查看更多>>摘要：Endothelial damage is the initial and crucial factor in the occurrence and development of vascular complications in diabetic patients,contributing to morbidity and mortality.Although hyperglycemia has been identified as a damaging effector,the detailed mechanisms remain elusive.In this study,identified by ATAC-seq and RNA-seq,JunB reverses the inhibition of proliferation and the promotion of apoptosis in human umbilical vein endothelial cells treated with high glucose,mainly through the cell cycle and p53 signaling pathways.Furthermore,JunB undergoes phase separation in the nucleus and in vitro,mediated by its intrinsic disordered region and DNA-binding domain.Nuclear localization and condensation behaviors are required for JunB-mediated proliferation and apoptosis.Thus,our study uncovers the roles of JunB and its coacervation in repairing vascular endothelial damage caused by high glucose,elucidating the involvement of phase separation in diabetes and diabetic endothelial dysfunction.
查看更多>>摘要：Glycogen synthase kinase 3(GSK3)signaling plays important and broad roles in regulating neural development in vitro and in vivo.Here,we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field.Overall,current evidence indicates that GSK3 β signaling serves as an important downstream mediator of the PI3K-AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway.Specifically,the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation,whereas GSK3 β signaling might be involved in regulating N6-methyladenosine mRNA methylation-mediated cap-independent protein translation.In addition,GSK3 signaling also plays a key role in reshaping the neuronal transcriptomic landscape during neural regeneration.Finally,we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets.Together,we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo.
查看更多>>摘要：Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined.Here,we characterized dNKAP,the Drosophila homolog of NKAP,and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics,including tissue overgrowth,cell-invasive behavior,abnormal cell polarity,and cell adhesion defects.dNKAP knockdown causes both R-loop accumulation and DNA damage,indicating the disruption of genome integrity.Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase(JNK)-dependent apoptosis and causes changes in cell proliferation in distinct cell populations.Activation of the Notch and Janus kinase/signal transducer and activator of transcription(JAK/STAT)signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues.Furthermore,JNK signaling is essential for dNKAP depletion-mediated cell invasion.Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAP knockdown and oncogenic Ras,Notch,or Yki mutations show synergies in driving tumorigenesis,further supporting the tumor-suppressive role of dNKAP.In summary,this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.
查看更多>>摘要：Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Herein,we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols.Moreover,environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups.Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane,which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly.In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella.These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.
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