TNIK(TRAF2 and NCK interacting kinase)属丝氨酸/苏氨酸激酶家族成员,在多种生理及病理过程中起关键作用。研究发现,TNIK在肺鳞癌组织中高表达且可驱动癌细胞增殖等恶性表型,但其在肺腺癌中的作用仍未知。该研究在构建稳定敲减TNIK表...TNIK(TRAF2 and NCK interacting kinase)属丝氨酸/苏氨酸激酶家族成员,在多种生理及病理过程中起关键作用。研究发现,TNIK在肺鳞癌组织中高表达且可驱动癌细胞增殖等恶性表型,但其在肺腺癌中的作用仍未知。该研究在构建稳定敲减TNIK表达的肺腺癌A549细胞后,流式细胞术检测发现稳定敲减TNIK阻滞细胞周期进程并诱发凋亡,细胞增殖及运动实验证明肺癌细胞增殖与迁移能力被显著抑制。进一步通过免疫荧光染色分析发现,稳定敲减TNIK表达后会诱导细胞微丝骨架排列紊乱并抑制黏着斑动态周转(组装/解聚)。综上研究结果表明,肺腺癌细胞中TNIK可能通过调节微丝骨架排列,从而影响黏着斑动态周转最终控制细胞增殖及迁移运动;推测肺腺癌细胞中高表达的TNIK可能通过调控细胞微丝骨架系统以维持癌细胞恶性表型。展开更多
精神分裂症(schizophrenia)是一组病因复杂的重性精神障碍,涉及感知觉、思维、情感和行为等多方面的障碍。根据世界卫生组织调查显示,精神分裂症在成年人群中的终生患病率接近1%,是发达国家十大致残疾病之一[1]。目前有关精神分裂症的...精神分裂症(schizophrenia)是一组病因复杂的重性精神障碍,涉及感知觉、思维、情感和行为等多方面的障碍。根据世界卫生组织调查显示,精神分裂症在成年人群中的终生患病率接近1%,是发达国家十大致残疾病之一[1]。目前有关精神分裂症的发病机制尚不清楚,但普遍认为遗传是导致疾病发生的重要因素之一[2]。近年来随着全基因组关联分析(genome-wide association study,GWAS)广泛应用于复杂性疾病的研究,越来越多精神分裂症危险基因被鉴别,其中便包括肿瘤坏死因子受体相关因子-2和NCK相互作用蛋白激酶(traf2-and NCK-interacting kinase,TNIK)基因[3-4]。此外,相关药物基因组学研究还提示TNIK基因与抗精神病药治疗反应显著关联,对药物疗效预测及个体化用药有一定指导作用[5-6]。展开更多
Epilepsy,one of the most common neurological disorders,is characterized by spon-taneous recurrent seizures.Temporal lobe epilepsy(TLE)is one of the most common medically intractable seizure disorders.Traf2-and NcK-int...Epilepsy,one of the most common neurological disorders,is characterized by spon-taneous recurrent seizures.Temporal lobe epilepsy(TLE)is one of the most common medically intractable seizure disorders.Traf2-and NcK-interacting kinase(TNIK)has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders,but its role in epilepsy remains unclear.In this study,we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpineinduced rat model of epilepsy by western blotting,immunofluorescence,and immunohistochemistry.A pentylenetetrazole(PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy.Coimmunoprecipitation(Co-IP)/mass spectrometry(MS)was used to identify the potential mechanism.Through Co-IP,we detected and confirmed the main potential TNIK interactors.Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density(PSD)fractions.We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls.NCB-0846 delayed kindling progression and decreased seizure severity.Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi,notably CaMKIl.Co-IP showed that TNIK might correlate with endogenous GRIA1,SYN2,PSD-95,CaMKIV,GABRG1,and GABRG2.In addition,the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling.Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.展开更多
文摘TNIK(TRAF2 and NCK interacting kinase)属丝氨酸/苏氨酸激酶家族成员,在多种生理及病理过程中起关键作用。研究发现,TNIK在肺鳞癌组织中高表达且可驱动癌细胞增殖等恶性表型,但其在肺腺癌中的作用仍未知。该研究在构建稳定敲减TNIK表达的肺腺癌A549细胞后,流式细胞术检测发现稳定敲减TNIK阻滞细胞周期进程并诱发凋亡,细胞增殖及运动实验证明肺癌细胞增殖与迁移能力被显著抑制。进一步通过免疫荧光染色分析发现,稳定敲减TNIK表达后会诱导细胞微丝骨架排列紊乱并抑制黏着斑动态周转(组装/解聚)。综上研究结果表明,肺腺癌细胞中TNIK可能通过调节微丝骨架排列,从而影响黏着斑动态周转最终控制细胞增殖及迁移运动;推测肺腺癌细胞中高表达的TNIK可能通过调控细胞微丝骨架系统以维持癌细胞恶性表型。
文摘精神分裂症(schizophrenia)是一组病因复杂的重性精神障碍,涉及感知觉、思维、情感和行为等多方面的障碍。根据世界卫生组织调查显示,精神分裂症在成年人群中的终生患病率接近1%,是发达国家十大致残疾病之一[1]。目前有关精神分裂症的发病机制尚不清楚,但普遍认为遗传是导致疾病发生的重要因素之一[2]。近年来随着全基因组关联分析(genome-wide association study,GWAS)广泛应用于复杂性疾病的研究,越来越多精神分裂症危险基因被鉴别,其中便包括肿瘤坏死因子受体相关因子-2和NCK相互作用蛋白激酶(traf2-and NCK-interacting kinase,TNIK)基因[3-4]。此外,相关药物基因组学研究还提示TNIK基因与抗精神病药治疗反应显著关联,对药物疗效预测及个体化用药有一定指导作用[5-6]。
基金supported by grants from the National Natural Science Foundation of China(No.81901324,82001378,82071395)China Postdoctoral Science Foundation(No.2021M693246)+4 种基金joint project of Chongqing Health Commission and Science and Technology Bureau(Chongqing,China)(No.2023QNXM009)Science and Technology Research Program of Chongqing Education Commission of China(No.KJQN202200435)Chongqing Talents:Exceptional Young Talents Project(Chongqing,China)(No.CQYC202005014)Natural Science Foundation of Chongqing,China(No.cstc2021ycjh-bgzxm0035,CSTB2022NSCQ-LZX0038)Key Research and Development Projects of Jining City,Shandong,China(No.2021YXNS057).
文摘Epilepsy,one of the most common neurological disorders,is characterized by spon-taneous recurrent seizures.Temporal lobe epilepsy(TLE)is one of the most common medically intractable seizure disorders.Traf2-and NcK-interacting kinase(TNIK)has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders,but its role in epilepsy remains unclear.In this study,we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpineinduced rat model of epilepsy by western blotting,immunofluorescence,and immunohistochemistry.A pentylenetetrazole(PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy.Coimmunoprecipitation(Co-IP)/mass spectrometry(MS)was used to identify the potential mechanism.Through Co-IP,we detected and confirmed the main potential TNIK interactors.Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density(PSD)fractions.We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls.NCB-0846 delayed kindling progression and decreased seizure severity.Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi,notably CaMKIl.Co-IP showed that TNIK might correlate with endogenous GRIA1,SYN2,PSD-95,CaMKIV,GABRG1,and GABRG2.In addition,the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling.Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.
