FBW7(F-box and WD repeat domain-containing7)是F-box蛋白家族成员,为SCF(SKP1-CUL1-F-box)型泛素连接酶的靶蛋白识别组分。FBW7通过靶降解周期蛋白E、Myc、Jun等多种癌蛋白,对细胞周期进程、细胞生长、分化起重要调控作用。在多种人...FBW7(F-box and WD repeat domain-containing7)是F-box蛋白家族成员,为SCF(SKP1-CUL1-F-box)型泛素连接酶的靶蛋白识别组分。FBW7通过靶降解周期蛋白E、Myc、Jun等多种癌蛋白,对细胞周期进程、细胞生长、分化起重要调控作用。在多种人类肿瘤中已发现FBW7突变,FBW7功能缺失会引起染色体不稳定及肿瘤发生,表明FBW7是一种肿瘤抑制因子。在FBW7缺失所致的肿瘤发生过程中,周期蛋白E、Myc等靶蛋白活性升高、p53功能缺失有重要作用。展开更多
Krüppel-like factor(KLF) family proteins are transcription factors that regulate numerous cellular functions, such as cell proliferation, differentiation, and cell death. Posttranslational modification of KLF pro...Krüppel-like factor(KLF) family proteins are transcription factors that regulate numerous cellular functions, such as cell proliferation, differentiation, and cell death. Posttranslational modification of KLF proteins is important for their transcriptional activities and biological functions. One KLF family member with important roles in cell proliferation and tumorigenesis is KLF5. The function of KLF5 is tightly controlled by post-translational modifications, including SUMOylation, phosphorylation, and ubiquitination. Recent studies from our lab and others' have demonstrated that the tumor suppressor FBW7 is an essential E3 ubiquitin ligase that targets KLF5 for ubiquitination and degradation. KLF5 contains functional Cdc4 phospho-degrons(CPDs), which are required for its interaction with FBW7. Mutation of CPDs in KLF5 blocks the ubiquitination and degradation of KLF5 by FBW7. The protein kinase Glycogen synthase kinase 3β is involved in the phosphorylation of KLF5 CPDs. In both cancer cell lines and mousemodels, it has been shown that FBW7 regulates the expression of KLF5 target genes through the modulation of KLF5 stability. In this review, we summarize the current progress on delineating FBW7-mediated KLF5 ubiquitination and degradation.展开更多
BACKGROUND: FBW7 is a tumor suppressor which regulates a network of proteins with central roles in cell division, cell growth and differentiation. This study aimed to evaluate the role of FBW7in chemosensitivity and e...BACKGROUND: FBW7 is a tumor suppressor which regulates a network of proteins with central roles in cell division, cell growth and differentiation. This study aimed to evaluate the role of FBW7in chemosensitivity and epithelial-mesenchymal transition (EMT) in different hepatocellular carcinoma (HCC) cell lines and to investigate the relevant underlying mechanisms.METHODS: Different human HCC cell lines (Hep3B, Huh-7,and SNU-449) were cultured. The cell viability was evaluated by cell counting kit-8, and FBW7 mRNA transcription and protein expression were quantitated by real-time PCR and Western blotting. Expressions of vimentin (mesenchymal biomarker)and E-cadherin (epithelial biomarker) were evaluated by Western blotting and immunocytochemistry. Cell invasion was assayed by Transwell migration, and FBW7 plasmid or siRNA was used to evaluate the effect of FBW7 overexpression or silencing on cell chemosensitivity.RESULTS: FBW7 expression affected tumor cell chemosensitivity to doxorubicin and tumor cell invasive capacity in different HCC cell lines. FBW7hi (high FBW7 expression) Hep3B and FBW7mi (median FBW7 expression) Huh-7 cells were more sensitive to doxorubicin and lower in invasive capacity than FBW7lo (low FBW7 expression) SNU-449 cells. Silencing of FBW7in Huh-7 and Hep3B cells induced the resistance to doxorubicin and enhanced cell invasion, whereas overexpression of FBW7in SNU-449 cells restored the sensitivity to doxorubicin andsignificantly reduced invasive capacity. Furthermore, doxorubicin induced EMT toward mesenchyme in HCC cells. Downregulation of FBW7 in Huh-7 and Hep3B cells or upregulation of FBW7 in SNU-449 cells altered the direction of EMT.CONCLUSIONS: The level of FBW7 expression impacted the tumor resistance to doxorubicin and the invasion capability of HCC cells. FBW7 therefore may be a potential target for the chemotherapy of HCC through the regulation of EMT.展开更多
文摘FBW7(F-box and WD repeat domain-containing7)是F-box蛋白家族成员,为SCF(SKP1-CUL1-F-box)型泛素连接酶的靶蛋白识别组分。FBW7通过靶降解周期蛋白E、Myc、Jun等多种癌蛋白,对细胞周期进程、细胞生长、分化起重要调控作用。在多种人类肿瘤中已发现FBW7突变,FBW7功能缺失会引起染色体不稳定及肿瘤发生,表明FBW7是一种肿瘤抑制因子。在FBW7缺失所致的肿瘤发生过程中,周期蛋白E、Myc等靶蛋白活性升高、p53功能缺失有重要作用。
基金Supported by Grants from National Basic Research Program of China,973 program,No.2010CB529704 and No.2012CB910404National Natural Science Foundation of China,No.30800587,No.30971521,and No.31171338+1 种基金the Science and Technology Commission of Shanghai Municipality,No.11DZ2260300a scholar of the Shanghai Rising-Star Program from Science and Technology Commission of Shanghai Municipality,No.09QA1401900 to Wang P
文摘Krüppel-like factor(KLF) family proteins are transcription factors that regulate numerous cellular functions, such as cell proliferation, differentiation, and cell death. Posttranslational modification of KLF proteins is important for their transcriptional activities and biological functions. One KLF family member with important roles in cell proliferation and tumorigenesis is KLF5. The function of KLF5 is tightly controlled by post-translational modifications, including SUMOylation, phosphorylation, and ubiquitination. Recent studies from our lab and others' have demonstrated that the tumor suppressor FBW7 is an essential E3 ubiquitin ligase that targets KLF5 for ubiquitination and degradation. KLF5 contains functional Cdc4 phospho-degrons(CPDs), which are required for its interaction with FBW7. Mutation of CPDs in KLF5 blocks the ubiquitination and degradation of KLF5 by FBW7. The protein kinase Glycogen synthase kinase 3β is involved in the phosphorylation of KLF5 CPDs. In both cancer cell lines and mousemodels, it has been shown that FBW7 regulates the expression of KLF5 target genes through the modulation of KLF5 stability. In this review, we summarize the current progress on delineating FBW7-mediated KLF5 ubiquitination and degradation.
基金supported by grants from NationalHigh-Tech Research and Development Projects (863 Program)(2012AA021002)Organ Transplantation Key Technology Project(863 Program) (2012AA022409)Zhejiang Province NaturalScience Foundation (LQ12H03002 and LY12H03010)
文摘BACKGROUND: FBW7 is a tumor suppressor which regulates a network of proteins with central roles in cell division, cell growth and differentiation. This study aimed to evaluate the role of FBW7in chemosensitivity and epithelial-mesenchymal transition (EMT) in different hepatocellular carcinoma (HCC) cell lines and to investigate the relevant underlying mechanisms.METHODS: Different human HCC cell lines (Hep3B, Huh-7,and SNU-449) were cultured. The cell viability was evaluated by cell counting kit-8, and FBW7 mRNA transcription and protein expression were quantitated by real-time PCR and Western blotting. Expressions of vimentin (mesenchymal biomarker)and E-cadherin (epithelial biomarker) were evaluated by Western blotting and immunocytochemistry. Cell invasion was assayed by Transwell migration, and FBW7 plasmid or siRNA was used to evaluate the effect of FBW7 overexpression or silencing on cell chemosensitivity.RESULTS: FBW7 expression affected tumor cell chemosensitivity to doxorubicin and tumor cell invasive capacity in different HCC cell lines. FBW7hi (high FBW7 expression) Hep3B and FBW7mi (median FBW7 expression) Huh-7 cells were more sensitive to doxorubicin and lower in invasive capacity than FBW7lo (low FBW7 expression) SNU-449 cells. Silencing of FBW7in Huh-7 and Hep3B cells induced the resistance to doxorubicin and enhanced cell invasion, whereas overexpression of FBW7in SNU-449 cells restored the sensitivity to doxorubicin andsignificantly reduced invasive capacity. Furthermore, doxorubicin induced EMT toward mesenchyme in HCC cells. Downregulation of FBW7 in Huh-7 and Hep3B cells or upregulation of FBW7 in SNU-449 cells altered the direction of EMT.CONCLUSIONS: The level of FBW7 expression impacted the tumor resistance to doxorubicin and the invasion capability of HCC cells. FBW7 therefore may be a potential target for the chemotherapy of HCC through the regulation of EMT.
