β-转录重复包含蛋白1(β-transducin repeat containing protein 1,β-TrCP1)是一种E3泛素连接酶的底物识别亚基,能特异性识别泛素化底物,在细胞增殖、信号转导以及细胞周期进程中发挥重要作用。β-TrCP1蛋白表达异常或功能失调常使泛...β-转录重复包含蛋白1(β-transducin repeat containing protein 1,β-TrCP1)是一种E3泛素连接酶的底物识别亚基,能特异性识别泛素化底物,在细胞增殖、信号转导以及细胞周期进程中发挥重要作用。β-TrCP1蛋白表达异常或功能失调常使泛素化修饰异常,影响多种肿瘤的发生、发展。该文现对β-TrCP1在恶性肿瘤中的作用及相关分子机制进行综述。展开更多
Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumoursuppression, but whether its downregulation in cancers is associated with posttranslational regu...Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumoursuppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, weobserved that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with thesurvival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR)activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked β-TrCP overexpression- or HLTF knockdownmediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlatedwith elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCCcell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that theβ-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potentialtherapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis.展开更多
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmem- bran...Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmem- brane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled （FZD） receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin f-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiqui- tinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phos- phorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regu- lation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.展开更多
The Hippo signaling pathway was first discovered in Drosophila as a conserved regulator of organ size.Genetic inactivation in mice demonstrates that the Hippo pathway functions as a fundamental inhibitor of organ grow...The Hippo signaling pathway was first discovered in Drosophila as a conserved regulator of organ size.Genetic inactivation in mice demonstrates that the Hippo pathway functions as a fundamental inhibitor of organ growth during development,and as a critical tumor suppressor in epithelial tissues.展开更多
Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent stud...Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.展开更多
文摘β-转录重复包含蛋白1(β-transducin repeat containing protein 1,β-TrCP1)是一种E3泛素连接酶的底物识别亚基,能特异性识别泛素化底物,在细胞增殖、信号转导以及细胞周期进程中发挥重要作用。β-TrCP1蛋白表达异常或功能失调常使泛素化修饰异常,影响多种肿瘤的发生、发展。该文现对β-TrCP1在恶性肿瘤中的作用及相关分子机制进行综述。
基金supported by the Introduction of Special Funds for Talents from the Third Military Medical University(Army Medical University,4174C6)to C.-M.X.
文摘Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumoursuppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, weobserved that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with thesurvival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR)activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked β-TrCP overexpression- or HLTF knockdownmediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlatedwith elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCCcell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that theβ-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potentialtherapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis.
基金We thank Dr. W. Wei as well as the He and Wei lab members for critical discussion and reading of the manuscript. X. Ci received financial supporc from the China Scholarship Council （CSC） （No.201606120241）. X. Dai is supported by National Research Service Award T-32 training grant. This work was partly supported by the National Natural Science Foundation of China No. 31571323 to Y. Li. X. He acknowledges support by NIH （RO1-GM057603） and by Boston Children＇s Hospital Intellectual and Developmental Disabili- ties Research Center （P30 HD-18655）. X. He is an American Cancer Society Research Professor.
文摘Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmem- brane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled （FZD） receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin f-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiqui- tinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phos- phorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regu- lation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.
基金supported in part by research grants from the National Institutes of Health(AT004418 and CA106569 to TCH).
文摘The Hippo signaling pathway was first discovered in Drosophila as a conserved regulator of organ size.Genetic inactivation in mice demonstrates that the Hippo pathway functions as a fundamental inhibitor of organ growth during development,and as a critical tumor suppressor in epithelial tissues.
基金supported by grants from the National Natural Science Foundation of China(82173853,82173379,82373914,82073892)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2022-I2M-2-002,2021-I2M-1e026 and 2021-I2M-1e016,China)+2 种基金CAMS Central Public-interest Scientific Institution Basal Research Fund(2018PT35004,China)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China)Peking Union Medical College Graduate Innovation Fund(2019-1007-05,China).
文摘Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.
