Contrary to the adult central nervous system,the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regenerationassociated genes,such as some kinesin family members.Kines...Contrary to the adult central nervous system,the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regenerationassociated genes,such as some kinesin family members.Kinesins contribute to nerve regeneration through the transport of specific cargo,such as proteins and membrane components,from the cell body towards the axon periphery.We show here that KIF4A,associated with neurodevelopmental disorders and previously believed to be only expressed during development,is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells.KIF4A is detected both in the cell bodies and regrowing axons of injured neurons,consistent with its function as an axonal transporter of cargoes such asβ1-integrin and L1CAM.Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps,particularly at a time when they are reprogrammed into an essential proliferative repair phenotype.Moreover,Kif4a m RNA levels were approximately~6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones.A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown,as this significantly reduced Schwann cell proliferation in vitro.Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury.The timing of KIF4A up-regulation,its location during regeneration,and its proliferative role,all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.展开更多
BACKGROUND Colorectal cancer(CRC)is the third most common cancer globally,causing over 900000 deaths annually.Risk factors include aging,diet,obesity,sedentary lifestyle,tobacco use,genetic predisposition,and inflamma...BACKGROUND Colorectal cancer(CRC)is the third most common cancer globally,causing over 900000 deaths annually.Risk factors include aging,diet,obesity,sedentary lifestyle,tobacco use,genetic predisposition,and inflammatory bowel disease.Despite current treatments,survival rates for advanced CRC remain low,highlighting the need for better therapeutic strategies.AIM To evaluate both the clinical significance and the pathological implications of the Kinesin family member 14(KIF14)expression within CRC specimens.Additionally,this study aims to investigate the interaction between nitidine chloride(NC)and KIF14,considering their potential as therapeutic targets.METHODS The expression of the KIF14 protein in CRC was analyzed using immunohistochemical staining.The integration of multicenter high-throughput data facilitated the calculation of the standardized mean difference(SMD)for KIF14 mRNA levels.The assessment of clinical and pathological impact was enhanced by analyzing combined receiver operating characteristic curves,along with measures of sensitivity,specificity,and likelihood ratios.Additionally,clustered regularly interspaced short palindromic repeats knockout screening for cell growth and single-cell sequencing were employed to validate the significance of KIF14 expression in CRC.Survival analysis established the prognostic value of KIF14 in CRC.The molecular mechanism of NC against CRC was elucidated through whole-genome sequencing and enrichment analysis,and molecular docking was utilized to explore the targeting affinity between NC and KIF14.RESULTS KIF14 was highly expressed in 208 CRC patients.Data from 17 platforms involving 2436 CRC samples and 1320 noncancerous colorectal tissue controls indicated that KIF14 expression was significantly higher in CRC samples,with an SMD of 1.92(95%CI:1.49-2.35).The area under the curve was 0.94(95%CI:0.92-0.96),with a sensitivity of 0.85(95%CI:0.78-0.90)and a specificity of 0.90(95%CI:0.85-0.93).The positive and negative likelihood ratios were 8.38(95%CI:5.39-13.02)and 0.17(95%CI:0.11-0.26),respectively.At the single-cell level,significant overexpression of KIF14 was observed in CRC cells(P<0.001),with 35 CRC cell lines dependent on KIF14 for growth.The K-M plots demonstrated that KIF14 possesses prognostic value in CRC patients within the GSE71187 and GSE103679 datasets(P<0.05).Binding energy calculations indicated that KIF14 is a potential target for NC(binding energy:10.3 kcal/mol).CONCLUSION KIF14 promotes the growth of CRC cells and acts as an oncogenic factor,potentially serving as a therapeutic target for NC in the treatment of CRC.展开更多
In this editorial,we comment on the article by Qin et al,recently published in the World Journal of Gastrointestinal Oncology.Malignant tumors of the digestive tract represent a significant health threat.Kinesin famil...In this editorial,we comment on the article by Qin et al,recently published in the World Journal of Gastrointestinal Oncology.Malignant tumors of the digestive tract represent a significant health threat.Kinesin family member 14(KIF14),a critical kinesin,is pivotal in the proliferation,migration,and invasion of tumor cells.It has emerged as a focal point in recent studies of malignant tumors in the digestive tract.This article reviews the current research on KIF14 within these tumors and details its significant role in tumor cell behaviors,including proliferation,apo-ptosis,migration,invasion,and angiogenesis,alongside the regulatory mechanisms of the associated intracellular signaling pathways.Additionally,it explores the clinical value of KIF14 as a potential biomarker for early diagnosis,disease monitoring,and prognostic evaluation in malignant tumors of the digestive tract.The article concludes by introducing the potential regulatory role of traditional Chinese medicine,aiming to combine the strengths of both modern and traditional medical approaches to enhance treatment outcomes and prognosis for patients with these tumors.展开更多
Kinesin is an archetypal microtubule-based molecular motor that can generate force to transport cargo in cells. The load dependence of the detachment rate is an important factor of the kinesin motor, the determination...Kinesin is an archetypal microtubule-based molecular motor that can generate force to transport cargo in cells. The load dependence of the detachment rate is an important factor of the kinesin motor, the determination of which is critically related to the chemomechanical coupling mechanism of the motor. Here, we use three models for the load dependence of the detachment rate of the kinesin motor to study theoretically and numerically the maximal force generated and microtubuleattachment duration of the motor. By comparing the theoretical and numerical results with the available experimental data,we show that only one model can explain well the available experimental data, indicating that only this model can be applicable to the kinesin motor.展开更多
BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacologic...BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacological potential,and kinesin family member 20A(KIF20A)is overexpressed in various tumors;however,their interaction in CRC remains unexplored.AIM To investigate the KIF20A expression characteristics in CRC cells and determine whether it is a potential target gene for NC in inhibiting CRC treatment.METHODS Single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and mRNA expression profiling were used to analyze KIF20A expression in CRC cells.Immunohistochemical staining was used to verify KIF20A expression in 416 clinical samples(208 CRC tissue samples and 208 noncancerous control tissue samples).Clustered regularly interspaced short palindromic repeats(CRISPR)technology was used to evaluate the impact of knocking out KIF20A on CRC cell growth.Molecular docking was applied to analyze NC–KIF20A binding.Finally,RNA sequencing and functional enrichment analysis were performed to explore the mechanism of action of NC in CRC cells.RESULTS Treating HCT116 cells with NC was found to significantly downregulate KIF20A(P<0.05),and the molecular docking analysis revealed high-affinity binding between NC and KIF20A(binding energy=-9.6 kcal/mol).The scRNA-seq,spatial transcriptomics,and mRNA expression profiling results confirmed the significantly high expression of KIF20A in CRC tissues(standardized mean difference=1.33,95%confidence interval:0.885-1.77,summary receiver operating characteristic curve area=0.94).The immunohistochemical analysis of the clinical samples showed high KIF20A expression in the CRC tissues(P<0.05),with significant correlation between the level of expression and gender,tumor size,and tumor grade(P<0.05).Knocking out KIF20A significantly inhibited the growth of various CRC cell lines(CRISPR score<-0.3).The functional enrichment analysis indicated that NC may inhibit CRC by disrupting several biological processes,such as mitotic nuclear division,chromosome segregation,and microtubule binding.CONCLUSION Our results indicate that NC binds to KIF20A with high affinity and downregulates its expression in CRC cells,leading to reduced proliferation.Hence,NC has promise as a therapeutic agent in the treatment of CRC,and targeting KIF20A also has potential as a therapeutic strategy.Further KIF20A knockout studies are needed to confirm the binding specificity and mechanistic roles of NC in CRC.展开更多
Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,ante...Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.展开更多
Grain shape is one of the important agronomic traits, which is closely related to the yield of rice.A new rice mutant, named small and round grain(srg1), was isolated from an indica cultivar Zhenong 34 by ethyl methan...Grain shape is one of the important agronomic traits, which is closely related to the yield of rice.A new rice mutant, named small and round grain(srg1), was isolated from an indica cultivar Zhenong 34 by ethyl methane sulfonate(EMS) mutagenesis. The microscopic analysis showed that the cell length of spikelet in srg1 was decreased compared with that in wild type(WT), which caused the grain length short.Meanwhile, the grains of srg1 were wider than those of WT because of the increased cell layers in spikelet in the lateral direction. Therefore, the inhibition of cell expansion and increased cell proliferation collectively led to the small and round grain. By map-based cloning, the gene SRG1 was located on the short arm of chromosome 9, which encodes a kinesin-4 protein, represented by the gene LOC_Os09 g02650. A single nucleotide polymorphism, occurred in the 16 th exon of SRG1, led to premature translation stop in mutant. The cell cycle-related genes were up-regulated in srg1, which conferred that SRG1 controlled grain width through the cell proliferation. Since the role of SRG1 in regulating grain shape was not clarified well before, it is valuable to explore the mechanism of grain development. This study could, hence, provide a morphogenesis and molecular basis for elucidating the function of SRG1, as well as a new germplasm resource for the further study of grain development.展开更多
Docking of the kinesin＇s neck linker （NL） to the motor domain is the key force-generation process of the kinesin. In this process, NL＇sβ10 portion forms four backbone hydrogen bonds （HBs） with the motor domain....Docking of the kinesin＇s neck linker （NL） to the motor domain is the key force-generation process of the kinesin. In this process, NL＇sβ10 portion forms four backbone hydrogen bonds （HBs） with the motor domain. These backbone hydrogen bonds show big differences in their effective strength. The origins of these strength differences are still unclear. Using molecular dynamics method, we investigate the stability of the backbone HBs in explicit water environment. We find that the strength differences of these backbone HBs mainly arise from their relationships with water molecules which are controlled by arranging the surrounding residue sidechains. The arrangement of the residues in the C-terminal part of /310 results in the existence of the water-attack channels around the backbone HBs in this region. Along these channels the water molecules can directly attack the backbone HBs and make these HBs relatively weak. In contrast, the backbone HB at the N-terminus ofβ 10 is protected by the surrounding hydrophobic and hydrophilic residues which cooperate positively with the central backbone HB and make this HB highly strong. The intimate relationship between the effective strength of protein backbone HB and water revealed here should be considered when performing mechanical analysis for protein conformational changes.展开更多
Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,...Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,motility,and maturation.Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.In dividing cells,kinesin superfamily protein 2A is involved in mitotic progression,spindle assembly,and chromosome segregation.In postmitotic neurons,it is required for axon/dendrite specification and extension,neuronal migration,connectivity,and survival.Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development,epilepsy,autism spectrum disorder,and neurodegeneration.In this review,we discuss how kinesin superfamily protein 2A regulates neuronal development and function,and how its deregulation causes neurodevelopmental and neurological disorders.展开更多
Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concern...Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.展开更多
基金supported by the Portuguese Foundation for Science and Technology(FCT),Centro 2020 and Portugol2020 and the EU FEDER program,via the project GoBack to SIV(PTDC/CVT-CVT/32261/2017,CENTRO-01-0145-FEDER-032261)the doctoral grants of PDC(SFRH/BD/139974/2018)and BMS(2020.06525.BD and DOI 10.54499/2020.06525.BD)+5 种基金the post-doctoral grant to JPF(SFRH/BPD/113359/2015-program-contract described in paragraphs 4,5,6 of art.23 of Law no.100157/2016,of August 29,as amended by Law no.57/2017 of July 2019),the project PTDC/MED-NEU/1677/2021 to JBRthe Institute of Biomedicine iBiMED(UIDB/04501/2020 and DOI 10.54499/UIDB/04501/2020,UIDP/04501/2020 and DOI 10.54499/UIDP/04501/2020)its LiM Bioimaging Facility-a PPBI node(POCI-01-0145-FEDER-022122)supported by the Research Commission of the Medical Faculty of the Heinrich-Heine-University(HHU)Düsseldorf,of the Biologisch-Medizinisches Forschungszentrum(BMFZ)of HHUfinanced by the Spanish"Plan Nacional de Investigacion Cientifica,Desarrollo e Innovacion Tecnologica,Ministerio de Economia y Competitividad(Instituto de Salud CarlosⅢ)",co-financed by the European Union(FEDER program),(grant FIS P/20/00318 and FIS P23/00337 to VC)grant CPP2021-009070 to VC by the"Proyectos de colaboracion publico-privada,Plan de Investigacion Cientifica,Tecnica y de inovacion 2021-2023,Ministerio de Ciencia e Innovacion,Union Europea,Agencia Estatal de Investigacion,Espana"。
文摘Contrary to the adult central nervous system,the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regenerationassociated genes,such as some kinesin family members.Kinesins contribute to nerve regeneration through the transport of specific cargo,such as proteins and membrane components,from the cell body towards the axon periphery.We show here that KIF4A,associated with neurodevelopmental disorders and previously believed to be only expressed during development,is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells.KIF4A is detected both in the cell bodies and regrowing axons of injured neurons,consistent with its function as an axonal transporter of cargoes such asβ1-integrin and L1CAM.Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps,particularly at a time when they are reprogrammed into an essential proliferative repair phenotype.Moreover,Kif4a m RNA levels were approximately~6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones.A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown,as this significantly reduced Schwann cell proliferation in vitro.Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury.The timing of KIF4A up-regulation,its location during regeneration,and its proliferative role,all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.
基金Natural Science Foundation of Shandong Province,No.ZR2020QH185Scientific Research Nurturing Fund of The First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qianfoshan Hospital,No.QYPY2020NSFC0803+2 种基金Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z-A20220415Guangxi Medical University Teacher Teaching Ability Development Project,No.2022JFA02Guangxi Medical University Undergraduate Education and Teaching Reform Project,No.2023Y05.
文摘BACKGROUND Colorectal cancer(CRC)is the third most common cancer globally,causing over 900000 deaths annually.Risk factors include aging,diet,obesity,sedentary lifestyle,tobacco use,genetic predisposition,and inflammatory bowel disease.Despite current treatments,survival rates for advanced CRC remain low,highlighting the need for better therapeutic strategies.AIM To evaluate both the clinical significance and the pathological implications of the Kinesin family member 14(KIF14)expression within CRC specimens.Additionally,this study aims to investigate the interaction between nitidine chloride(NC)and KIF14,considering their potential as therapeutic targets.METHODS The expression of the KIF14 protein in CRC was analyzed using immunohistochemical staining.The integration of multicenter high-throughput data facilitated the calculation of the standardized mean difference(SMD)for KIF14 mRNA levels.The assessment of clinical and pathological impact was enhanced by analyzing combined receiver operating characteristic curves,along with measures of sensitivity,specificity,and likelihood ratios.Additionally,clustered regularly interspaced short palindromic repeats knockout screening for cell growth and single-cell sequencing were employed to validate the significance of KIF14 expression in CRC.Survival analysis established the prognostic value of KIF14 in CRC.The molecular mechanism of NC against CRC was elucidated through whole-genome sequencing and enrichment analysis,and molecular docking was utilized to explore the targeting affinity between NC and KIF14.RESULTS KIF14 was highly expressed in 208 CRC patients.Data from 17 platforms involving 2436 CRC samples and 1320 noncancerous colorectal tissue controls indicated that KIF14 expression was significantly higher in CRC samples,with an SMD of 1.92(95%CI:1.49-2.35).The area under the curve was 0.94(95%CI:0.92-0.96),with a sensitivity of 0.85(95%CI:0.78-0.90)and a specificity of 0.90(95%CI:0.85-0.93).The positive and negative likelihood ratios were 8.38(95%CI:5.39-13.02)and 0.17(95%CI:0.11-0.26),respectively.At the single-cell level,significant overexpression of KIF14 was observed in CRC cells(P<0.001),with 35 CRC cell lines dependent on KIF14 for growth.The K-M plots demonstrated that KIF14 possesses prognostic value in CRC patients within the GSE71187 and GSE103679 datasets(P<0.05).Binding energy calculations indicated that KIF14 is a potential target for NC(binding energy:10.3 kcal/mol).CONCLUSION KIF14 promotes the growth of CRC cells and acts as an oncogenic factor,potentially serving as a therapeutic target for NC in the treatment of CRC.
基金Supported by the 2023 Government-funded Project of the Outstanding Talents Training Program in Clinical Medicine,No.ZF2023165Key Research and Development Projects of Hebei Province,No.18277731D+1 种基金Natural Science Foundation of Hebei Province,No.H202423105Hebei Provincial Administration of Traditional Chinese Medicine,Scientific Research Project,No.2020014.
文摘In this editorial,we comment on the article by Qin et al,recently published in the World Journal of Gastrointestinal Oncology.Malignant tumors of the digestive tract represent a significant health threat.Kinesin family member 14(KIF14),a critical kinesin,is pivotal in the proliferation,migration,and invasion of tumor cells.It has emerged as a focal point in recent studies of malignant tumors in the digestive tract.This article reviews the current research on KIF14 within these tumors and details its significant role in tumor cell behaviors,including proliferation,apo-ptosis,migration,invasion,and angiogenesis,alongside the regulatory mechanisms of the associated intracellular signaling pathways.Additionally,it explores the clinical value of KIF14 as a potential biomarker for early diagnosis,disease monitoring,and prognostic evaluation in malignant tumors of the digestive tract.The article concludes by introducing the potential regulatory role of traditional Chinese medicine,aiming to combine the strengths of both modern and traditional medical approaches to enhance treatment outcomes and prognosis for patients with these tumors.
基金Project supported by Youth Project of Science and Technology Research Program of Chongqing Education Commission of China (Grant No. KJQN202404522)。
文摘Kinesin is an archetypal microtubule-based molecular motor that can generate force to transport cargo in cells. The load dependence of the detachment rate is an important factor of the kinesin motor, the determination of which is critically related to the chemomechanical coupling mechanism of the motor. Here, we use three models for the load dependence of the detachment rate of the kinesin motor to study theoretically and numerically the maximal force generated and microtubuleattachment duration of the motor. By comparing the theoretical and numerical results with the available experimental data,we show that only one model can explain well the available experimental data, indicating that only this model can be applicable to the kinesin motor.
基金Supported by the Promoting Project of Basic Capacity for Young and Middle-aged University Teachers in Guangxi,No.2025KY0164Youth Science Foundation of Guangxi Medical University,No.GXMUYSF202423Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z-A20220415 and No.Z20210442.
文摘BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacological potential,and kinesin family member 20A(KIF20A)is overexpressed in various tumors;however,their interaction in CRC remains unexplored.AIM To investigate the KIF20A expression characteristics in CRC cells and determine whether it is a potential target gene for NC in inhibiting CRC treatment.METHODS Single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and mRNA expression profiling were used to analyze KIF20A expression in CRC cells.Immunohistochemical staining was used to verify KIF20A expression in 416 clinical samples(208 CRC tissue samples and 208 noncancerous control tissue samples).Clustered regularly interspaced short palindromic repeats(CRISPR)technology was used to evaluate the impact of knocking out KIF20A on CRC cell growth.Molecular docking was applied to analyze NC–KIF20A binding.Finally,RNA sequencing and functional enrichment analysis were performed to explore the mechanism of action of NC in CRC cells.RESULTS Treating HCT116 cells with NC was found to significantly downregulate KIF20A(P<0.05),and the molecular docking analysis revealed high-affinity binding between NC and KIF20A(binding energy=-9.6 kcal/mol).The scRNA-seq,spatial transcriptomics,and mRNA expression profiling results confirmed the significantly high expression of KIF20A in CRC tissues(standardized mean difference=1.33,95%confidence interval:0.885-1.77,summary receiver operating characteristic curve area=0.94).The immunohistochemical analysis of the clinical samples showed high KIF20A expression in the CRC tissues(P<0.05),with significant correlation between the level of expression and gender,tumor size,and tumor grade(P<0.05).Knocking out KIF20A significantly inhibited the growth of various CRC cell lines(CRISPR score<-0.3).The functional enrichment analysis indicated that NC may inhibit CRC by disrupting several biological processes,such as mitotic nuclear division,chromosome segregation,and microtubule binding.CONCLUSION Our results indicate that NC binds to KIF20A with high affinity and downregulates its expression in CRC cells,leading to reduced proliferation.Hence,NC has promise as a therapeutic agent in the treatment of CRC,and targeting KIF20A also has potential as a therapeutic strategy.Further KIF20A knockout studies are needed to confirm the binding specificity and mechanistic roles of NC in CRC.
基金supported by King Abdul-Aziz University postgraduate scholarship(to SHM)the National Multiple Sclerosis Society(USA)Project Grant ID#RG43981/1(to SP)
文摘Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.
基金supported by the Science and Technology Office of Zhejiang Province(Grant Nos.2012C12901-2,2016C32085 and 2016C02050-6)
文摘Grain shape is one of the important agronomic traits, which is closely related to the yield of rice.A new rice mutant, named small and round grain(srg1), was isolated from an indica cultivar Zhenong 34 by ethyl methane sulfonate(EMS) mutagenesis. The microscopic analysis showed that the cell length of spikelet in srg1 was decreased compared with that in wild type(WT), which caused the grain length short.Meanwhile, the grains of srg1 were wider than those of WT because of the increased cell layers in spikelet in the lateral direction. Therefore, the inhibition of cell expansion and increased cell proliferation collectively led to the small and round grain. By map-based cloning, the gene SRG1 was located on the short arm of chromosome 9, which encodes a kinesin-4 protein, represented by the gene LOC_Os09 g02650. A single nucleotide polymorphism, occurred in the 16 th exon of SRG1, led to premature translation stop in mutant. The cell cycle-related genes were up-regulated in srg1, which conferred that SRG1 controlled grain width through the cell proliferation. Since the role of SRG1 in regulating grain shape was not clarified well before, it is valuable to explore the mechanism of grain development. This study could, hence, provide a morphogenesis and molecular basis for elucidating the function of SRG1, as well as a new germplasm resource for the further study of grain development.
基金Project supported by the National Natural Science Foundation of China(Grant No.11605038)the Open Project Program of State Key Laboratory of Theoretical Physics,Institute of Theoretical Physics,Chinese Academy of Sciences,China(Grant No.Y5KF211CJ1)
文摘Docking of the kinesin＇s neck linker （NL） to the motor domain is the key force-generation process of the kinesin. In this process, NL＇sβ10 portion forms four backbone hydrogen bonds （HBs） with the motor domain. These backbone hydrogen bonds show big differences in their effective strength. The origins of these strength differences are still unclear. Using molecular dynamics method, we investigate the stability of the backbone HBs in explicit water environment. We find that the strength differences of these backbone HBs mainly arise from their relationships with water molecules which are controlled by arranging the surrounding residue sidechains. The arrangement of the residues in the C-terminal part of /310 results in the existence of the water-attack channels around the backbone HBs in this region. Along these channels the water molecules can directly attack the backbone HBs and make these HBs relatively weak. In contrast, the backbone HB at the N-terminus ofβ 10 is protected by the surrounding hydrophobic and hydrophilic residues which cooperate positively with the central backbone HB and make this HB highly strong. The intimate relationship between the effective strength of protein backbone HB and water revealed here should be considered when performing mechanical analysis for protein conformational changes.
基金Fund for Scientific Research(FNRS)PDR T0236.20FNRS-Exellence of Science 30913351FNRS CDR J.0175.23(to FT)。
文摘Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,motility,and maturation.Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.In dividing cells,kinesin superfamily protein 2A is involved in mitotic progression,spindle assembly,and chromosome segregation.In postmitotic neurons,it is required for axon/dendrite specification and extension,neuronal migration,connectivity,and survival.Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development,epilepsy,autism spectrum disorder,and neurodegeneration.In this review,we discuss how kinesin superfamily protein 2A regulates neuronal development and function,and how its deregulation causes neurodevelopmental and neurological disorders.
基金discussed here on kinesin-5 inhibition as a means for augmenting nerve regeneration after injury was supported mainly by grants from the Craig H.Neilsen Foundation
文摘Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.
