine with Cullin1、β-TRCP1、Skp1and Rbx1Which are the compositionsof SCFβ-TRCP1E3ubiquitin ligase compounds.
（2） The inhibition of Cullin1and β-TRCP by shRNA increased the expression ofMTSS1protein level. The half-life experimental showed that the inhibition ofβ-TRCP level obviously decreased the degradation rate of MTSS1protein.
（3） Protein degradation experimental showed that kinase CKIδ involved in thedegradation of substrates protein by SCFβ-TRCP1E3ubiquitin ligase compounds.Mutate the serine of MTSS1322site inhibited the ubiquitylation of MTSS1protein mediated by β-TRCP.
（4） Mutant-type MTSS1(S322A) inhibited the combination of β-TRCP and MTSSand the degradation of MTSS1mediated by CKIδ.
（5） The wide-type cell line of MTSS1high expression and mutant cell line wereestablished, the results of cell counting and BrdU showed that cellproliferation rate of wide-type cell line of MTSS1high expression be notablydecreased, the cell number in S phase be obviously reduced, however the cell proliferation rate of MTSS1mutant-type cell line further be suppressed.
（6） The results of nick experimental and transwell experimental showed that thehigh expression of MTSS1can obviously inhibite cell migration, and aftermutate the identification domain of β-TRCP, the cell migration ability furtherbe decreased.
Conclusions:
E3ubiquitin ligase SCFβ-TRCP1mediated the MTSS1ubiquitin proteindegradation process through phosphorylate322serine of MTSS1by CKIδ. Thedegradation of regulation MTSS1protein by SCFβ-TRCP1E3ubiquitin ligase involvedin cell growth and metastasis in prostate and breast cancer.
引文
[1] Hershko A, Ciechanover A, Varshavsky A. Basic Medical Research Award. Theubiquitin system [J]. Nat Med,2000,6:1073-1081.
[2] Nalepa G, Rolfe M, Harper JW. Drug discovery in the ubiquitin-proteasomesystem[J]. Nat Rev Drug Discov,2006,5:596-613.
[3] Ravid T, Hochstrasser M. Diversity of degradation signals in theubiquitin-proteasome system[J]. Nat Rev Mol Cell Biol,2008,9:679-690.
[4] Hershko A, Ciechanover A. The ubiquitin system[J]. Annu Rev Biochem,1998,67:425-479.
[5] Nagy V, Dikic I. Ubiquitin ligase complexes: from substrate selectivity toconjugational specificity[J]. Biol Chem,2010,391:163-169.
[6] Zhao Y, Sun Y. Cullin-RING ligases (CRLs) as attractive anti-cancer targets[J].Curr Pharm Des,2013,19:3215-3225.
[7] Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16E6andE6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination ofp53[J]. Cell,1993,75:495-505.
[8] Lipkowitz S, Weissman AM. RINGs of good and evil: RING finger ubiquitinligases at the crossroads of tumour suppression and oncogenesis[J]. Nat RevCancer,2011,11:629-643.
[9] Chau V, Tobias JW, Bachmair A, et al. A multiubiquitin chain is confined tospecific lysine in a targeted short-lived protein[J]. Science,1989,243:1576-1583.
[10] Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatorypathways[J]. Annu Rev Biochem,2009,78:769-796.
[11] Spence J, Gali RR, Dittmar G, et al. Cell cycle-regulated modification of theribosome by a variant multiubiquitin chain[J]. Cell,2000,102:67-76.
[12] Ulrich HD, Walden H. Ubiquitin signalling in DNA replication and repair[J]. NatRev Mol Cell Biol,2010,11:479-489.
[13] Acconcia F, Sigismund S, Polo S. Ubiquitin in trafficking: the network atwork[J]. Exp Cell Res,2009,315:1610-1618.
[14] Hicke L. Protein regulation by monoubiquitin[J]. Nat Rev Mol Cell Biol,2001,2:195-201.
[15] Weihua Zhou, Wenyi Wei, Yi Sun. Genetically engineered mouse models forfunctional studies of SKP1-CUL1-F-box-protein (SCF) E3ubiquitin ligases[J].Cell Research,2013,23:599-619.
[16] Jin J, Li X, Gygi SP, Harper JW. Dual E1activation systems for ubiquitindifferentially regulate E2enzyme charging[J]. Nature,2007,447:1135–1138.
[17] van Wijk SJ, Timmers HT. The family of ubiquitin-conjugating enzymes (E2s):deciding between life and death of proteins[J]. FASEB J,2010,24:981–993.
[18] Metzger MB, Hristova VA, Weissman AM. HECT and RING finger families ofE3ubiquitin ligases at a glance[J]. J Cell Sci,2012,125:531–537.
[19] Matsumoto ML, Wickliffe KE, Dong KC, et al. K11-linked polyubiquitination incell cycle control revealed by a K11linkage-specific antibody[J]. Mol Cell,2010,39:477–484.
[20] Komander D, Rape M. The ubiquitin code[J]. Annu Rev Biochem,2012,81:203–229.
[21] Min Shen, Sara Schmitt, Daniela Buac, and Q Ping Dou, PhD. Targeting theubiquitin–proteasome system for cancer therapy[J]. Expert Opin Ther Targets,2013,17:1091–1108.
[22] Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway:destruction for the sake of construction[J]. Physiol Rev,2002,82:373–428.
[23] Goldberg AL, Akopian TN, Kisselev AF, et al. New insights into themechanisms and importance of the proteasome in intracellular proteindegradation[J]. Biol Chem,1997,378:131–140.
[24] Gallastegui N, Groll M. The26S proteasome: assembly and function of adestructive machine[J]. Trends Biochem Sci,2010,35:634–642.
[25] Strehl B, Seifert U, Kruger E, et al. Interferon-gamma, the functional plasticity ofthe ubiquitinproteasome system, and MHC class I antigen processing[J].Immunol Rev,2005,207:19–30.
[26] Angeles A, Fung G, Luo H. Immune and non-immune functions of theimmunoproteasome[J]. Front Biosci,2012,17:1904–1916.
[27] Fraile JM, Quesada V, Rodriguez D, et al. Deubiquitinases in cancer: newfunctions and therapeutic options[J]. Oncogene,2012,31:2373–2388.
[28] Deshaies RJ, Joazeiro CA. RING domain E3ubiquitin ligases[J]. Annu RevBiochem,2009,8:399-434.
[29] Sarikas A, Hartmann T, Pan ZQ. The cullin protein family[J]. Genome Biol,2011,12:220.
[30] Willems AR, Schwab M, Tyers M. A hitchhiker’s guide to the cullin ubiquitinligases: SCF and its kin[J]. Biochim Biophys Acta,2004,1695:133-170.
[31] Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. A complex of Cdc4p, Skp1p,and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitorSic1p[J]. Cell,1997,91:221-230.
[32] Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW.F-box proteins arereceptors that recruit phosphorylated substrates to the SCF ubiquitin-ligasecomplex[J]. Cell,1997,91:209-219.
[33] Bai C, Sen P, Hofmann K, et al. SKP1connects cell cycle regulators to theubiquitin proteolysis machinery through a novel motif, the F-box[J]. Cell,1996,86:263-274.
[34] Kamura T, Conrad MN, Yan Q, Conaway RC, Conaway JW. The Rbx1subunitof SCF and VHL E3ubiquitin ligase activates Rub1modification of cullinsCdc53and Cul2[J]. Genes Dev,1999,13:2928-2933.
[35] Ohta T, Michel JJ, Schottelius AJ, Xiong Y. ROC1, a homolog of APC11,represents a family of cullin partners with an associated ubiquitin ligaseactivity[J]. Mol Cell,1999,3:535-541.
[36] Seol JH, Feldman RMR, Zachariae WZ, et al. Cdc53/cullin and the essential Hrt1RING-H2subunit of SCF define a ubiquitin ligase module that activates the E2enzyme Cdc34[J]. Genes Dev,1999,13:1614-1626.
[37] Tan P, Fuchs SY, Chen A, et al. Recruitment of a ROC1-CUL1ubiquitin ligaseby Skp1and HOS to catalyze the ubiquitination of IκBα[J]. Mol Cell1999,3:527-533.
[38] Duan H, Wang Y, Aviram M, et al. SAG, a novel zinc RING finger protein thatprotects cells from apoptosis induced by redox agents[J]. Mol Cell Biol,1999,19:3145-3155.
[39] Swaroop M, Wang Y, Miller P, et al. Yeast homolog of humanSAG/ROC2/Rbx2/Hrt2is essential for cell growth, but not for germination:Chip profiling implicates its role in cell cycle regulation[J]. Oncogene,2000,19:2855-2866.
[40] Zheng N, Schulman BA, Song L, et al. Structure of the Cul1-Rbx1-Skp1-FboxSkp2SCF ubiquitin ligase complex[J]. Nature,2002,416:703-709.
[41] Cardozo T, Pagano M. The SCF ubiquitin ligase: insights into a molecularmachine[J]. Nat Rev Mol Cell Biol,2004,5:739-751.
[42] Wu K, Chen A, Pan ZQ. Conjugation of Nedd8to CUL1enhances the ability ofthe ROC1-CUL1complex to promote ubiquitin polymerization[J]. J Biol Chem,2000,275:32317-32324.
[43] Yen HC, Elledge SJ. Identification of SCF ubiquitin ligase substrates by globalprotein stability profiling[J]. Science,2008,322:923-929.
[44] Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer[J].Nat Rev Cancer,2006,6:369-381.
[45] Silverman JS, Skaar JR, Pagano M. SCF ubiquitin ligases in the maintenance ofgenome stability[J]. Trends Biochem Sci,2012,37:66-73.
[46] Jia L, Sun Y. SCF E3ubiquitin ligases as anticancer targets[J]. Curr Cancer DrugTargets,2011,11:347-356.
[47] Zhang H, Kobayashi R, Galaktionov K, Beach D. p19Skp1and p45Skp2areessential elements of the cyclin A-CDK2S phase kinase[J]. Cell,1995,82:915-925.
[48] Galan JM, Wiederkehr A, Seol JH, et al. Skp1p and the Fbox protein Rcy1p forma non-SCF complex involved in recycling of the SNARE Snc1p in yeast[J]. MolCell Biol,2001,21:3105-3117.
[49] Jourdain I, Spielewoy N, Thompson J, et al. Identification of a conserved F-boxprotein6interactor essential for endocytosis and cytokinesis in fission yeast[J].Biochem J,2009,420:169-177.
[50] Piva R, Liu J, Chiarle R, et al. In vivo interference with Skp1function leads togenetic instability and neoplastic transformation[J]. Mol Cell Biol,2002,22:8375-8387.
[51] Mandel SA, Fishman-Jacob T, Youdim MB. Modeling sporadic Parkinson’sdisease by silencing the ubiquitin E3ligase component, SKP1A[J].Parkinsonism Relat Disord,2009,15:S148-S151.
[52] Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock EM.cul-1is required forcell cycle exit in C. elegans and identifies a novel gene family[J]. Cell,1996,85:829-839.
[53] Mathias N, Johnson SL, Winey M, et al. Cdc53p acts in concert with Cdc4p andCdc34p to control the G1-to-S-phase transition and identifies a conservedfamily of proteins[J]. Mol Cell Biol,1996,16:6634-6643.
[54] Duda DM, Borg LA, Scott DC, et al. Structural insights into NEDD8activationof cullin-RING ligases: conformational control of conjugation[J]. Cell,2008,134:995-1006.
[55] Goldenberg SJ, Cascio TC, Shumway SD, et al. Structure of theCand1-Cul1-Roc1complex reveals regulatory mechanisms for the assembly ofthe multisubunit cullin-dependent ubiquitin ligases[J]. Cell,2004,119:517-528.
[56] Dealy MJ, Nguyen KV, Lo J, et al. Loss of Cul1results in early embryoniclethality and dysregulation of cyclin E[J]. Nat Genet,1999,23:245-248.
[57] Wang Y, Penfold S, Tang X, et al. Deletion of the Cul1gene in mice causesarrest in early embryogenesis and accumulation of cyclin E[J]. Curr Biol,1999,9:1191-1194.
[58] Salon C, Brambilla E, Brambilla C, et al. Altered pattern of Cul-1proteinexpression and neddylation in human lung tumours: relationships with CAND1and cyclin E protein levels[J]. J Pathol,2007,213:303-310.
[59] Chen G, Cheng Y, Martinka M, Li G. Cul1expression is increased in early stagesof human melanoma[J]. Pigment Cell Melanoma Res,2010,23:572-574.
[60] Singer JD, Gurian-West M, Clurman B, Roberts JM. Cullin-3targets cyclin E forubiquitination and controls S phase in mammalian cells[J]. Genes Dev,1999,13:2375-2387.
[61] McEvoy JD, Kossatz U, Malek N, Singer JD. Constitutive turnover of cyclin Eby Cul3maintains quiescence[J]. Mol Cell Biol,2007,27:3651-3666.
[62] Kossatz U, Breuhahn K, Wolf B, et al. The cyclin E regulator cullin3preventsmouse hepatic progenitor cells from becoming tumor-initiating cells[J]. J ClinInvest,2010,120:3820-3833.
[63] Mathew R, Seiler MP, Scanlon ST, et al. BTB-ZF factors recruit the E3ligasecullin3to regulate lymphoid effector programs[J]. Nature,2012,491:618-621.
[64] Siu KT, Rosner MR, Minella AC. An integrated view of cyclin E function andregulation[J]. Cell Cycle,2012,11:57-64.
[65] Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of theKeap1-Nrf2pathway in stress response and cancer evolution[J]. Genes Cells,2011,16:123-140.
[66] Loignon M, Miao W, Hu L, et al. Cul3overexpression depletes Nrf2in breastcancer and is associated with sensitivity to carcinogens, to oxidative stress, andto chemotherapy[J]. Mol Cancer Ther,2009,8:2432-2440.
[67] Yuan WC, Lee YR, Huang SF, et al. A Cullin3-KLHL20ubiquitinligase-dependent pathway targets PML to potentiate HIF-1signaling andprostate cancer progression[J]. Cancer Cell,2011,20:214-228.
[68] Haagenson KK, Tait L, Wang J, et al. Cullin-3protein expression levels correlatewith breast cancer progression[J]. Cancer Biol Ther,2012,13:1042-1046.
[69] Hammerman PS, Hayes DN, Wilkerson MD, et al. Comprehensive genomiccharacterization of squamous cell lung cancers[J]. Nature,2012,489:519-525.
[70] Boyden LM, Choi M, Choate KA, et al. Mutations in kelchlike3and cullin3cause hypertension and electrolyte abnormalities[J]. Nature,2012,482:98-102.
[71] Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHLmediateddestruction by proline hydroxylation: implications for O2sensing[J]. Science,2001,292:464-468.
[72] Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the vonHippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation[J].Science,2001,292:468-472.
[73] Laszlo GS, Cooper JA. Restriction of Src activity by Cullin-5[J]. Curr Biol,2009,19:157-162.
[74] Lee J, Zhou P. Cullins and cancer[J]. Genes Cancer,2010,1:690-699.
[75] Sun Y, Li H. Functional characterization of SAG/RBX2/ROC2/RNF7, anantioxidant protein and an E3ubiquitin ligase[J]. Protein Cell,2013,4:103-116.
[76] Park SW, Chung NG, Hur SY, et al. Mutational analysis of hypoxia-related genesHIF1alpha and CUL2in common human cancers[J]. APMIS,2009,117:880-885.
[77] Jackson S, Xiong Y. CRL4s: the CUL4-RING E3ubiquitin ligases[J]. TrendsBiochem Sci,2009,34:562-570.
[78] Liu L, Lee S, Zhang J, et al. CUL4A abrogation augments DNA damageresponse and protection against skin carcinogenesis[J]. Mol Cell,2009,34:451-460.
[79] Li B, Ruiz JC, Chun KT. CUL-4A is critical for early embryonic development[J].Mol Cell Biol,2002,22:4997-5005.
[80] Kopanja D, Stoyanova T, Okur MN, et al. Proliferation defects and genomeinstability in cells lacking Cul4A[J]. Oncogene,2009,28:2456-2465.
[81] Kopanja D, Roy N, Stoyanova T, et al. Cul4A is essential for spermatogenesisand male fertility[J]. Dev Biol,2011,352:278-287.
[82] Yin Y, Lin C, Kim ST, et al. The E3ubiquitin ligase Cullin4A regulates meioticprogression in mouse spermatogenesis[J]. Dev Biol,2011,356:51-62.
[83] Jiang B, Zhao W, Yuan J, et al. Lack of Cul4b, an E3ubiquitin ligase component,leads to embryonic lethality and abnormal placental development[J]. PLoS One,2012,7:e37070.
[84] Liu L, Yin Y, Li Y, et al. Essential role of the CUL4B ubiquitin ligase inextra-embryonic tissue development during mouse embryogenesis[J]. Cell Res,2012,22:1258-1269.
[85] Wei D, Sun Y. Small RING finger proteins RBX1and RBX2of SCF E3ubiquitin ligases: the role in cancer and as cancer targets[J]. Genes Cancer,2010,1:700-707.
[86] Schindl M, Gnant M, Schoppmann SF, Horvat R, Birner P. Overexpression ofthe human homologue for Caenorhabditis elegans cul-4gene is associated withpoor outcome in nodenegative breast cancer[J]. Anticancer Res,2007,27:949-952.
[87] Tarpey PS, Raymond FL, O’Meara S, et al. Mutations in CUL4B, which encodesa ubiquitin E3ligase subunit, cause an X-linked mental retardation syndromeassociated with aggressive outbursts, seizures, relative macrocephaly, centralobesity, hypogonadism, pes cavus, and tremor[J]. Am J Hum Genet,2007,80:345-352.
[88] Zou Y, Liu Q, Chen B, et al. Mutation in CUL4B, which encodes a member ofcullin-RING ubiquitin ligase complex,causes X-linked mental retardation[J].Am J Hum Genet,2007,80:561-566.
[89] Zhao Y, Sun Y. CUL4B ubiquitin ligase in mouse development: a model forhuman X-linked mental retardation syndrome?[J]. Cell Res,2012,22:1224-1226.
[90] Li T, Hung MS, Wang Y, et al. Transgenic mice for creinducible overexpressionof the Cul4A gene[J]. Genesis,2011,49:134-141.
[91] Arai T, Kasper JS, Skaar JR, et al. Targeted disruption of p185/Cul7gene resultsin abnormal vascular morphogenesis[J]. Proc Natl Acad Sci USA,2003,100:9855-9860.
[92] Skaar JR, Arai T, DeCaprio JA. Dimerization of CUL7and PARC is not requiredfor all CUL7functions and mouse development[J]. Mol Cell Biol,2005,25:5579-5589.
[93] Huber C, Dias-Santagata D, Glaser A, et al. Identification of mutations in CUL7in3-M syndrome[J]. Nat Genet,2005,37:1119-1124.
[94] Sasaki K, Okamoto N, Kosaki K, et al. Maternal uniparental isodisomy andheterodisomy on chromosome6encompassing a CUL7gene mutation causing3M syndrome[J]. Clin Genet,2011,80:478-483.
[95] Maksimova N, Hara K, Miyashia A, et al. Clinical, molecular andhistopathological features of short stature syndrome with novel CUL7mutationin Yakuts: new population isolate in Asia[J]. J Med Genet,2007,44:772-778.
[96] Guo G, Gui Y, Gao S, et al. Frequent mutations of genes encodingubiquitin-mediated proteolysis pathway components in clear cell renal cellcarcinoma[J]. Nat Genet,2012,44:17-19.
[97] Jin J, Cardozo T, Lovering RC, et al. Systematic analysis and nomenclature ofmammalian F-box proteins[J]. Genes Dev,2004,18:2573-2580.
[98] Cenciarelli C, Chiaur DS, Guardavaccaro D, et al. Identification of a family ofhuman F-box proteins[J]. Curr Biol,1999,9:1177-1179.
[99] Winston JT, Koepp DM, Zhu C, Elledge SJ, Harper JW.A family of mammalianF-box proteins[J]. Curr Biol,1999,9:1180-1182.
[100] Yoshida Y, Chiba T, Tokunaga F, et al. E3ubiquitin ligase that recognizessugar chains[J]. Nature,2002,418:438-442.
[101] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2andbeta-TrCP: tipping the scales of cancer[J]. Nat Rev Cancer,2008,8:438-449.
[102] Harper JW, Tan MK. Ubiquitin pathway proteomics[J]. Mol Cell Proteomics,2012,11:1541-1550.
[103] Skaar JR, D’Angiolella V, Pagan JK, Pagano M. Snapshot: F box proteins II[J].Cell,2009,137:1358.
[104] Fuchs SY. The role of ubiquitin-proteasome pathway in oncogenic signaling [J].Cancer Biol. Ther.,2002,1:337-341.
[105]Joazeiro CA and Weissman AM. RING finger proteins: mediators of ubiquitinligase activity [J]. Cell,2002,102:549-552.
[106]Laney JD and Hochstrasser M. Substrate targeting in the ubiquitin system [J].Cell,1999,97:427-430.
[107]Jiang J and Struhl G. Regulation of the Hedgehog and Wingless signallingpathways by the F-box/WD40-repeat protein Slimb [J]. Nature,1998,391:493-496.
[108]Spevak W, Keiper BD, Stratowa C and Castanon MJ. Saccharomyces cerevisiaecdc15mutants arrested at a late stage in anaphase are rescued by XenopuscDNAs encoding N-ras or a protein with beta-transducin repeats [J]. Mol. CellBiol.,1993,13:4953-4966.
[109]Margottin F, Bour SP, Durand H, Selig L, Benichou S,Richard V, Thomas D,Strebel K and Benarous R. A novel human WD protein, h-beta TrCp, thatinteracts with HIV-1Vpu connects CD4to the ER degradation pathway throughan F-box motif [J]. Mol. Cell,1998,1:565-574.
[110]Bhatia N, Herter JR, Slaga TJ, Fuchs SY and Spiegelman VS. Mousehomologue of HOS (mHOS) is overexpressed in skin tumors and implicated inconstitutive activation of NF-kappaB [J]. Oncogene,2002,21:1501-1509.
[111] Ballarino M, Marchioni M and Carnevali F. The Xenopus laevis beta TrCP gene:genomic organization, alternative splicing,5' and3' region characterization andcomparison of its structure with that of human beta TrCP genes [J].Biochim.Biophys. Acta,2002,1577:81-92.
[112] Chiaur DS, Murthy S, Cenciarelli C, Parks W, Loda M,Inghirami G, DemetrickD and Pagano M. Five human genes encoding F-box proteins: chromosomemapping and analysis in human tumors [J]. Cytogenet. Cell Genet.,2000,88:255-258.
[113] Koike J, Sagara N, Kirikoshi H, Takagi A, Miwa T, Hirai M and Katoh M.Molecular cloning and genomic structure of the betaTRCP2gene onchromosome5q35.1[J]. Biochem. Biophys. Res. Commun.,2000,269:103-109.
[114]Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M,Furuichi K,Shikama H and Tanaka K. Homodimer of two F-box proteins betaTrCP1orbetaTrCP2binds to IkappaBalpha for signal-dependent ubiquitination [J]. J.Biol.Chem.,2000,275:2877-2884.
[115]Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L,Donzelli M,Margottin-Goguet F, Jackson PK, Yamasaki L and Pagano M. Control ofmeiotic and mitotic progression by the F box protein beta-Trcp1in vivo [J]. Dev.Cell,2003,4:799-812.
[116]Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S,Mercurio F,Manning AM, Ciechanover A and Ben-Neriah Y. Inhibition of NF-kappa-Bcellular function via specific targeting of the I-kappa-B-ubiquitin ligase [J].EMBO J.,1997,16:6486-6494.
[117]Aberle H, Bauer A, Stappert J, Kispert A and Kemler R. beta-catenin is a targetfor the ubiquitin-proteasome pathway [J]. EMBO J.,1997,16:3797-3804.
[118]Hattori K, Hatakeyama S, Shirane M, Matsumoto M and Nakayama K.Molecular dissection of the interactions among IkappaBalpha, FWD1, and Skp1required for ubiquitin-mediated proteolysis of IkappaBalpha [J].J. Biol. Chem.,1999,274:29641-29647.
[119]Orlicky S, Tang X, Willems A, Tyers M and Sicheri F. Structural basis forphosphodependent substrate selection and orientation by the SCFCdc4ubiquitinligase [J]. Cell,2003,112:243-256.
[120]Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW and Pavletich NP. Structureof a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding andlysine specificity of the SCF(beta-TrCP1) ubiquitin ligase [J]. Mol. Cell,2003,11:1445-1456.
[121]Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A, Allen H, HayRT, Ben-Neriah Y and Ley SC. betaTrCP-mediated proteolysis of NF-kappaB1p105requires phosphorylation of p105serines927and932[J]. Mol. Cell Biol.,2003,23:402-413.
[122] Kroll M, Margottin F, Kohl A, Renard P, Durand H,Concordet JP, Bachelerie F,Arenzana-Seisdedos F and Benarous R. Inducible degradation of IkappaBalphaby the proteasome requires interaction with the F-box protein h-betaTrCP [J]. J.Biol. Chem.,1999,274:7941-7945.
[123] Besnard-Guerin C, Belaidouni N, Lassot I, Segeral E, Jobart A, Marchal C andBenarous R. HIV-1Vpu sequesters beta-transducin repeat-containing protein(betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin andother SCFbetaTrCP substrates [J]. J. Biol. Chem.,2004,279:788-795.
[124]Tang W, Pavlish OA, Spiegelman VS, Parkhitko AA and Fuchs SY. Interactionof Epstein-Barr virus latent membrane protein1with SCFHOS/beta-TrCP E3ubiquitin ligase regulates extent of NF-kappaB activation [J]. J. Biol. Chem.,2003,278:48942-48949.
[125]Davis M, Hatzubai A, Andersen JS, Ben-Shushan E, Fisher GZ, Yaron A,Bauskin A, Mercurio F, Mann M and Ben-Neriah Y. Pseudosubstrate regulationof the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U [J]. Genes Dev.,2002,16:439-451.
[126]Nakayama K, Hatakeyama S, Maruyama SI, Kikuchi A, Onoe K, Good RA andNakayama KI [J]. Proc. Natl.Acad. Sci. USA,2003,100:8752-8757.
[127]Spiegelman VS, Stavropoulos P, Latres E, Pagano M, Ronai Z, Slaga TJ andFuchs SY. Impaired degradation of inhibitory subunit of NF-kappa B (I kappa B)and beta-catenin as a result of targeted disruption of the beta-TrCP1gene [J]. J.Biol. Chem.,2001,276:27152-27158.
[128]Spiegelman VS, Slaga TJ, Pagano M, Minamoto T, Ronai Z and Fuchs SY.Wnt/beta-catenin signaling induces the expression and activity of betaTrCPubiquitin ligase receptor [J]. Mol. Cell,2000,5:877-882.
[129]Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM,Byers S and GaynorRB. Regulation of beta-catenin function by the IkappaB kinases [J]. J. Biol.Chem.,2001,276:42276-42286.
[130]Bour S, Perrin C, Akari H and Strebel K. The human immunodeficiency virustype1Vpu protein inhibits NF-kappa B activation by interfering with betaTrCP-mediated degradation of Ikappa B [J]. J. Biol.Chem.,2001,276:15920-15928.
[131]Akari H, Bour S, Kao S, Adachi A and Strebel K. The human immunodeficiencyvirus type1accessory protein Vpu induces apoptosis by suppressing the nuclearfactor kappaB-dependent expression of antiapoptotic factors [J]. J.Exp. Med.,2001,194:1299-1311.
[132]Karin M, Cao Y, Greten FR and Li ZW. NF-kappaB in cancer: from innocentbystander to major culprit [J]. Nat. Rev.Cancer,2002,2:301-310.
[133]Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth [J].Nat. Rev. Immunol.,2002,2:664-674.
[134] Saitoh T and Katoh M. Expression profiles of betaTRCP1and betaTRCP2, andmutation analysis of betaTRCP2in gastric cancer [J]. Int. J. Oncol.,2001,18:959-964.
[135] Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B and Pestell RG. NF-kappaBand cell-cycle regulation: the cyclin connection [J]. Cytokine Growth FactorRev.,2001,12:73–90.
[136]Eldar-Finkelman H, Seger R, Vandenheede JR and Krebs EG. Inactivation ofglycogen synthase kinase-3by epidermal growth factor is mediated bymitogen-activated protein kinase/p90ribosomal protein S6kinase signalingpathway in NIH/3T3cells [J]. J. Biol. Chem.,1995,270:987-990.
[137] Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T,Ruzicka T and Reifenberger G. Molecular genetic analysis of malignantmelanomas for aberrations of the WNT signaling pathway genes CTNNB1,APC, ICAT and BTRC [J].Int J.Cancer,2002,100:549-556.
[138] Gerstein AV, Almeida TA, Zhao G, Chess E, Shih Ie M,Buhler K, Pienta K,Rubin MA, Vessella R and Papadopoulos N. APC/CTNNB1(beta-catenin)pathway alterations in human prostate cancers [J]. Genes Chromosomes Cancer,2002,34:9-16.
[139] Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX,Gelinas C and Rabson AB.Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells [J].Prostate,2002,52:83-200.
[140]Soldatenkov VA, Dritschilo A, Ronai Z and Fuchs SY. Inhibition of homologueof Slimb (HOS) function sensitizes human melanoma cells for apoptosis [J].Cancer Res.,1999,59:5085-5088.
[141]Hayakawa M, Miyashita H, Sakamoto I, Kitagawa M,Tanaka H, Yasuda H,Karin M and Kikugawa K. Evidence that reactive oxygen species do notmediate NF-kappaB activation [J]. EMBO J.,2003,22:3356-3366.
[142]Gunawardena K, Murray DK, Swope RE and Meikle AW. Inhibition of nuclearfactor kappaB induces apoptosis following treatment with tumor necrosis factoralpha and an antioxidant in human prostate cancer cells [J]. Cancer Detect. Prev.,2002,26:29-237.
[143]Hadjiolov D, Frank N, Moog C and Spirov K. Proline dithiocarbamate inhibitsN-nitrosodiethylamine induced liver carcinogenesis [J].J.Cancer Res. Clin.Oncol.,1992,118:401-404.
[144] Zhou P, Bogacki R, McReynolds L and Howley PM. Harnessing theubiquitination machinery to target the degradation of specific cellular proteins[J]. Mol. Cell,2000,6:751-756.
[145] Cong F, Zhang J, Pao W, Zhou P and Varmus H. A protein knockdown strategyto study the function of beta-catenin in tumorigenesis [J]. BMC Mol. Biol.,2003,4:10.
[146] Steeg, P. S.: Metastasis suppressors alter the signal transduction of cancercells[J]. Nat Rev Cancer,2003,3:55-63.
[147] Lee, Y., J. A. Macoskay, S. Korenchukx and K. J.Pientay: MIM, a potentialmetastasis suppressor gene in bladder cancer[J]. Neoplasia,2002,4:291-294.
[148] Nixdorf, S., M. Grimm, R. Loberg, A. Marreiros, P. J.Russell, K. J. Pienta, andP. Jackson: Expression and regulation of MIM (missing in metastasis), a novelputative metastasis suppressor gene, and MIM-B, in bladder cancer cell lines[J].Cancer Lett,2004,215:209-220.
[149] Utikal1, J., A. Gratchev, I. Muller-Molinet, S. Oerther, J.Kzhyshkowska, N.Arens, R. Grobholz, S. Kannookadan and S. Goerdt: The expression ofmetastasis suppressor MIM/MTSS1is regulated by DNA methylation[J]. Int JCancer,2006,119:2287-2293.
[150] Loberg, R. D., C. K. Neeley, L. L. Adam-day, Y.Fridman, L. N. St John, S.Nixdorf, P. Jackson, L. M. Kalikin and K. J. Pienta: Differential expressionanalysis of MIM (MTSS1) splice variants and a functional role of MIM inprostate cancer cell biology[J]. Int J Oncol,2005,26:1699-1705.
[151] Bompard, G., S. J. Sharp, G. Freiss and L. M. Machesky:Involvement of Rac inactin cytoskeleton rearrangements induced by MIM-B[J]. J Cell Sci,2005,118:5393-5403.
[152] Lin, J., J. Liu, Y. Wang, J. Zhu, K. Zhou, N. Smith and X. Zhan: Differentialregulation of cortactin and N-WASPmediated actin polymerization by missingin metastasis (MIM) protein[J]. Oncogene,2005,24:2059-2066.
[153] Yamagishi, A., M. Masuda, T. Ohki, H. Onishi, and N.Mochizuki: A novelactin bundling/filopodium-forming domain conserved in insulin receptortyrosine kinase substrate p53and missing in metastasis protein[J]. J Biol Chem,2004,279:14929-14936.
[154] Mattila, P. K., M. Salminen, T. Yamashiro, and P.Lappalainen: Mouse MIM, atissue-specific regulator of cytoskeletal dynamics, interacts with ATP-actinmonomers through its C-terminal WH2domain[J]. J Biol Chem,2003,278:8452-8459.
[155] Woodings, J. A., S. J. Sharp and L. M. Machesky:MIM-B, a putative metastasissuppressor protein, binds to actin and to protein tyrosine phosphatase delta[J].Biochem J,2003,371:463-471.
[156] Wang, Y., K. Zhou, X. Zeng, J. Lin, and X. Zhan:Tyrosine phosphorylation ofmissing in metastasis protein is implicated in platelet-derived growthfactor-mediated cell shape changes[J]. J Biol Chem,2007,282:7624-7631.
[157] Callahan, C. A., T. Ofstad, L. Horng, J. K. Wang, H. H.Zhen, P. A. Coulombe,and A. E. Oro: MIM/BEG4, a Sonic hedgehog-responsive gene that potentiatesGli-dependent transcription[J]. Genes Dev,2004,18:2724-2729.
[158] Ma, S., X Guan, T. K. Lee, and K. W. Chan:Clinicopathological significance ofmissing in metastasis B expression in hepatocellular carcinoma[J]. Hum Pathol,2007,38:1201-1206.
[159] Parr, C., W. G. Jiang: Metastasis suppressor1(MTSS1) demonstratesprognostic value and anti-metastatic properties in breast cancer[J]. Eur J Cancer,2009,45:1673-1683.
[160] Wang, Y., J. Liu, E. Smith, K. Zhou, J. Liao, G.Yang, M. Tan and X. Zhan:Downregulation of missing in metastasis Gene (MIM) is associated with theprogression of bladder transitional carcinomas[J]. Cancer Invest,2007,25:79-86.
[161] Yamashita, S., Y. Tsujino, K. Moriguchi, M.Tatematsu, T. Ushijima: Chemicalgenomic screening for methylation-silenced genes in gastric cancer cell linesusing5-aza-20deoxycytidine treatment and oligonucleotide microarray[J].Cancer Sci,2006,97:64-71.
[162]Fei Xie, Lin Ye, Martin TA, Lijian Zhang, Wen G. Jiang. MTSS1: amultifunctional protein and its role in cancer invasion and metastasis[J]. FrontBiosci (Schol Ed),2011,3:621-631
[163] Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ and Harper JW.SCFbeta-TRCP links Chk1signaling to degradation of the Cdc25A proteinphosphatase[J]. Genes Dev,2003,17:3062-3074.
[164]Spiegelman VS, Tang W, Chan AM, Igarashi M, Aaronson SA, Sassoon DA,Katoh M, Slaga TJ and Fuchs SY. Induction of homologue of Slimb ubiquitinligase receptor by mitogen signaling[J]. J Biol Chem,2002,277:36624-36630.
[165] Knippschild U, Wolff S, Giamas G, Brockschmidt C, Wittau M, Wurl PU,Eismann T and Stoter M. The role of the casein kinase1(CK1) family indifferent signaling pathways linked to cancer development[J]. Onkologie,2005,28:508-514.
[166] Brockschmidt C, Hirner H, Huber N, Eismann T, Hillenbrand A, Giamas G,Radunsky B, Ammerpohl O, Bohm B, Henne-Bruns D, Kalthoff H, LeithauserF, Trauzold A and Knippschild U. Anti-apoptotic and growth-stimulatoryfunctions of CK1delta and epsilon in ductal adenocarcinoma of the pancreasare inhibited by IC261in vitro and in vivo[J]. Gut,2008,57:799-806.
[167] Hirner H, Gunes C, Bischof J, Wolff S, Grothey A, Kuhl M, Oswald F,Wegwitz F, Bosl MR, Trauzold A, Henne-Bruns D, Peifer C, Leithauser F,Deppert W and Knippschild U. Impaired CK1delta activity attenuatesSV40-induced cellular transformation in vitro and mouse mammarycarcinogenesis in vivo[J]. PLoS One,2012,7:e29709.
[168]Fuchs SY, Spiegelman VS and Kumar KG. The many faces of beta-TrCP E3ubiquitin ligases: reflections in the magic mirror of cancer[J]. Oncogene,2004,23:2028-2036.
[169]Lau AW, Fukushima H and Wei W. The Fbw7and betaTRCP E3ubiquitinligases and their roles in tumorigenesis[J]. Front Biosci (Landmark Ed),2012,17:2197-2212.
[170]Dawson JC, Bruche S, Spence HJ, Braga VM and Machesky LM. Mtss1promotes cell-cell junction assembly and stability through the small GTPaseRac1[J]. PLoS One,2012,7:e31141.
[171] Dawson JC, Timpson P, Kalna G and Machesky LM. Mtss1regulates epidermalgrowth factor signaling in head and neck squamous carcinoma cells[J].Oncogene,2012,31:1781-1793.
[2] Nalepa G, Rolfe M, Harper JW. Drug discovery in the ubiquitin-proteasomesystem[J]. Nat Rev Drug Discov,2006,5:596-613.
[3] Ravid T, Hochstrasser M. Diversity of degradation signals in theubiquitin-proteasome system[J]. Nat Rev Mol Cell Biol,2008,9:679-690.
[4] Hershko A, Ciechanover A. The ubiquitin system[J]. Annu Rev Biochem,1998,67:425-479.
[5] Nagy V, Dikic I. Ubiquitin ligase complexes: from substrate selectivity toconjugational specificity[J]. Biol Chem,2010,391:163-169.
[6] Zhao Y, Sun Y. Cullin-RING ligases (CRLs) as attractive anti-cancer targets[J].Curr Pharm Des,2013,19:3215-3225.
[7] Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16E6andE6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination ofp53[J]. Cell,1993,75:495-505.
[8] Lipkowitz S, Weissman AM. RINGs of good and evil: RING finger ubiquitinligases at the crossroads of tumour suppression and oncogenesis[J]. Nat RevCancer,2011,11:629-643.
[9] Chau V, Tobias JW, Bachmair A, et al. A multiubiquitin chain is confined tospecific lysine in a targeted short-lived protein[J]. Science,1989,243:1576-1583.
[10] Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatorypathways[J]. Annu Rev Biochem,2009,78:769-796.
[11] Spence J, Gali RR, Dittmar G, et al. Cell cycle-regulated modification of theribosome by a variant multiubiquitin chain[J]. Cell,2000,102:67-76.
[12] Ulrich HD, Walden H. Ubiquitin signalling in DNA replication and repair[J]. NatRev Mol Cell Biol,2010,11:479-489.
[13] Acconcia F, Sigismund S, Polo S. Ubiquitin in trafficking: the network atwork[J]. Exp Cell Res,2009,315:1610-1618.
[14] Hicke L. Protein regulation by monoubiquitin[J]. Nat Rev Mol Cell Biol,2001,2:195-201.
[15] Weihua Zhou, Wenyi Wei, Yi Sun. Genetically engineered mouse models forfunctional studies of SKP1-CUL1-F-box-protein (SCF) E3ubiquitin ligases[J].Cell Research,2013,23:599-619.
[16] Jin J, Li X, Gygi SP, Harper JW. Dual E1activation systems for ubiquitindifferentially regulate E2enzyme charging[J]. Nature,2007,447:1135–1138.
[17] van Wijk SJ, Timmers HT. The family of ubiquitin-conjugating enzymes (E2s):deciding between life and death of proteins[J]. FASEB J,2010,24:981–993.
[18] Metzger MB, Hristova VA, Weissman AM. HECT and RING finger families ofE3ubiquitin ligases at a glance[J]. J Cell Sci,2012,125:531–537.
[19] Matsumoto ML, Wickliffe KE, Dong KC, et al. K11-linked polyubiquitination incell cycle control revealed by a K11linkage-specific antibody[J]. Mol Cell,2010,39:477–484.
[20] Komander D, Rape M. The ubiquitin code[J]. Annu Rev Biochem,2012,81:203–229.
[21] Min Shen, Sara Schmitt, Daniela Buac, and Q Ping Dou, PhD. Targeting theubiquitin–proteasome system for cancer therapy[J]. Expert Opin Ther Targets,2013,17:1091–1108.
[22] Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway:destruction for the sake of construction[J]. Physiol Rev,2002,82:373–428.
[23] Goldberg AL, Akopian TN, Kisselev AF, et al. New insights into themechanisms and importance of the proteasome in intracellular proteindegradation[J]. Biol Chem,1997,378:131–140.
[24] Gallastegui N, Groll M. The26S proteasome: assembly and function of adestructive machine[J]. Trends Biochem Sci,2010,35:634–642.
[25] Strehl B, Seifert U, Kruger E, et al. Interferon-gamma, the functional plasticity ofthe ubiquitinproteasome system, and MHC class I antigen processing[J].Immunol Rev,2005,207:19–30.
[26] Angeles A, Fung G, Luo H. Immune and non-immune functions of theimmunoproteasome[J]. Front Biosci,2012,17:1904–1916.
[27] Fraile JM, Quesada V, Rodriguez D, et al. Deubiquitinases in cancer: newfunctions and therapeutic options[J]. Oncogene,2012,31:2373–2388.
[28] Deshaies RJ, Joazeiro CA. RING domain E3ubiquitin ligases[J]. Annu RevBiochem,2009,8:399-434.
[29] Sarikas A, Hartmann T, Pan ZQ. The cullin protein family[J]. Genome Biol,2011,12:220.
[30] Willems AR, Schwab M, Tyers M. A hitchhiker’s guide to the cullin ubiquitinligases: SCF and its kin[J]. Biochim Biophys Acta,2004,1695:133-170.
[31] Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. A complex of Cdc4p, Skp1p,and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitorSic1p[J]. Cell,1997,91:221-230.
[32] Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW.F-box proteins arereceptors that recruit phosphorylated substrates to the SCF ubiquitin-ligasecomplex[J]. Cell,1997,91:209-219.
[33] Bai C, Sen P, Hofmann K, et al. SKP1connects cell cycle regulators to theubiquitin proteolysis machinery through a novel motif, the F-box[J]. Cell,1996,86:263-274.
[34] Kamura T, Conrad MN, Yan Q, Conaway RC, Conaway JW. The Rbx1subunitof SCF and VHL E3ubiquitin ligase activates Rub1modification of cullinsCdc53and Cul2[J]. Genes Dev,1999,13:2928-2933.
[35] Ohta T, Michel JJ, Schottelius AJ, Xiong Y. ROC1, a homolog of APC11,represents a family of cullin partners with an associated ubiquitin ligaseactivity[J]. Mol Cell,1999,3:535-541.
[36] Seol JH, Feldman RMR, Zachariae WZ, et al. Cdc53/cullin and the essential Hrt1RING-H2subunit of SCF define a ubiquitin ligase module that activates the E2enzyme Cdc34[J]. Genes Dev,1999,13:1614-1626.
[37] Tan P, Fuchs SY, Chen A, et al. Recruitment of a ROC1-CUL1ubiquitin ligaseby Skp1and HOS to catalyze the ubiquitination of IκBα[J]. Mol Cell1999,3:527-533.
[38] Duan H, Wang Y, Aviram M, et al. SAG, a novel zinc RING finger protein thatprotects cells from apoptosis induced by redox agents[J]. Mol Cell Biol,1999,19:3145-3155.
[39] Swaroop M, Wang Y, Miller P, et al. Yeast homolog of humanSAG/ROC2/Rbx2/Hrt2is essential for cell growth, but not for germination:Chip profiling implicates its role in cell cycle regulation[J]. Oncogene,2000,19:2855-2866.
[40] Zheng N, Schulman BA, Song L, et al. Structure of the Cul1-Rbx1-Skp1-FboxSkp2SCF ubiquitin ligase complex[J]. Nature,2002,416:703-709.
[41] Cardozo T, Pagano M. The SCF ubiquitin ligase: insights into a molecularmachine[J]. Nat Rev Mol Cell Biol,2004,5:739-751.
[42] Wu K, Chen A, Pan ZQ. Conjugation of Nedd8to CUL1enhances the ability ofthe ROC1-CUL1complex to promote ubiquitin polymerization[J]. J Biol Chem,2000,275:32317-32324.
[43] Yen HC, Elledge SJ. Identification of SCF ubiquitin ligase substrates by globalprotein stability profiling[J]. Science,2008,322:923-929.
[44] Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer[J].Nat Rev Cancer,2006,6:369-381.
[45] Silverman JS, Skaar JR, Pagano M. SCF ubiquitin ligases in the maintenance ofgenome stability[J]. Trends Biochem Sci,2012,37:66-73.
[46] Jia L, Sun Y. SCF E3ubiquitin ligases as anticancer targets[J]. Curr Cancer DrugTargets,2011,11:347-356.
[47] Zhang H, Kobayashi R, Galaktionov K, Beach D. p19Skp1and p45Skp2areessential elements of the cyclin A-CDK2S phase kinase[J]. Cell,1995,82:915-925.
[48] Galan JM, Wiederkehr A, Seol JH, et al. Skp1p and the Fbox protein Rcy1p forma non-SCF complex involved in recycling of the SNARE Snc1p in yeast[J]. MolCell Biol,2001,21:3105-3117.
[49] Jourdain I, Spielewoy N, Thompson J, et al. Identification of a conserved F-boxprotein6interactor essential for endocytosis and cytokinesis in fission yeast[J].Biochem J,2009,420:169-177.
[50] Piva R, Liu J, Chiarle R, et al. In vivo interference with Skp1function leads togenetic instability and neoplastic transformation[J]. Mol Cell Biol,2002,22:8375-8387.
[51] Mandel SA, Fishman-Jacob T, Youdim MB. Modeling sporadic Parkinson’sdisease by silencing the ubiquitin E3ligase component, SKP1A[J].Parkinsonism Relat Disord,2009,15:S148-S151.
[52] Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock EM.cul-1is required forcell cycle exit in C. elegans and identifies a novel gene family[J]. Cell,1996,85:829-839.
[53] Mathias N, Johnson SL, Winey M, et al. Cdc53p acts in concert with Cdc4p andCdc34p to control the G1-to-S-phase transition and identifies a conservedfamily of proteins[J]. Mol Cell Biol,1996,16:6634-6643.
[54] Duda DM, Borg LA, Scott DC, et al. Structural insights into NEDD8activationof cullin-RING ligases: conformational control of conjugation[J]. Cell,2008,134:995-1006.
[55] Goldenberg SJ, Cascio TC, Shumway SD, et al. Structure of theCand1-Cul1-Roc1complex reveals regulatory mechanisms for the assembly ofthe multisubunit cullin-dependent ubiquitin ligases[J]. Cell,2004,119:517-528.
[56] Dealy MJ, Nguyen KV, Lo J, et al. Loss of Cul1results in early embryoniclethality and dysregulation of cyclin E[J]. Nat Genet,1999,23:245-248.
[57] Wang Y, Penfold S, Tang X, et al. Deletion of the Cul1gene in mice causesarrest in early embryogenesis and accumulation of cyclin E[J]. Curr Biol,1999,9:1191-1194.
[58] Salon C, Brambilla E, Brambilla C, et al. Altered pattern of Cul-1proteinexpression and neddylation in human lung tumours: relationships with CAND1and cyclin E protein levels[J]. J Pathol,2007,213:303-310.
[59] Chen G, Cheng Y, Martinka M, Li G. Cul1expression is increased in early stagesof human melanoma[J]. Pigment Cell Melanoma Res,2010,23:572-574.
[60] Singer JD, Gurian-West M, Clurman B, Roberts JM. Cullin-3targets cyclin E forubiquitination and controls S phase in mammalian cells[J]. Genes Dev,1999,13:2375-2387.
[61] McEvoy JD, Kossatz U, Malek N, Singer JD. Constitutive turnover of cyclin Eby Cul3maintains quiescence[J]. Mol Cell Biol,2007,27:3651-3666.
[62] Kossatz U, Breuhahn K, Wolf B, et al. The cyclin E regulator cullin3preventsmouse hepatic progenitor cells from becoming tumor-initiating cells[J]. J ClinInvest,2010,120:3820-3833.
[63] Mathew R, Seiler MP, Scanlon ST, et al. BTB-ZF factors recruit the E3ligasecullin3to regulate lymphoid effector programs[J]. Nature,2012,491:618-621.
[64] Siu KT, Rosner MR, Minella AC. An integrated view of cyclin E function andregulation[J]. Cell Cycle,2012,11:57-64.
[65] Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of theKeap1-Nrf2pathway in stress response and cancer evolution[J]. Genes Cells,2011,16:123-140.
[66] Loignon M, Miao W, Hu L, et al. Cul3overexpression depletes Nrf2in breastcancer and is associated with sensitivity to carcinogens, to oxidative stress, andto chemotherapy[J]. Mol Cancer Ther,2009,8:2432-2440.
[67] Yuan WC, Lee YR, Huang SF, et al. A Cullin3-KLHL20ubiquitinligase-dependent pathway targets PML to potentiate HIF-1signaling andprostate cancer progression[J]. Cancer Cell,2011,20:214-228.
[68] Haagenson KK, Tait L, Wang J, et al. Cullin-3protein expression levels correlatewith breast cancer progression[J]. Cancer Biol Ther,2012,13:1042-1046.
[69] Hammerman PS, Hayes DN, Wilkerson MD, et al. Comprehensive genomiccharacterization of squamous cell lung cancers[J]. Nature,2012,489:519-525.
[70] Boyden LM, Choi M, Choate KA, et al. Mutations in kelchlike3and cullin3cause hypertension and electrolyte abnormalities[J]. Nature,2012,482:98-102.
[71] Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHLmediateddestruction by proline hydroxylation: implications for O2sensing[J]. Science,2001,292:464-468.
[72] Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the vonHippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation[J].Science,2001,292:468-472.
[73] Laszlo GS, Cooper JA. Restriction of Src activity by Cullin-5[J]. Curr Biol,2009,19:157-162.
[74] Lee J, Zhou P. Cullins and cancer[J]. Genes Cancer,2010,1:690-699.
[75] Sun Y, Li H. Functional characterization of SAG/RBX2/ROC2/RNF7, anantioxidant protein and an E3ubiquitin ligase[J]. Protein Cell,2013,4:103-116.
[76] Park SW, Chung NG, Hur SY, et al. Mutational analysis of hypoxia-related genesHIF1alpha and CUL2in common human cancers[J]. APMIS,2009,117:880-885.
[77] Jackson S, Xiong Y. CRL4s: the CUL4-RING E3ubiquitin ligases[J]. TrendsBiochem Sci,2009,34:562-570.
[78] Liu L, Lee S, Zhang J, et al. CUL4A abrogation augments DNA damageresponse and protection against skin carcinogenesis[J]. Mol Cell,2009,34:451-460.
[79] Li B, Ruiz JC, Chun KT. CUL-4A is critical for early embryonic development[J].Mol Cell Biol,2002,22:4997-5005.
[80] Kopanja D, Stoyanova T, Okur MN, et al. Proliferation defects and genomeinstability in cells lacking Cul4A[J]. Oncogene,2009,28:2456-2465.
[81] Kopanja D, Roy N, Stoyanova T, et al. Cul4A is essential for spermatogenesisand male fertility[J]. Dev Biol,2011,352:278-287.
[82] Yin Y, Lin C, Kim ST, et al. The E3ubiquitin ligase Cullin4A regulates meioticprogression in mouse spermatogenesis[J]. Dev Biol,2011,356:51-62.
[83] Jiang B, Zhao W, Yuan J, et al. Lack of Cul4b, an E3ubiquitin ligase component,leads to embryonic lethality and abnormal placental development[J]. PLoS One,2012,7:e37070.
[84] Liu L, Yin Y, Li Y, et al. Essential role of the CUL4B ubiquitin ligase inextra-embryonic tissue development during mouse embryogenesis[J]. Cell Res,2012,22:1258-1269.
[85] Wei D, Sun Y. Small RING finger proteins RBX1and RBX2of SCF E3ubiquitin ligases: the role in cancer and as cancer targets[J]. Genes Cancer,2010,1:700-707.
[86] Schindl M, Gnant M, Schoppmann SF, Horvat R, Birner P. Overexpression ofthe human homologue for Caenorhabditis elegans cul-4gene is associated withpoor outcome in nodenegative breast cancer[J]. Anticancer Res,2007,27:949-952.
[87] Tarpey PS, Raymond FL, O’Meara S, et al. Mutations in CUL4B, which encodesa ubiquitin E3ligase subunit, cause an X-linked mental retardation syndromeassociated with aggressive outbursts, seizures, relative macrocephaly, centralobesity, hypogonadism, pes cavus, and tremor[J]. Am J Hum Genet,2007,80:345-352.
[88] Zou Y, Liu Q, Chen B, et al. Mutation in CUL4B, which encodes a member ofcullin-RING ubiquitin ligase complex,causes X-linked mental retardation[J].Am J Hum Genet,2007,80:561-566.
[89] Zhao Y, Sun Y. CUL4B ubiquitin ligase in mouse development: a model forhuman X-linked mental retardation syndrome?[J]. Cell Res,2012,22:1224-1226.
[90] Li T, Hung MS, Wang Y, et al. Transgenic mice for creinducible overexpressionof the Cul4A gene[J]. Genesis,2011,49:134-141.
[91] Arai T, Kasper JS, Skaar JR, et al. Targeted disruption of p185/Cul7gene resultsin abnormal vascular morphogenesis[J]. Proc Natl Acad Sci USA,2003,100:9855-9860.
[92] Skaar JR, Arai T, DeCaprio JA. Dimerization of CUL7and PARC is not requiredfor all CUL7functions and mouse development[J]. Mol Cell Biol,2005,25:5579-5589.
[93] Huber C, Dias-Santagata D, Glaser A, et al. Identification of mutations in CUL7in3-M syndrome[J]. Nat Genet,2005,37:1119-1124.
[94] Sasaki K, Okamoto N, Kosaki K, et al. Maternal uniparental isodisomy andheterodisomy on chromosome6encompassing a CUL7gene mutation causing3M syndrome[J]. Clin Genet,2011,80:478-483.
[95] Maksimova N, Hara K, Miyashia A, et al. Clinical, molecular andhistopathological features of short stature syndrome with novel CUL7mutationin Yakuts: new population isolate in Asia[J]. J Med Genet,2007,44:772-778.
[96] Guo G, Gui Y, Gao S, et al. Frequent mutations of genes encodingubiquitin-mediated proteolysis pathway components in clear cell renal cellcarcinoma[J]. Nat Genet,2012,44:17-19.
[97] Jin J, Cardozo T, Lovering RC, et al. Systematic analysis and nomenclature ofmammalian F-box proteins[J]. Genes Dev,2004,18:2573-2580.
[98] Cenciarelli C, Chiaur DS, Guardavaccaro D, et al. Identification of a family ofhuman F-box proteins[J]. Curr Biol,1999,9:1177-1179.
[99] Winston JT, Koepp DM, Zhu C, Elledge SJ, Harper JW.A family of mammalianF-box proteins[J]. Curr Biol,1999,9:1180-1182.
[100] Yoshida Y, Chiba T, Tokunaga F, et al. E3ubiquitin ligase that recognizessugar chains[J]. Nature,2002,418:438-442.
[101] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2andbeta-TrCP: tipping the scales of cancer[J]. Nat Rev Cancer,2008,8:438-449.
[102] Harper JW, Tan MK. Ubiquitin pathway proteomics[J]. Mol Cell Proteomics,2012,11:1541-1550.
[103] Skaar JR, D’Angiolella V, Pagan JK, Pagano M. Snapshot: F box proteins II[J].Cell,2009,137:1358.
[104] Fuchs SY. The role of ubiquitin-proteasome pathway in oncogenic signaling [J].Cancer Biol. Ther.,2002,1:337-341.
[105]Joazeiro CA and Weissman AM. RING finger proteins: mediators of ubiquitinligase activity [J]. Cell,2002,102:549-552.
[106]Laney JD and Hochstrasser M. Substrate targeting in the ubiquitin system [J].Cell,1999,97:427-430.
[107]Jiang J and Struhl G. Regulation of the Hedgehog and Wingless signallingpathways by the F-box/WD40-repeat protein Slimb [J]. Nature,1998,391:493-496.
[108]Spevak W, Keiper BD, Stratowa C and Castanon MJ. Saccharomyces cerevisiaecdc15mutants arrested at a late stage in anaphase are rescued by XenopuscDNAs encoding N-ras or a protein with beta-transducin repeats [J]. Mol. CellBiol.,1993,13:4953-4966.
[109]Margottin F, Bour SP, Durand H, Selig L, Benichou S,Richard V, Thomas D,Strebel K and Benarous R. A novel human WD protein, h-beta TrCp, thatinteracts with HIV-1Vpu connects CD4to the ER degradation pathway throughan F-box motif [J]. Mol. Cell,1998,1:565-574.
[110]Bhatia N, Herter JR, Slaga TJ, Fuchs SY and Spiegelman VS. Mousehomologue of HOS (mHOS) is overexpressed in skin tumors and implicated inconstitutive activation of NF-kappaB [J]. Oncogene,2002,21:1501-1509.
[111] Ballarino M, Marchioni M and Carnevali F. The Xenopus laevis beta TrCP gene:genomic organization, alternative splicing,5' and3' region characterization andcomparison of its structure with that of human beta TrCP genes [J].Biochim.Biophys. Acta,2002,1577:81-92.
[112] Chiaur DS, Murthy S, Cenciarelli C, Parks W, Loda M,Inghirami G, DemetrickD and Pagano M. Five human genes encoding F-box proteins: chromosomemapping and analysis in human tumors [J]. Cytogenet. Cell Genet.,2000,88:255-258.
[113] Koike J, Sagara N, Kirikoshi H, Takagi A, Miwa T, Hirai M and Katoh M.Molecular cloning and genomic structure of the betaTRCP2gene onchromosome5q35.1[J]. Biochem. Biophys. Res. Commun.,2000,269:103-109.
[114]Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M,Furuichi K,Shikama H and Tanaka K. Homodimer of two F-box proteins betaTrCP1orbetaTrCP2binds to IkappaBalpha for signal-dependent ubiquitination [J]. J.Biol.Chem.,2000,275:2877-2884.
[115]Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L,Donzelli M,Margottin-Goguet F, Jackson PK, Yamasaki L and Pagano M. Control ofmeiotic and mitotic progression by the F box protein beta-Trcp1in vivo [J]. Dev.Cell,2003,4:799-812.
[116]Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S,Mercurio F,Manning AM, Ciechanover A and Ben-Neriah Y. Inhibition of NF-kappa-Bcellular function via specific targeting of the I-kappa-B-ubiquitin ligase [J].EMBO J.,1997,16:6486-6494.
[117]Aberle H, Bauer A, Stappert J, Kispert A and Kemler R. beta-catenin is a targetfor the ubiquitin-proteasome pathway [J]. EMBO J.,1997,16:3797-3804.
[118]Hattori K, Hatakeyama S, Shirane M, Matsumoto M and Nakayama K.Molecular dissection of the interactions among IkappaBalpha, FWD1, and Skp1required for ubiquitin-mediated proteolysis of IkappaBalpha [J].J. Biol. Chem.,1999,274:29641-29647.
[119]Orlicky S, Tang X, Willems A, Tyers M and Sicheri F. Structural basis forphosphodependent substrate selection and orientation by the SCFCdc4ubiquitinligase [J]. Cell,2003,112:243-256.
[120]Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW and Pavletich NP. Structureof a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding andlysine specificity of the SCF(beta-TrCP1) ubiquitin ligase [J]. Mol. Cell,2003,11:1445-1456.
[121]Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A, Allen H, HayRT, Ben-Neriah Y and Ley SC. betaTrCP-mediated proteolysis of NF-kappaB1p105requires phosphorylation of p105serines927and932[J]. Mol. Cell Biol.,2003,23:402-413.
[122] Kroll M, Margottin F, Kohl A, Renard P, Durand H,Concordet JP, Bachelerie F,Arenzana-Seisdedos F and Benarous R. Inducible degradation of IkappaBalphaby the proteasome requires interaction with the F-box protein h-betaTrCP [J]. J.Biol. Chem.,1999,274:7941-7945.
[123] Besnard-Guerin C, Belaidouni N, Lassot I, Segeral E, Jobart A, Marchal C andBenarous R. HIV-1Vpu sequesters beta-transducin repeat-containing protein(betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin andother SCFbetaTrCP substrates [J]. J. Biol. Chem.,2004,279:788-795.
[124]Tang W, Pavlish OA, Spiegelman VS, Parkhitko AA and Fuchs SY. Interactionof Epstein-Barr virus latent membrane protein1with SCFHOS/beta-TrCP E3ubiquitin ligase regulates extent of NF-kappaB activation [J]. J. Biol. Chem.,2003,278:48942-48949.
[125]Davis M, Hatzubai A, Andersen JS, Ben-Shushan E, Fisher GZ, Yaron A,Bauskin A, Mercurio F, Mann M and Ben-Neriah Y. Pseudosubstrate regulationof the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U [J]. Genes Dev.,2002,16:439-451.
[126]Nakayama K, Hatakeyama S, Maruyama SI, Kikuchi A, Onoe K, Good RA andNakayama KI [J]. Proc. Natl.Acad. Sci. USA,2003,100:8752-8757.
[127]Spiegelman VS, Stavropoulos P, Latres E, Pagano M, Ronai Z, Slaga TJ andFuchs SY. Impaired degradation of inhibitory subunit of NF-kappa B (I kappa B)and beta-catenin as a result of targeted disruption of the beta-TrCP1gene [J]. J.Biol. Chem.,2001,276:27152-27158.
[128]Spiegelman VS, Slaga TJ, Pagano M, Minamoto T, Ronai Z and Fuchs SY.Wnt/beta-catenin signaling induces the expression and activity of betaTrCPubiquitin ligase receptor [J]. Mol. Cell,2000,5:877-882.
[129]Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM,Byers S and GaynorRB. Regulation of beta-catenin function by the IkappaB kinases [J]. J. Biol.Chem.,2001,276:42276-42286.
[130]Bour S, Perrin C, Akari H and Strebel K. The human immunodeficiency virustype1Vpu protein inhibits NF-kappa B activation by interfering with betaTrCP-mediated degradation of Ikappa B [J]. J. Biol.Chem.,2001,276:15920-15928.
[131]Akari H, Bour S, Kao S, Adachi A and Strebel K. The human immunodeficiencyvirus type1accessory protein Vpu induces apoptosis by suppressing the nuclearfactor kappaB-dependent expression of antiapoptotic factors [J]. J.Exp. Med.,2001,194:1299-1311.
[132]Karin M, Cao Y, Greten FR and Li ZW. NF-kappaB in cancer: from innocentbystander to major culprit [J]. Nat. Rev.Cancer,2002,2:301-310.
[133]Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth [J].Nat. Rev. Immunol.,2002,2:664-674.
[134] Saitoh T and Katoh M. Expression profiles of betaTRCP1and betaTRCP2, andmutation analysis of betaTRCP2in gastric cancer [J]. Int. J. Oncol.,2001,18:959-964.
[135] Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B and Pestell RG. NF-kappaBand cell-cycle regulation: the cyclin connection [J]. Cytokine Growth FactorRev.,2001,12:73–90.
[136]Eldar-Finkelman H, Seger R, Vandenheede JR and Krebs EG. Inactivation ofglycogen synthase kinase-3by epidermal growth factor is mediated bymitogen-activated protein kinase/p90ribosomal protein S6kinase signalingpathway in NIH/3T3cells [J]. J. Biol. Chem.,1995,270:987-990.
[137] Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T,Ruzicka T and Reifenberger G. Molecular genetic analysis of malignantmelanomas for aberrations of the WNT signaling pathway genes CTNNB1,APC, ICAT and BTRC [J].Int J.Cancer,2002,100:549-556.
[138] Gerstein AV, Almeida TA, Zhao G, Chess E, Shih Ie M,Buhler K, Pienta K,Rubin MA, Vessella R and Papadopoulos N. APC/CTNNB1(beta-catenin)pathway alterations in human prostate cancers [J]. Genes Chromosomes Cancer,2002,34:9-16.
[139] Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX,Gelinas C and Rabson AB.Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells [J].Prostate,2002,52:83-200.
[140]Soldatenkov VA, Dritschilo A, Ronai Z and Fuchs SY. Inhibition of homologueof Slimb (HOS) function sensitizes human melanoma cells for apoptosis [J].Cancer Res.,1999,59:5085-5088.
[141]Hayakawa M, Miyashita H, Sakamoto I, Kitagawa M,Tanaka H, Yasuda H,Karin M and Kikugawa K. Evidence that reactive oxygen species do notmediate NF-kappaB activation [J]. EMBO J.,2003,22:3356-3366.
[142]Gunawardena K, Murray DK, Swope RE and Meikle AW. Inhibition of nuclearfactor kappaB induces apoptosis following treatment with tumor necrosis factoralpha and an antioxidant in human prostate cancer cells [J]. Cancer Detect. Prev.,2002,26:29-237.
[143]Hadjiolov D, Frank N, Moog C and Spirov K. Proline dithiocarbamate inhibitsN-nitrosodiethylamine induced liver carcinogenesis [J].J.Cancer Res. Clin.Oncol.,1992,118:401-404.
[144] Zhou P, Bogacki R, McReynolds L and Howley PM. Harnessing theubiquitination machinery to target the degradation of specific cellular proteins[J]. Mol. Cell,2000,6:751-756.
[145] Cong F, Zhang J, Pao W, Zhou P and Varmus H. A protein knockdown strategyto study the function of beta-catenin in tumorigenesis [J]. BMC Mol. Biol.,2003,4:10.
[146] Steeg, P. S.: Metastasis suppressors alter the signal transduction of cancercells[J]. Nat Rev Cancer,2003,3:55-63.
[147] Lee, Y., J. A. Macoskay, S. Korenchukx and K. J.Pientay: MIM, a potentialmetastasis suppressor gene in bladder cancer[J]. Neoplasia,2002,4:291-294.
[148] Nixdorf, S., M. Grimm, R. Loberg, A. Marreiros, P. J.Russell, K. J. Pienta, andP. Jackson: Expression and regulation of MIM (missing in metastasis), a novelputative metastasis suppressor gene, and MIM-B, in bladder cancer cell lines[J].Cancer Lett,2004,215:209-220.
[149] Utikal1, J., A. Gratchev, I. Muller-Molinet, S. Oerther, J.Kzhyshkowska, N.Arens, R. Grobholz, S. Kannookadan and S. Goerdt: The expression ofmetastasis suppressor MIM/MTSS1is regulated by DNA methylation[J]. Int JCancer,2006,119:2287-2293.
[150] Loberg, R. D., C. K. Neeley, L. L. Adam-day, Y.Fridman, L. N. St John, S.Nixdorf, P. Jackson, L. M. Kalikin and K. J. Pienta: Differential expressionanalysis of MIM (MTSS1) splice variants and a functional role of MIM inprostate cancer cell biology[J]. Int J Oncol,2005,26:1699-1705.
[151] Bompard, G., S. J. Sharp, G. Freiss and L. M. Machesky:Involvement of Rac inactin cytoskeleton rearrangements induced by MIM-B[J]. J Cell Sci,2005,118:5393-5403.
[152] Lin, J., J. Liu, Y. Wang, J. Zhu, K. Zhou, N. Smith and X. Zhan: Differentialregulation of cortactin and N-WASPmediated actin polymerization by missingin metastasis (MIM) protein[J]. Oncogene,2005,24:2059-2066.
[153] Yamagishi, A., M. Masuda, T. Ohki, H. Onishi, and N.Mochizuki: A novelactin bundling/filopodium-forming domain conserved in insulin receptortyrosine kinase substrate p53and missing in metastasis protein[J]. J Biol Chem,2004,279:14929-14936.
[154] Mattila, P. K., M. Salminen, T. Yamashiro, and P.Lappalainen: Mouse MIM, atissue-specific regulator of cytoskeletal dynamics, interacts with ATP-actinmonomers through its C-terminal WH2domain[J]. J Biol Chem,2003,278:8452-8459.
[155] Woodings, J. A., S. J. Sharp and L. M. Machesky:MIM-B, a putative metastasissuppressor protein, binds to actin and to protein tyrosine phosphatase delta[J].Biochem J,2003,371:463-471.
[156] Wang, Y., K. Zhou, X. Zeng, J. Lin, and X. Zhan:Tyrosine phosphorylation ofmissing in metastasis protein is implicated in platelet-derived growthfactor-mediated cell shape changes[J]. J Biol Chem,2007,282:7624-7631.
[157] Callahan, C. A., T. Ofstad, L. Horng, J. K. Wang, H. H.Zhen, P. A. Coulombe,and A. E. Oro: MIM/BEG4, a Sonic hedgehog-responsive gene that potentiatesGli-dependent transcription[J]. Genes Dev,2004,18:2724-2729.
[158] Ma, S., X Guan, T. K. Lee, and K. W. Chan:Clinicopathological significance ofmissing in metastasis B expression in hepatocellular carcinoma[J]. Hum Pathol,2007,38:1201-1206.
[159] Parr, C., W. G. Jiang: Metastasis suppressor1(MTSS1) demonstratesprognostic value and anti-metastatic properties in breast cancer[J]. Eur J Cancer,2009,45:1673-1683.
[160] Wang, Y., J. Liu, E. Smith, K. Zhou, J. Liao, G.Yang, M. Tan and X. Zhan:Downregulation of missing in metastasis Gene (MIM) is associated with theprogression of bladder transitional carcinomas[J]. Cancer Invest,2007,25:79-86.
[161] Yamashita, S., Y. Tsujino, K. Moriguchi, M.Tatematsu, T. Ushijima: Chemicalgenomic screening for methylation-silenced genes in gastric cancer cell linesusing5-aza-20deoxycytidine treatment and oligonucleotide microarray[J].Cancer Sci,2006,97:64-71.
[162]Fei Xie, Lin Ye, Martin TA, Lijian Zhang, Wen G. Jiang. MTSS1: amultifunctional protein and its role in cancer invasion and metastasis[J]. FrontBiosci (Schol Ed),2011,3:621-631
[163] Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ and Harper JW.SCFbeta-TRCP links Chk1signaling to degradation of the Cdc25A proteinphosphatase[J]. Genes Dev,2003,17:3062-3074.
[164]Spiegelman VS, Tang W, Chan AM, Igarashi M, Aaronson SA, Sassoon DA,Katoh M, Slaga TJ and Fuchs SY. Induction of homologue of Slimb ubiquitinligase receptor by mitogen signaling[J]. J Biol Chem,2002,277:36624-36630.
[165] Knippschild U, Wolff S, Giamas G, Brockschmidt C, Wittau M, Wurl PU,Eismann T and Stoter M. The role of the casein kinase1(CK1) family indifferent signaling pathways linked to cancer development[J]. Onkologie,2005,28:508-514.
[166] Brockschmidt C, Hirner H, Huber N, Eismann T, Hillenbrand A, Giamas G,Radunsky B, Ammerpohl O, Bohm B, Henne-Bruns D, Kalthoff H, LeithauserF, Trauzold A and Knippschild U. Anti-apoptotic and growth-stimulatoryfunctions of CK1delta and epsilon in ductal adenocarcinoma of the pancreasare inhibited by IC261in vitro and in vivo[J]. Gut,2008,57:799-806.
[167] Hirner H, Gunes C, Bischof J, Wolff S, Grothey A, Kuhl M, Oswald F,Wegwitz F, Bosl MR, Trauzold A, Henne-Bruns D, Peifer C, Leithauser F,Deppert W and Knippschild U. Impaired CK1delta activity attenuatesSV40-induced cellular transformation in vitro and mouse mammarycarcinogenesis in vivo[J]. PLoS One,2012,7:e29709.
[168]Fuchs SY, Spiegelman VS and Kumar KG. The many faces of beta-TrCP E3ubiquitin ligases: reflections in the magic mirror of cancer[J]. Oncogene,2004,23:2028-2036.
[169]Lau AW, Fukushima H and Wei W. The Fbw7and betaTRCP E3ubiquitinligases and their roles in tumorigenesis[J]. Front Biosci (Landmark Ed),2012,17:2197-2212.
[170]Dawson JC, Bruche S, Spence HJ, Braga VM and Machesky LM. Mtss1promotes cell-cell junction assembly and stability through the small GTPaseRac1[J]. PLoS One,2012,7:e31141.
[171] Dawson JC, Timpson P, Kalna G and Machesky LM. Mtss1regulates epidermalgrowth factor signaling in head and neck squamous carcinoma cells[J].Oncogene,2012,31:1781-1793.