Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most mal...Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most malignant tumors and promotes cancer cell growth.Heat shock protein 90(HSP90)is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival.Methods:DDX5 m RNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot,respectively.The interaction of DDX5-HSP90 was determined by molecular docking,immunoprecipitation,and laser scanning confocal microscopy.The autophagy signal was detected by Western blot.The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines.Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor.Results:HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway.The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating theβ-catenin signaling pathway.The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model.High levels of HSP90 and DDX5 protein were associated with poor prognoses.Conclusions:HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation.DDX5 and HSP90 are therefore potential therapeutic targets for HCC.展开更多
Previous studies have confirmed that heat shock protein 90 overexpression can lead to dopami- nergic neuronal death. This study was designed to further investigate what effects are produced by heat shock protein 90 af...Previous studies have confirmed that heat shock protein 90 overexpression can lead to dopami- nergic neuronal death. This study was designed to further investigate what effects are produced by heat shock protein 90 after endurance exercise training. Immunohistochemistry results showed that exercise training significantly inhibited heat shock protein 90 overexpression in the soleus and gastrocnemius in Parkinson＇s disease rats, which is a potential therapeutic target for ameliorating skeletal muscle abnormalities in Parkinso^s disease.展开更多
Dear Editor,Protein-protein interactions（PPIs）often play important roles in biological processes（Zhang et al.,2016）.The split Renilla luciferase complementation assay（SRLCA）is one of the methods in studying PPIs...Dear Editor,Protein-protein interactions（PPIs）often play important roles in biological processes（Zhang et al.,2016）.The split Renilla luciferase complementation assay（SRLCA）is one of the methods in studying PPIs.SRLCA is based on the complementation of the N-terminal domains of Renilla luciferase（LN）and C-terminal domains of Renilla luciferase （LC） non-functional halves of Renilla luciferase fused to possibly interacting proteins and emit luminescence （Deng et al., 2011; Jiang et al., 2010） （Supplementary Figure S1A）.展开更多
BACKGROUND The upregulation of serpin family B member 5(SERPINB5)has been linked to the progression of rectal cancer.However,the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully unde...BACKGROUND The upregulation of serpin family B member 5(SERPINB5)has been linked to the progression of rectal cancer.However,the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully understood.AIM To investigate the roles and mechanisms of SERPINB5 in rectal cancer.METHODS SERPINB5 protein level in rectal cancer tissues and cell lines was measured through western blot analysis.SW480 cells were transfected with pcDNASERPINB5 or short-hairpin RNA targeting SERPINB5(sh-SERPINB5).Cell proliferation,invasion,and apoptosis were then evaluated.The interaction between SERPINB5 and heat shock protein 90 alpha class A member 1(HSP90AA1)was confirmed through a co-immunoprecipitation assay.Subsequently,pcDNAHSP90AA1 or sh-HSP90AA1 was transfected into SW480 cells,and cell progression was then detected.Moreover,rescue experiments were used to investigate the effect of the SERPINB5/HSP90AA1 axis on rectal cancer progression.Additionally,sh-SERPINB5-transfected SW480 cells were implanted into nude mice,and xenograft tumor growth was then evaluated.RESULTS SERPINB5 was prominently upregulated in rectal cancer tissues and cells.SERPINB5 overexpression increased SW480 cell proliferation and invasion while reducing apoptosis.In contrast,SERPINB5 knockdown had the opposite effects.Moreover,SERPINB5 could interact with HSP90AA1 and promote HSP90AA1 expression in SW480 cells.HSP90AA1 overexpression facilitated SW480 cell proliferation and invasion and restrained apoptosis.By contrast,HSP90AA1 knockdown suppressed cell progression.The upregulation of HSP90AA1 reversed the SERPINB5 silencing-mediated inhibition of SW480 cell progression.Additionally,SERPINB5 knockdown retarded the growth of rectal cancer tumors in vivo.CONCLUSION SERPINB5 knockdown inhibited rectal cancer cell proliferation and invasion and retarded xenograft tumor growth by inhibiting HSP90AA1 expression.展开更多
Objective To investigate the expression of glucocerticoid receptor (GR) and heat shock protein 90(HSP90) mRNA in peripheral blood mononuclear cells (PBMCs) from steroid-sensitive (SS), steroiddependent (SD) and stero...Objective To investigate the expression of glucocerticoid receptor (GR) and heat shock protein 90(HSP90) mRNA in peripheral blood mononuclear cells (PBMCs) from steroid-sensitive (SS), steroiddependent (SD) and steroid-resistant (SR) asthmatics patients, and to evaluate the role of GR and HSP90in the pathogenesis of SR.Methods Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expressions of GR and HSP90 mRNA in PBMC stimulated with IL-2 and/or IL-4 from 10 normal volunteers,10 SS, 5 SD and 6 SR patients.Results The expressions of GR and HSP90 mRNA were the highest in PBMC from SR patients (0.730±0.171 and 1.122±0.165, respectively) compared with the normals (P＜0.05). The second was from SS patients (0.359±0.350 and 0.885±0.250, respectively). The lowest was from the SD patients (0.017±0.008 and 0.078 ± 0.039, respectively). The ratio of HSP90/GR in SR was significantly lower than that in the others, and it suggested that the expression of HSP90 mRNA was not sufficient in this group of patients. When PBMC from SS, SD and SR was incubated with IL-2 or IL-4 alone, no changes in GR and HSP90 mRNA expression were observed. While incubated with combination of IL-2 and IL-4, a significantly higher expression of GR mRNA was observed in all asthmatics, and a significantly higher expression of HSP90 mRNA was observed only in SS and SD patients.Conclusion The lowering of HSP90/GR ratio may be one of the causes of SR. IL-2 and IL-4 may play roles in the imbalance of HSP90/GR.展开更多
Heat shock protein 90(Hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers.Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones ...Heat shock protein 90(Hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers.Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones resulting in the degradation of Hsp90-dependent client proteins through the ubiqui tina tion-proteasome pathway,thereby leading to the growth inhibition of tumor cells.This review will briefy discuss the molecular structure and biological function of Hsp90,and focus on a summary of recent progress in the development and testing of natural Hsp90 inhibitors and their different means by which they interact with Hsp90.展开更多
Elevated expression of heat shock protein 90 （HSP90） has been found in kidneys and serum of systemic lupus erythematosus （SLE） patients and MRLIMp-FasIprIFasJpr（MRLIIpr） autoimmune mice. We investigated if inhib...Elevated expression of heat shock protein 90 （HSP90） has been found in kidneys and serum of systemic lupus erythematosus （SLE） patients and MRLIMp-FasIprIFasJpr（MRLIIpr） autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ Ipr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/Ipr kidneys when compared to C57BL/6 mice and MRIJIpr mice treated with HSP90 inhibitor 17-DMAG. MRIJIpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRIJIpr. 17-DMAG increased CD8＋ T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.展开更多
The Heat shock proteins(HSPs)are a group of molecular chaperones that play a crucial role in cell response to various stresses.A full-length cDNA of the heat shock protein 90(PuHsp90)was cloned and sequenced from the ...The Heat shock proteins(HSPs)are a group of molecular chaperones that play a crucial role in cell response to various stresses.A full-length cDNA of the heat shock protein 90(PuHsp90)was cloned and sequenced from the clam Paphia undulata.Phylogenetic analysis revealed that PuHsp90 grouped with the Hsp90 from other metazoan species.Expression of PuHsp90 was highly detected in the gonad,followed by digest gland,gills and heart but was found poorly expressed in mantle,adductor muscle and hemocytes.After a heat shock stress at 32℃up-regulation of PuHsp90 was detected in the mantle,adductor muscle,gills and hemocytes.Maximal expression levels occurred at 4 h after the heat shock and up-regulation is indicative of protein denaturation and of an increase in energy consumption.In contrast after the heat shock,PuHsp90 was continuously down-regulated in the digestive gland and in the gonad suggesting modifications of the biochemical pathways and energy budgets involved in the synthesis of other protein,such as catalase and of other Hsp proteins.These results reveal that PuHsp90 may play an important role in the clam response to a temperature stress.展开更多
To investigate the dynamic change of heat shock protein 90 （Hsp90） in the genesis and development of tumor, we successfully established tumor animal model using Marek’s disease and then determined the location of H...To investigate the dynamic change of heat shock protein 90 （Hsp90） in the genesis and development of tumor, we successfully established tumor animal model using Marek’s disease and then determined the location of Hsp90 in the tumor tissue using immunohistochemistry method, the antibody titer level of Hsp90 in the serum and the expression level in the tissue using enzyme-linked immunosorbent assay （ELISA） method. Our result showed that Hsp90 location in the tumor tissue was signiifcantly associated with the tumor cell and most in the cytoplasm of the tumor cell, and Hsp90 expression level in the tissue and the antibody titer level in the serum was most signiifcantly increased with the development of tumor. This is the ifrst report to show the presence of Hsp90 in tumor tissues induced by the Marek’s disease, with its expression correlated to the tumoral grading. These data may also be valuable for developing new molecular anti-cancer therapies.展开更多
基金funding support from the National Natural Science Foundation of China(Grant Nos.81672467,81702773,81702389,and 81672368)the Major National R&D Project(Grant Nos.2018ZX10723204,2018ZX10302205,and 2018ZX09J18107)the Natural Science Foundation of Beijing(Grant No.7172207)。
文摘Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most malignant tumors and promotes cancer cell growth.Heat shock protein 90(HSP90)is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival.Methods:DDX5 m RNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot,respectively.The interaction of DDX5-HSP90 was determined by molecular docking,immunoprecipitation,and laser scanning confocal microscopy.The autophagy signal was detected by Western blot.The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines.Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor.Results:HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway.The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating theβ-catenin signaling pathway.The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model.High levels of HSP90 and DDX5 protein were associated with poor prognoses.Conclusions:HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation.DDX5 and HSP90 are therefore potential therapeutic targets for HCC.
基金financially supported by the Deanship of Research at Jordan University of Science and Technology,Irbid,Jordan
文摘Previous studies have confirmed that heat shock protein 90 overexpression can lead to dopami- nergic neuronal death. This study was designed to further investigate what effects are produced by heat shock protein 90 after endurance exercise training. Immunohistochemistry results showed that exercise training significantly inhibited heat shock protein 90 overexpression in the soleus and gastrocnemius in Parkinson＇s disease rats, which is a potential therapeutic target for ameliorating skeletal muscle abnormalities in Parkinso^s disease.
基金supported by the Initiative Research Program of Wuhan University(No.410100020)the advanced talent independent research program of Wuhan University(No.410100011)the National Natural Science Foundation of China(No.210700228)
文摘Dear Editor,Protein-protein interactions（PPIs）often play important roles in biological processes（Zhang et al.,2016）.The split Renilla luciferase complementation assay（SRLCA）is one of the methods in studying PPIs.SRLCA is based on the complementation of the N-terminal domains of Renilla luciferase（LN）and C-terminal domains of Renilla luciferase （LC） non-functional halves of Renilla luciferase fused to possibly interacting proteins and emit luminescence （Deng et al., 2011; Jiang et al., 2010） （Supplementary Figure S1A）.
基金Supported by the Medical Science Research Project Plan of the Hebei Provincial Health Commission,No.20210027.
文摘BACKGROUND The upregulation of serpin family B member 5(SERPINB5)has been linked to the progression of rectal cancer.However,the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully understood.AIM To investigate the roles and mechanisms of SERPINB5 in rectal cancer.METHODS SERPINB5 protein level in rectal cancer tissues and cell lines was measured through western blot analysis.SW480 cells were transfected with pcDNASERPINB5 or short-hairpin RNA targeting SERPINB5(sh-SERPINB5).Cell proliferation,invasion,and apoptosis were then evaluated.The interaction between SERPINB5 and heat shock protein 90 alpha class A member 1(HSP90AA1)was confirmed through a co-immunoprecipitation assay.Subsequently,pcDNAHSP90AA1 or sh-HSP90AA1 was transfected into SW480 cells,and cell progression was then detected.Moreover,rescue experiments were used to investigate the effect of the SERPINB5/HSP90AA1 axis on rectal cancer progression.Additionally,sh-SERPINB5-transfected SW480 cells were implanted into nude mice,and xenograft tumor growth was then evaluated.RESULTS SERPINB5 was prominently upregulated in rectal cancer tissues and cells.SERPINB5 overexpression increased SW480 cell proliferation and invasion while reducing apoptosis.In contrast,SERPINB5 knockdown had the opposite effects.Moreover,SERPINB5 could interact with HSP90AA1 and promote HSP90AA1 expression in SW480 cells.HSP90AA1 overexpression facilitated SW480 cell proliferation and invasion and restrained apoptosis.By contrast,HSP90AA1 knockdown suppressed cell progression.The upregulation of HSP90AA1 reversed the SERPINB5 silencing-mediated inhibition of SW480 cell progression.Additionally,SERPINB5 knockdown retarded the growth of rectal cancer tumors in vivo.CONCLUSION SERPINB5 knockdown inhibited rectal cancer cell proliferation and invasion and retarded xenograft tumor growth by inhibiting HSP90AA1 expression.
文摘Objective To investigate the expression of glucocerticoid receptor (GR) and heat shock protein 90(HSP90) mRNA in peripheral blood mononuclear cells (PBMCs) from steroid-sensitive (SS), steroiddependent (SD) and steroid-resistant (SR) asthmatics patients, and to evaluate the role of GR and HSP90in the pathogenesis of SR.Methods Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expressions of GR and HSP90 mRNA in PBMC stimulated with IL-2 and/or IL-4 from 10 normal volunteers,10 SS, 5 SD and 6 SR patients.Results The expressions of GR and HSP90 mRNA were the highest in PBMC from SR patients (0.730±0.171 and 1.122±0.165, respectively) compared with the normals (P＜0.05). The second was from SS patients (0.359±0.350 and 0.885±0.250, respectively). The lowest was from the SD patients (0.017±0.008 and 0.078 ± 0.039, respectively). The ratio of HSP90/GR in SR was significantly lower than that in the others, and it suggested that the expression of HSP90 mRNA was not sufficient in this group of patients. When PBMC from SS, SD and SR was incubated with IL-2 or IL-4 alone, no changes in GR and HSP90 mRNA expression were observed. While incubated with combination of IL-2 and IL-4, a significantly higher expression of GR mRNA was observed in all asthmatics, and a significantly higher expression of HSP90 mRNA was observed only in SS and SD patients.Conclusion The lowering of HSP90/GR ratio may be one of the causes of SR. IL-2 and IL-4 may play roles in the imbalance of HSP90/GR.
基金This work was supported by National Science Foundation of China(90913020 and 30901847)Science and Technology Program of China(2012ZX09103-101-053)Science and Technology Star of Zhujiang of Guangzhou City(Dongmei Zhang).
文摘Heat shock protein 90(Hsp90)is a highly conserved molecular chaperone that plays a vital role in the signal transduction of cancers.Hsp90 inhibitors are able to inhibit Hsp90 or the complex of Hsp90 and co-chaperones resulting in the degradation of Hsp90-dependent client proteins through the ubiqui tina tion-proteasome pathway,thereby leading to the growth inhibition of tumor cells.This review will briefy discuss the molecular structure and biological function of Hsp90,and focus on a summary of recent progress in the development and testing of natural Hsp90 inhibitors and their different means by which they interact with Hsp90.
文摘Elevated expression of heat shock protein 90 （HSP90） has been found in kidneys and serum of systemic lupus erythematosus （SLE） patients and MRLIMp-FasIprIFasJpr（MRLIIpr） autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ Ipr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/Ipr kidneys when compared to C57BL/6 mice and MRIJIpr mice treated with HSP90 inhibitor 17-DMAG. MRIJIpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRIJIpr. 17-DMAG increased CD8＋ T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.
基金This work was supported by the Open Program of Key Laboratory of Cultivation and High-value Utilization of Marine Organisms in Fujian Province(2015fjscq05)the New Century Excellent Talents of Fujian Province University(No.JA14167).
文摘The Heat shock proteins(HSPs)are a group of molecular chaperones that play a crucial role in cell response to various stresses.A full-length cDNA of the heat shock protein 90(PuHsp90)was cloned and sequenced from the clam Paphia undulata.Phylogenetic analysis revealed that PuHsp90 grouped with the Hsp90 from other metazoan species.Expression of PuHsp90 was highly detected in the gonad,followed by digest gland,gills and heart but was found poorly expressed in mantle,adductor muscle and hemocytes.After a heat shock stress at 32℃up-regulation of PuHsp90 was detected in the mantle,adductor muscle,gills and hemocytes.Maximal expression levels occurred at 4 h after the heat shock and up-regulation is indicative of protein denaturation and of an increase in energy consumption.In contrast after the heat shock,PuHsp90 was continuously down-regulated in the digestive gland and in the gonad suggesting modifications of the biochemical pathways and energy budgets involved in the synthesis of other protein,such as catalase and of other Hsp proteins.These results reveal that PuHsp90 may play an important role in the clam response to a temperature stress.
基金supported by the National Natural Science Foundation of China (31101787)the Natural Science Foundation of Shandong Province,China (ZR2010CM035)
文摘To investigate the dynamic change of heat shock protein 90 （Hsp90） in the genesis and development of tumor, we successfully established tumor animal model using Marek’s disease and then determined the location of Hsp90 in the tumor tissue using immunohistochemistry method, the antibody titer level of Hsp90 in the serum and the expression level in the tissue using enzyme-linked immunosorbent assay （ELISA） method. Our result showed that Hsp90 location in the tumor tissue was signiifcantly associated with the tumor cell and most in the cytoplasm of the tumor cell, and Hsp90 expression level in the tissue and the antibody titer level in the serum was most signiifcantly increased with the development of tumor. This is the ifrst report to show the presence of Hsp90 in tumor tissues induced by the Marek’s disease, with its expression correlated to the tumoral grading. These data may also be valuable for developing new molecular anti-cancer therapies.
