scholarly journals Changes in intracellular copper concentration and copper-regulating gene expression after PC12 differentiation into neurons

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yasumitsu Ogra ◽  
Aya Tejima ◽  
Naohiro Hatakeyama ◽  
Moeko Shiraiwa ◽  
Siyuan Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copper Concentration ◽  
Pc12 Differentiation ◽  
Intracellular Copper

scholarly journals Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-β Precursor Protein Gene

2004 ◽  
Vol 279 (19) ◽  
pp. 20378-20386 ◽  
Author(s):  
Shayne A. Bellingham ◽  
Debomoy K. Lahiri ◽  
Bryan Maloney ◽  
Sharon La Fontaine ◽  
Gerd Multhaup ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Fibroblasts ◽  
Amyloid Β ◽  
Copper Homeostasis ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Copper Depletion ◽  
Intracellular Copper

Alzheimer's disease is characterized by the accumulation of amyloid-β peptide, which is cleaved from the amyloid-β precursor protein (APP). Reduction in levels of the potentially toxic amyloid-β has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of theAPPgene. Recentin vivoandin vitrostudies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-β in copper homeostasis. We hypothesized that metals and in particular copper might alterAPPgene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein.MNKdeletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulatedAPPgene expression. Furthermore,APPpromoter deletion constructs identified the copper-regulatory region between -490 and +104 of theAPPgene promoter in both basal MNK overexpressing cells and in copper-chelatedMNKdeletion cells. Overall these data support the hypothesis that copper can regulateAPPexpression and further support a role for APP to function in copper homeostasis. Copper-regulatedAPPexpression may also provide a potential therapeutic target in Alzheimer's disease.

scholarly journals Impact of Endocytosis and Lysosomal Acidification on the Toxicity of Copper Oxide Nano- and Microsized Particles: Uptake and Gene Expression Related to Oxidative Stress and the DNA Damage Response

Nanomaterials ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 679 ◽  
Author(s):  
Bettina Maria Strauch ◽  
Wera Hubele ◽  
Andrea Hartwig
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Dna Damage ◽  
Copper Oxide ◽  
Copper Ions ◽  
Mediated Effects ◽  
Intracellular Release ◽  
The Impact ◽  
Lysosomal Acidification ◽  
Intracellular Copper

The toxicity of the copper oxide nanoparticles (CuO NP) has been attributed to the so-called “Trojan horse”-type mechanism, relying on the particle uptake and extensive intracellular release of copper ions, due to acidic pH in the lysosomes. Nevertheless, a clear distinction between extra- and intracellular-mediated effects is still missing. Therefore, the impact of the endocytosis inhibitor hydroxy-dynasore (OH-dyn), as well as bafilomycin A1 (bafA1), inhibiting the vacuolar type H+-ATPase (V-ATPase), on the cellular toxicity of nano- and microsized CuO particles, was investigated in BEAS 2 B cells. Selected endpoints were cytotoxicity, copper uptake, glutathione (GSH) levels, and the transcriptional DNA damage and (oxidative) stress response using the high-throughput reverse transcription quantitative polymerase chain reaction (RT-qPCR). OH-dyn markedly reduced intracellular copper accumulation in the cases of CuO NP and CuO MP; the modulation of gene expression, induced by both particle types affecting especially HMOX1, HSPA1A, MT1X, SCL30A1, IL8 and GADD45A, were completely abolished. BafA1 lowered the intracellular copper concentration in case of CuO NP and strongly reduced transcriptional changes, while any CuO MP-mediated effects were not affected by bafA1. In conclusion, the toxicity of CuO NP depended almost exclusively upon dynamin-dependent endocytosis and the intracellular release of redox-active copper ions due to lysosomal acidification, while particle interactions with cellular membranes appeared to be not relevant.

Copper‐Transporting ATPases: Key Regulators of Intracellular Copper Concentration

2004 ◽  
pp. 99-158 ◽  
Author(s):  
Ruslan Tsivkovskii ◽  
Tina Purnat ◽  
Svetlana Lutsenko
Keyword(s):  
Copper Concentration ◽  
Intracellular Copper

scholarly journals P0735ELAVATED INTRACELLULAR COPPER CONTRIBUTES A UNIQUE ROLE TO KIDNEY FIBROSIS BY LYSYL OXIDASE MEDIATED MATRIX CROSSLINGKING

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yangyang Niu ◽  
Chen Yu
Keyword(s):  
Renal Fibrosis ◽  
Copper Concentration ◽  
Lysyl Oxidase ◽  
Kidney Tissue ◽  
Underlying Mechanism ◽  
Cross Linking ◽  
Tgf Β1 ◽  
Collagen Cross Linking ◽  
Intracellular Copper

Abstract Background and Aims Copper is an essential trace element required for many biological processes. Some studies have demonstrated that copper accumulating was related to liver fibrosis and lung fibrosis, but the underlying mechanism is not very clear. Copper is the essential unit of lysyl oxidase (LOXs), which are the key enzymes of crosslinking of extracellular matrix. Method Sprague-Dawley rats were divided into the sham group, unilateral ureteral obstruction (UUO) operated group and UUO treated with copper chelating agents tetrathiomolybdate (TM). Rat kidney fibroblast cells (NRK-49F) were used in vitro. The concentration of copper, the LOXs activity and the degree of cross-linking of extracellular collagen were detected in vivo and vitro. Results (1) The copper concentration in serum, urine and kidney of rats increased significantly at 7 days after UUO surgery; After treatment of TGF-β1, the intracellular copper concentration was increased significantly in cells; The concentration of copper in patients` serum is on the rise with the progression of chronic kidney disease (CKD). (2) The expression of CTR1 was upregulated in the kidneys of UUO rats; The level of CTR1 was increased significantly by TGF-β1 in vitro; (3) Blockage of Smad2/3 suppresses TGF-β1-induced expression of CTR1; (4) Downregulation of CTR1 significantly inhibited the intracellular copper concentration; (5) The activity of LOXs was increased significantly after TGF-β1 treatment; (6) Downregulation of CTR1 significantly inhibited the activity of LOXs and the cross-linking of extracellular collagen induced by TGF-β1 in vitro; (7) The concentration of copper, the degree of collagen cross-linking and the deposition of collagen were decreased in the kidney tissue of UUO rats after treatment with TM. The concentration of intracellular copper, the activity of LOXs and the degree of collagen cross-linking were attenuated with treatment of TM in vitro. Conclusion We firstly found that the intracellular copper accumulating was closely to renal fibrosis. The underlying mechanism was related with the increasing expression of CTR1 and activity of LOXs. Treatment with TM ameliorated the renal fibrosis. This study presented a novel treatment target for renal fibrosis.

Molecular and Microscopic Analysis of Altered Gene Expression in Transgenic and Gene Targeted Mice

1996 ◽  
Vol 54 ◽  
pp. 12-13
Author(s):  
W. K. Jones ◽  
J. Robbins
Keyword(s):  
Gene Expression ◽  
Pulmonary Veins ◽  
Microscopic Analysis ◽  
Mouse Tissue ◽  
Adult Heart ◽  
Heavy Chains ◽  
Altered Gene Expression ◽  
Altered Gene ◽  
Pulmonary Myocardium

Two myosin heavy chains (MyHC) are expressed in the mammalian heart and are differentially regulated during development. In the mouse, the α-MyHC is expressed constitutively in the atrium. At birth, the β-MyHC is downregulated and replaced by the α-MyHC, which is the sole cardiac MyHC isoform in the adult heart. We have employed transgenic and gene-targeting methodologies to study the regulation of cardiac MyHC gene expression and the functional and developmental consequences of altered α-MyHC expression in the mouse.We previously characterized an α-MyHC promoter capable of driving tissue-specific and developmentally correct expression of a CAT (chloramphenicol acetyltransferase) marker in the mouse. Tissue surveys detected a small amount of CAT activity in the lung (Fig. 1a). The results of in situ hybridization analyses indicated that the pattern of CAT transcript in the adult heart (Fig. 1b, top panel) is the same as that of α-MyHC (Fig. 1b, lower panel). The α-MyHC gene is expressed in a layer of cardiac muscle (pulmonary myocardium) associated with the pulmonary veins (Fig. 1c). These studies extend our understanding of α-MyHC expression and delimit a third cardiac compartment.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

Role of small nuclear RNAs in eukaryotic gene expression

2013 ◽  
Vol 54 ◽  
pp. 79-90 ◽  
Author(s):  
Saba Valadkhan ◽  
Lalith S. Gunawardane
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Rna Stability ◽  
Splice Sites ◽  
Branch Site ◽  
Small Nuclear Rnas ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Rna Biogenesis

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.

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