目的探讨驱动蛋白家族成员11(kinesin family member 11,KIF11)、β-连环蛋白(β-catenin)、糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)在宫颈癌中的表达情况及临床意义。方法采用免疫组化法检测KIF11、β-catenin、GS...目的探讨驱动蛋白家族成员11(kinesin family member 11,KIF11)、β-连环蛋白(β-catenin)、糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)在宫颈癌中的表达情况及临床意义。方法采用免疫组化法检测KIF11、β-catenin、GSK-3β在102例宫颈癌、52例高级别鳞状上皮内病变(high-grade squamous intraepithelial lesion,HSIL)、46例低级别鳞状上皮内病变(low-grade squamous intraepithelial lesion,LSIL)及40例慢性宫颈炎组织中的表达情况,分析三者的表达与宫颈癌患者临床病理特征的关系,分析三者之间的相关性,COX比例风险模型分析影响宫颈癌患者预后的影响因素。结果随着宫颈病变进展,KIF11、β-catenin阳性率逐渐升高,GSK-3β阳性率逐渐减低(P<0.05)。KIF11、β-catenin、GSK-3β在宫颈癌组织中的阳性表达在国际妇产科联盟(International Federation of Gynecology and Obstetrics,FIGO)分期、分化程度、淋巴结转移方面比较,差异有统计学意义(P<0.05),但在不同年龄及病理类型间比较,差异无统计学意义(P>0.05)。宫颈癌患者组织中KIF11与β-catenin的表达呈正相关(r=0.461,P<0.05),β-catenin与GSK-3β的表达呈负相关(r=-0.692,P<0.05),KIF11与GSK-3β的表达呈负相关(r=-0.336,P<0.05)。KIF11、β-catenin阳性表达患者的平均生存时间短于阴性表达患者,GSK-3β阳性表达患者的平均生存时间长于阴性表达患者。COX回归分析显示,FIGO分期、淋巴结转移、KIF11、β-catenin为宫颈癌患者预后的独立危险因素,GSK-3β为独立保护因素。结论KIF11、β-catenin、GSK-3β在宫颈癌患者组织中异常表达,KIF11可能参与宫颈癌发生、发展中Wnt/β-catenin通路的调节,三者联合检测可为宫颈癌的诊断及预后提供新的参考。展开更多
NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin ...NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a major executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NORE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NORE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NORE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NORE1A. The GSK-3β interaction with NORE1A plays an important role in the biology of NORE1A as a GSK-3β inhibitor blocks NORE1A induced senescence. Thus, we identify a new role for the tumor suppressor NORE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NORE1A may be able to influence all of them via this new kinase scaffolding interaction.展开更多
Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we id...Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.展开更多
文摘目的探讨驱动蛋白家族成员11(kinesin family member 11,KIF11)、β-连环蛋白(β-catenin)、糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)在宫颈癌中的表达情况及临床意义。方法采用免疫组化法检测KIF11、β-catenin、GSK-3β在102例宫颈癌、52例高级别鳞状上皮内病变(high-grade squamous intraepithelial lesion,HSIL)、46例低级别鳞状上皮内病变(low-grade squamous intraepithelial lesion,LSIL)及40例慢性宫颈炎组织中的表达情况,分析三者的表达与宫颈癌患者临床病理特征的关系,分析三者之间的相关性,COX比例风险模型分析影响宫颈癌患者预后的影响因素。结果随着宫颈病变进展,KIF11、β-catenin阳性率逐渐升高,GSK-3β阳性率逐渐减低(P<0.05)。KIF11、β-catenin、GSK-3β在宫颈癌组织中的阳性表达在国际妇产科联盟(International Federation of Gynecology and Obstetrics,FIGO)分期、分化程度、淋巴结转移方面比较,差异有统计学意义(P<0.05),但在不同年龄及病理类型间比较,差异无统计学意义(P>0.05)。宫颈癌患者组织中KIF11与β-catenin的表达呈正相关(r=0.461,P<0.05),β-catenin与GSK-3β的表达呈负相关(r=-0.692,P<0.05),KIF11与GSK-3β的表达呈负相关(r=-0.336,P<0.05)。KIF11、β-catenin阳性表达患者的平均生存时间短于阴性表达患者,GSK-3β阳性表达患者的平均生存时间长于阴性表达患者。COX回归分析显示,FIGO分期、淋巴结转移、KIF11、β-catenin为宫颈癌患者预后的独立危险因素,GSK-3β为独立保护因素。结论KIF11、β-catenin、GSK-3β在宫颈癌患者组织中异常表达,KIF11可能参与宫颈癌发生、发展中Wnt/β-catenin通路的调节,三者联合检测可为宫颈癌的诊断及预后提供新的参考。
文摘NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a major executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NORE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NORE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NORE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NORE1A. The GSK-3β interaction with NORE1A plays an important role in the biology of NORE1A as a GSK-3β inhibitor blocks NORE1A induced senescence. Thus, we identify a new role for the tumor suppressor NORE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NORE1A may be able to influence all of them via this new kinase scaffolding interaction.
基金National Natural Science Foundation of China(81870850)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_0322)。
文摘Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.
