scholarly journals The Impact of Coilin Nonsynonymous SNP Variants E121K and V145I on Cell Growth and Cajal Body Formation: The First Characterization

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 895
Author(s):  
Yue Yao ◽  
Heng Wee Tan ◽  
Zhan-Ling Liang ◽  
Gao-Qi Wu ◽  
Yan-Ming Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Structure ◽  
Cell Growth ◽  
Subcellular Localization ◽  
Structure Prediction ◽  
Bioinformatic Analysis ◽  
Survival Motor Neuron ◽  
Cajal Body ◽  
Survival Motor Neuron Protein ◽  
The Impact

Coilin is the main component of Cajal body (CB), a membraneless organelle that is involved in the biogenesis of ribonucleoproteins and telomerase, cell cycle, and cell growth. The disruption of CBs is linked to neurodegenerative diseases and potentially cancers. The coilin gene (COIL) contains two nonsynonymous SNPs: rs116022828 (E121K) and rs61731978 (V145I). Here, we investigated for the first time the functional impacts of these coilin SNPs on CB formation, coilin subcellular localization, microtubule formation, cell growth, and coilin expression and protein structure. We revealed that both E121K and V145I mutants could disrupt CB formation and result in various patterns of subcellular localization with survival motor neuron protein. Noteworthy, many of the E121K cells showed nucleolar coilin accumulation. The microtubule regrowth and cell cycle assays indicated that the E121K cells appeared to be trapped in the S and G2/M phases of cell cycle, resulting in reduced cell proliferation. In silico protein structure prediction suggested that the E121K mutation caused greater destabilization on the coilin structure than the V145I mutation. Additionally, clinical bioinformatic analysis indicated that coilin expression levels could be a risk factor for cancer, depending on the cancer types and races.

scholarly journals Decreased function of survival motor neuron protein impairs endocytic pathways

2016 ◽  
Vol 113 (30) ◽  
pp. E4377-E4386 ◽  
Author(s):  
Maria Dimitriadi ◽  
Aaron Derdowski ◽  
Geetika Kalloo ◽  
Melissa S. Maginnis ◽  
Patrick O’Hern ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Muscular Atrophy ◽  
Ultrastructural Level ◽  
Synaptic Function ◽  
Survival Motor Neuron ◽  
Endosomal Trafficking ◽  
Survival Motor Neuron Protein ◽  
Ribonucleoprotein Complexes ◽  
The Impact ◽  
Endocytic Pathways

Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.

scholarly journals Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2643
Author(s):  
Fuguang Zhao ◽  
Olesya Vakhrusheva ◽  
Sascha D. Markowitsch ◽  
Kimberly S. Slade ◽  
Igor Tsaur ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Significant Inhibition ◽  
Cycle Arrest ◽  
Damage Repair ◽  
Autophagy Induction ◽  
Cell Growth And Proliferation ◽  
The Impact

Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.

scholarly journals Dynamic metabolic network modeling of a mammalian cell cycle using time-course multi-omics data

2021 ◽  
Author(s):  
Ho-Joon Lee ◽  
Fangzhou Shen ◽  
Alec Eames ◽  
Mark P Jedrychowski ◽  
Sriram Chandrasekaran
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Time Course ◽  
Metabolic Networks ◽  
Proteomics Data ◽  
Modeling Framework ◽  
Dynamic Genome ◽  
Metabolic Network Modeling ◽  
Cell Growth And Proliferation ◽  
The Impact

Cell cycle is a fundamental process for cell growth and proliferation, and its dysregulation leads to many diseases. How metabolic networks are regulated and rewired during the cell cycle is unknown. Here we apply a dynamic genome-scale metabolic modeling framework (DFA) to simulate a cell cycle of cytokine-activated murine pro-B cells. Phase-specific reaction activity predicted by DFA using time-course metabolomics were validated using matched time-course proteomics and phospho-proteomics data. Our model correctly predicted changes in methionine metabolism at the G1/S transition and the activation of lysine metabolism, nucleotides synthesis, fatty acid elongation and heme biosynthesis at the critical G0/G1 transition into cell growth and proliferation. Metabolic fluxes predicted from proteomics and phosphoproteomics constrained metabolic models were highly consistent with DFA fluxes and revealed that most reaction fluxes are regulated indirectly. Our model can help predict the impact of changes in nutrients, enzymes, or regulators on this critical cellular process.

scholarly journals Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3842
Author(s):  
Yang-Jean Li ◽  
Tai-Heng Chen ◽  
Yan-Zhang Wu ◽  
Yung-Hao Tseng
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Nutritional Assessment ◽  
Muscular Atrophy ◽  
Nutritional Therapy ◽  
Survival Motor Neuron ◽  
Nutrition Support ◽  
Metabolic Abnormalities ◽  
Survival Motor Neuron Protein ◽  
The Impact

Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.

scholarly journals Protein Structure Prediction and Bioinfamatic Analysis of Novel Fusion Gene IKZF1/Pfas in BPDCN

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4319-4319
Author(s):  
Yin Le ◽  
Qian Yu ◽  
Hongkai Zhu ◽  
Yi Jiang ◽  
Zhihua Wang ◽  
...  
Keyword(s):  
Protein Structure ◽  
Structure Prediction ◽  
Cancer Metastasis ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Plasmacytoid Dendritic Cell ◽  
Bioinformatic Analysis ◽  
3D Protein Structure ◽  
Key Genes

Abstract A novel fusion gene, IKAROS Family Zinc Finger 1 (IKZF1)/Phosphoribosylformylglycinamidine Synthase (PFAS), was identified in a patient diagnosed with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Secondary protein structure analysis, 3D protein structure determination and domain analysis revealed loss of the ZnF-C2H2 domains of IKZF1 caused by premature translation termination at amino acid (AA) residue 55, which might cause dysfunction of IKZF1. Bioinformatic analysis was conducted using RNA-seq data for 37 BPDCN samples from the GSE database (GSE62014 and GSE89565) to elucidate the role of IKZF1 in BPDCN. WGCNA showed that IKZF1 expression could be used to categorize BPDCN samples into two distinct clusters (IKZF1 high and IKZF1 low). Differentially expressed genes (DEGs) were identified in these two subgroups and subjected to GO and KEGG analyses. Mitochondrial function-related pathways and ubiquitin-mediated proteolysis were the most enriched pathways in the GO and KEGG analyses, respectively. A PPI network of the DEGs was constructed, and 10 key genes were identified (CSTF2, SF3B1, U2AF2, HNRNPH1, SF3B3, SNRNP200, LSM2, SLU7, CPSF4 and UPF3B). Most of these genes are related to tumorigenesis, cancer metastasis, and hematopoietic malignancies. In conclusion, the novel IKZF1/PFAS fusion gene could cause dysfunction of the IKZF1. The bioinformatic analysis results emphasized the role of IKZF1 in BPDCN and identified 10 key genes closely related to IKZF1, most of which are tumorigenesis-related. Disclosures No relevant conflicts of interest to declare.

Differential Subcellular Localization of the Survival Motor Neuron Protein in Spinal Cord and Skeletal Muscle

1999 ◽  
Vol 254 (1) ◽  
pp. 10-14 ◽  
Author(s):  
Barbara Y. Williams ◽  
Shyamala Vinnakota ◽  
Cheryl A. Sawyer ◽  
J.Clifford Waldrep ◽  
Susan L. Hamilton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Subcellular Localization ◽  
Motor Neuron ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Protein ◽  
Motor Neuron Protein

scholarly journals LINC00518 Promotes Cell Proliferation by Regulating the Cell Cycle of Lung Adenocarcinoma Through miR-185-3p Targeting MECP2

2021 ◽  
Vol 11 ◽  
Author(s):  
Xu Han ◽  
Jixiang Wu ◽  
Yajun Zhang ◽  
Jianxiang Song ◽  
Zhan Shi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Lung Adenocarcinoma ◽  
Human Cancer ◽  
Survival Rates ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter

Previous studies have shown that long intergenic non-protein coding RNA 00518 (LINC00518) are essential for the cell growth and metastasis of human cancer. However, the role of LINC00518 in lung adenocarcinoma (LUAD) is still unknown. This research put emphasis on the function of LINC00518 on the cell growth of LUAD. The lncRNA, miRNA and mRNA expression were measured by using qRT-PCR. Protein levels were measured by using Western blotting. CCK-8, colony formation assays and transwell assay were performed to evaluate the cell proliferation ability and invasion. Bioinformatic analysis and luciferase reporter assays were chosen to confirm the mechanism of LINC00518 in LUAD. We found that LINC00518 was highly expressed in LUAD specimens and the high-expression was negatively correlated with the overall survival rates. This finding was also proved in the LUAD cell lines. Through a series of in vitro and in vivo experiments, we proved that LICN00518 promoted the cell growth of LUAD by regulating the cell cycle. Moreover, LICN00518 upregulated the expression of MECP2 by mutagenesis of miR-185-3p. The results suggested that LICN00518 could be used as a survival indicator and potential therapeutic target for LUAD patients.

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