BACKGROUND BIR repeat-containing ubiquitin conjugating enzyme(BRUCE)is a liver tumor suppressor,which is downregulated in a large number of patients with liver diseases.BRUCE facilitates DNA damage repair to protect t...BACKGROUND BIR repeat-containing ubiquitin conjugating enzyme(BRUCE)is a liver tumor suppressor,which is downregulated in a large number of patients with liver diseases.BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine(DEN)-dependent acute liver injury and carcinogenesis.While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma(HCC),DEN exposure alone does not induce robust hepatic fibrosis.Further studies are warranted to identify new suppressive mechanisms contributing to DEN-induced fibrosis and HCC.AIM To investigate the suppressive mechanisms of BRUCE in hepatic fibrosis and HCC development.METHODS Male C57/BL6/J control mice[loxp/Loxp;albumin-cre(Alb-cre)-]and BRUCE Alb-Cre KO mice(loxp/Loxp;Alb-Cre+)were injected with a single dose of DEN at postnatal day 15 and sacrificed at different time points to examine liver disease progression.RESULTS By using a liver-specific BRUCE knockout(LKO)mouse model,we found that BRUCE deficiency,in conjunction with DEN exposure,induced hepatic fibrosis in both premalignant as well as malignant stages,thus recapitulating the chronic fibrosis background often observed in HCC patients.Activated in fibrosis and HCC,β-catenin activity depends on its stabilization and subsequent translocation to the nucleus.Interestingly,we observed that livers from BRUCE KO mice demonstrated an increased nuclear accumulation and elevated activity ofβ-catenin in the three stages of carcinogenesis:Pre-malignancy,tumor initiation,and HCC.This suggests that BRUCE negatively regulatesβ-catenin activity during liver disease progression.β-catenin can be activated by phosphorylation by protein kinases,such as protein kinase A(PKA),which phosphorylates it at Ser-675(pSer-675-β-catenin).Mechanistically,BRUCE and PKA were colocalized in the cytoplasm of hepatocytes where PKA activity is maintained at the basal level.However,in BRUCE deficient mouse livers or a human liver cancer cell line,both PKA activity and pSer-675-β-catenin levels were observed to be elevated.CONCLUSION Our data support a“BRUCE-PKA-β-catenin”signaling axis in the mouse liver.The BRUCE interaction with PKA in hepatocytes suppresses PKA-dependent phosphorylation and activation ofβ-catenin.This study implicates BRUCE as a novel negative regulator of both PKA andβ-catenin in chronic liver disease progression.Furthermore,BRUCE-liver specific KO mice serve as a promising model for understanding hepatic fibrosis and HCC in patients with aberrant activation of PKA andβ-catenin.展开更多
国际回收局(BIR)负责人Ranj it Baxi宣布,将2018年的3月18日设为首个'世界回收日'。这一天也标志着BIR创建70周年。Baxi说'我很高兴宣布这个非常重要的日期,我们想利用这一天来促进世界各地的回收行动。我们的成员都是行业...国际回收局(BIR)负责人Ranj it Baxi宣布,将2018年的3月18日设为首个'世界回收日'。这一天也标志着BIR创建70周年。Baxi说'我很高兴宣布这个非常重要的日期,我们想利用这一天来促进世界各地的回收行动。我们的成员都是行业中最负盛名的回收公司。展开更多
Large-scale genetic population used for genetic breeding researches covers a large area in the field experiment,and the effect of local control would be gradually weakened.The block in replication(BIR)design is suitab...Large-scale genetic population used for genetic breeding researches covers a large area in the field experiment,and the effect of local control would be gradually weakened.The block in replication(BIR)design is suitable for large population,which is applied to the field experiment of genetic population.The statistical methods of analysis of variance(ANOVA)and heritability estimation in single and multiple environments were derived and implemented using the statistical analysis system(SAS)program for the analysis of BIR.As a work example,a comparison of statistical analysis between BIR design and the completely random block(CRB)design were conducted for the protein content from a panel containing 455 soybean germplasms.The results indicated the different estimates of average heritability in multiple environments.The research results provided technical support for the application of BIR design in genetics and breeding studies.展开更多
IAP(inhibitor of apoptosis)是内源性凋亡抑制蛋白家族,其中效力最强的是X连锁凋亡抑制蛋白(X chromosome linked inhibitor of apoptosis protein,XIAP)。它主要通过BIR结构域和RING锌指结构域抑制caspase活性、调节核因子NF2κB并参...IAP(inhibitor of apoptosis)是内源性凋亡抑制蛋白家族,其中效力最强的是X连锁凋亡抑制蛋白(X chromosome linked inhibitor of apoptosis protein,XIAP)。它主要通过BIR结构域和RING锌指结构域抑制caspase活性、调节核因子NF2κB并参与信号的转导过程。XIAP受到不均一核糖核酸蛋白C1和C2等的正向调节和XAF1和Smac/DIABLO等的负向调节。近年来XIAP在临床方面的研究也取得了很大进展。展开更多
基金Supported by NIH(Du CY),No.R21CA241025-01NIH(Du CY),No.RO1CA158323+3 种基金NCI RO1 Diversity Supplement(Du CY),No.R01CA158323-05SNational Center for Advancing Translational Sciences of the National Institutes of Health(Du CY),No.2UL1TR001425-05A1University of Cincinnati Center for Environmental Genetics-NIH/NIEHS Award(Du CY),No.P30 ES006096Pathways to Cancer Therapeutics T32(Du CY and Vilfranc CL),No.CA117846-12.
文摘BACKGROUND BIR repeat-containing ubiquitin conjugating enzyme(BRUCE)is a liver tumor suppressor,which is downregulated in a large number of patients with liver diseases.BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine(DEN)-dependent acute liver injury and carcinogenesis.While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma(HCC),DEN exposure alone does not induce robust hepatic fibrosis.Further studies are warranted to identify new suppressive mechanisms contributing to DEN-induced fibrosis and HCC.AIM To investigate the suppressive mechanisms of BRUCE in hepatic fibrosis and HCC development.METHODS Male C57/BL6/J control mice[loxp/Loxp;albumin-cre(Alb-cre)-]and BRUCE Alb-Cre KO mice(loxp/Loxp;Alb-Cre+)were injected with a single dose of DEN at postnatal day 15 and sacrificed at different time points to examine liver disease progression.RESULTS By using a liver-specific BRUCE knockout(LKO)mouse model,we found that BRUCE deficiency,in conjunction with DEN exposure,induced hepatic fibrosis in both premalignant as well as malignant stages,thus recapitulating the chronic fibrosis background often observed in HCC patients.Activated in fibrosis and HCC,β-catenin activity depends on its stabilization and subsequent translocation to the nucleus.Interestingly,we observed that livers from BRUCE KO mice demonstrated an increased nuclear accumulation and elevated activity ofβ-catenin in the three stages of carcinogenesis:Pre-malignancy,tumor initiation,and HCC.This suggests that BRUCE negatively regulatesβ-catenin activity during liver disease progression.β-catenin can be activated by phosphorylation by protein kinases,such as protein kinase A(PKA),which phosphorylates it at Ser-675(pSer-675-β-catenin).Mechanistically,BRUCE and PKA were colocalized in the cytoplasm of hepatocytes where PKA activity is maintained at the basal level.However,in BRUCE deficient mouse livers or a human liver cancer cell line,both PKA activity and pSer-675-β-catenin levels were observed to be elevated.CONCLUSION Our data support a“BRUCE-PKA-β-catenin”signaling axis in the mouse liver.The BRUCE interaction with PKA in hepatocytes suppresses PKA-dependent phosphorylation and activation ofβ-catenin.This study implicates BRUCE as a novel negative regulator of both PKA andβ-catenin in chronic liver disease progression.Furthermore,BRUCE-liver specific KO mice serve as a promising model for understanding hepatic fibrosis and HCC in patients with aberrant activation of PKA andβ-catenin.
基金Supported by Key Research and Development Project of Heilongjiang Province(GA21B009-6)Heilongjiang Province Natural Science Foundation(C2015009)。
文摘Large-scale genetic population used for genetic breeding researches covers a large area in the field experiment,and the effect of local control would be gradually weakened.The block in replication(BIR)design is suitable for large population,which is applied to the field experiment of genetic population.The statistical methods of analysis of variance(ANOVA)and heritability estimation in single and multiple environments were derived and implemented using the statistical analysis system(SAS)program for the analysis of BIR.As a work example,a comparison of statistical analysis between BIR design and the completely random block(CRB)design were conducted for the protein content from a panel containing 455 soybean germplasms.The results indicated the different estimates of average heritability in multiple environments.The research results provided technical support for the application of BIR design in genetics and breeding studies.
文摘IAP(inhibitor of apoptosis)是内源性凋亡抑制蛋白家族,其中效力最强的是X连锁凋亡抑制蛋白(X chromosome linked inhibitor of apoptosis protein,XIAP)。它主要通过BIR结构域和RING锌指结构域抑制caspase活性、调节核因子NF2κB并参与信号的转导过程。XIAP受到不均一核糖核酸蛋白C1和C2等的正向调节和XAF1和Smac/DIABLO等的负向调节。近年来XIAP在临床方面的研究也取得了很大进展。
