New roles for copper metabolism in cell proliferation, signaling, and disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Turski ML
PROVIDER: S-EPMC2613604 | biostudies-literature | 2009 Jan
REPOSITORIES: biostudies-literature
Publications
New roles for copper metabolism in cell proliferation, signaling, and disease.
Turski Michelle L ML Thiele Dennis J DJ
The Journal of biological chemistry 20080829 2
Similar Datasets
Project description:β-Arrestin 1 (ARRB1) has been recognized as a multifunctional adaptor protein in the last decade, beyond its original role in desensitizing G protein-coupled receptor signaling. Here, we identify that ARRB1 plays essential roles in mediating gastric cancer (GC) cell metabolism and proliferation, by combining cohort analysis and functional investigation using patient-derived preclinical models. Overexpression of ARRB1 was associated with poor outcome of GC patients and knockdown of ARRB1 impaired cell proliferation both ex vivo and in vivo. Intriguingly, ARRB1 depicted diverse subcellular localizations during a passage of organoid cultures (7 d) to exert dual functions. Further analysis revealed that nuclear ARRB1 binds with transcription factor E2F1 triggering up-regulation of proliferative genes, while cytoplasmic ARRB1 modulates metabolic flux by binding with the pyruvate kinase M2 isoform (PKM2) and hindering PKM2 tetramerization, which reduces pyruvate kinase activity and leads to cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis. As ARRB1 localization was shown mostly in the cytoplasm in human GC samples, therapeutic potential of the ARRB1-PKM2 axis was tested, and we found tumor proliferation could be attenuated by the PKM2 activator DASA-58, especially in ARRB1high organoids. Together, the data in our study highlight a spatiotemporally dependent role of ARRB1 in mediating GC cell metabolism and proliferation and implies reactivating PKM2 may be a promising therapeutic strategy in a subset of GC patients.
| S-EPMC9546581 | biostudies-literature
Project description:The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.
| S-EPMC4728329 | biostudies-literature
Project description: Not available
| S-EPMC10351475 | biostudies-literature
Project description:MTF1 is a highly conserved metal-binding transcription factor in eukaryotes. MTF1 binds to DNA sequence motifs, termed metal response elements (MREs) to induce the expression of genes involved in metal and oxidative stress homeostasis. MTF1 is responsive to both metal excess and deprivation, and can also protect cells from oxidative and hypoxic stresses. Disruption of metal homeostasis leads to the development of several pathological states. Despite its roles in these processes , MTF1 has been shown to be required for developmental processes such as embryonic liver formation. In this study, we used multiple strategies to understand the mechanism by which MTF1 functions in skeletal muscle differentiation and to determine the role cellular copper (Cu) status plays in this process. We provide the functional relationships between MTF1, Cu, myogenic gene promoters, and MyoD, an specific component of the myogenic transcriptional machinery in differentiating primary myoblasts derived from mouse satellite cells. We found that MTF1 is induced and translocated to the nucleus upon initiation of myogenesis. Consistent with previous studies from our laboratory , addition of non-toxic concentrations of Cu promote myogenesis and enhanced MTF1 expression. CRISPR/Cas9-mediated depletion of MTF1 demonstrated that MTF1 is essential for proper development of skeletal muscle, as partial Mtf1 knockdown leads to apoptosis to differentiating myoblasts. MTF1 was also found to bind Cu at a carboxy-terminal tetra-cysteine cluster, which may contribute to the mobilization of Cu to the nucleus during myogenesis. ChIP-seq and ChIP-qPCR analyses showed that MTF1 binds at the promoter regions of myogenic genes as part of a complex with MyoD, the master transcriptional regulator of the myogenic lineage. These results have the potential to initiate a new area of research in MTF1 function and in the regulation of myogenesis. Furthermore, these studies set the basis to understand the role of Cu at the transcriptional level, affects growth and development and will contribute to the largely unexplored are of muscular phenotypes observed in human pathologies associated to Cu misbalance, such as Menkes’ and Wilson’s diseases.
2019-10-04 | GSE116331 | GEO
Project description:Ascites plays a key role in supporting the metastatic potential of ovarian cancer cells. Shear stress and carry-over of cancer cells by ascites flow support carcinogenesis and metastasis formation. In addition, soluble factors may participate in the procarcinogenic effects of ascites in ovarian cancer. This study aimed to determine the biological effects of cell-free ascites on carcinogenesis in ovarian cancer cells. Cell-free ascites from ovarian cancer patients (ASC) non-selectively induced cell proliferation in multiple models of ovarian cancer and untransformed primary human dermal fibroblasts. Furthermore, ASC induced a Warburg-type rearrangement of cellular metabolism in A2780 ovarian cancer cells characterized by increases in cellular oxygen consumption and glycolytic flux; increases in glycolytic flux were dominant. ASC induced mitochondrial uncoupling and fundamentally reduced fatty acid oxidation. Ascites-elicited effects were uniform among ascites specimens. ASC-elicited transcriptomic changes in A2780 ovarian cancer cells included induction of the TGFβ-ERK/MEK pathway, which plays a key role in inducing cell proliferation and oncometabolism. ASC-induced gene expression changes, as well as the overexpression of members of the TGFβ signaling system, were associated with poor survival in ovarian cancer patients. We provided evidence that the activation of the autocrine/paracrine of TGFβ signaling system may be present in bladder urothelial carcinoma and stomach adenocarcinoma. Database analysis suggests that the TGFβ system may feed forward bladder urothelial carcinoma and stomach adenocarcinoma. Soluble components of ASC support the progression of ovarian cancer. These results suggest that reducing ascites production may play an essential role in the treatment of ovarian cancer by inhibiting the progression and reducing the severity of the disease.
| S-EPMC11226691 | biostudies-literature
Project description:Metabolic reprogramming is a driver of autosomal dominant polycystic kidney disease (ADPKD) progression and a potential therapeutic intervention route. We showed before that the AMP-associated protein kinase (AMPK) activator salsalate attenuates cystic disease progression. Here, we aim to study the early, direct effects of short salsalate treatment in adult-onset conditional Pkd1 deletion mice. Cystic mice were treated with salsalate for two weeks, after which NMR metabolomics and RNA sequencing analyses were performed. Pkd1 deletion resulted in clear metabolomic dysregulation. Short salsalate treatment has small, but significant, effects, reverting acetylcarnitine and phosphocholine concentrations back to wildtype levels, and showing associations with altered purine metabolism. RNA sequencing revealed that short salsalate treatment, next to restoring energy metabolism toward wildtype levels, also affects cell proliferation and inflammation, in PKD. We show that salsalate positively affects major dysregulated processes in ADPKD: energy metabolism, cell proliferation, and inflammation, providing more insights into its working mechanisms.
| S-EPMC10665819 | biostudies-literature
Project description:ObjectivesThis study aimed to identify key genes related to copper metabolism in Parkinson's disease (PD), providing insight into their roles in disease progression.MethodsUsing bioinformatic analyses, the study identified hub genes related to copper metabolism in PD patients. Differentially expressed genes (DEGs) were identified using the limma package, and copper-metabolism-related genes (CMRGs) were sourced from the Genecard database. Immune cell-related genes were derived through immune infiltration and Weighted Gene Co-expression Network Analysis (WGCNA). Hub genes were pinpointed by integrating DEGs, CMRGs, and immune cell-related genes. Functional analyses included Receiver Operating Characteristic (ROC) analysis, Ingenuity Pathway Analysis (IPA), and networks for miRNA-mRNA-transcription factor (TF), Competitive Endogenous RNA (ceRNA), and hub gene-drug interactions. Validation was performed in cerebrospinal fluid (CSF) samples from PD patients, while in vitro experiments utilized GBE1- overexpressing SH-SY5Y cells to examine cell proliferation, migration, and viability.ResultsNine hub genes (HPRT1, GLS, SNCA, MDH1, GBE1, DDC, STXBP1, ACHE, and AGTR1) were identified from 753 CMRGs, 416 DEGs, and 951 immune cell-related genes. ROC analysis showed high predictive accuracy for PD, and principal component analysis (PCA) effectively distinguished PD patients from controls. IPA identified 20 significant pathways, and various networks highlighted miRNA, TF, and drug interactions with the hub genes. Hub gene expression was validated in PD CSF samples. GBE1-overexpressing cells displayed enhanced proliferation, migration, and viability.ConclusionsThe study identified nine copper metabolism-related genes as potential therapeutic targets in PD, highlighting their relevance in PD pathology and possible treatment pathways.
| S-EPMC11574951 | biostudies-literature
Project description:Copper is an important transition metal cofactor in plant metabolism, which enables diverse biocatalysis in aerobic environments. Multiple classes of plant metalloenzymes evolved and underwent genetic expansions during the evolution of terrestrial plants and, to date, several representatives of these copper enzyme classes have characterized mechanisms. In this review, we give an updated overview of chemistry, structure, mechanism, function and phylogenetic distribution of plant copper metalloenzymes with an emphasis on biosynthesis of aromatic compounds such as phenylpropanoids (lignin, lignan, flavonoids) and cyclic peptides with macrocyclizations via aromatic amino acids. We also review a recent addition to plant copper enzymology in a copper-dependent peptide cyclase called the BURP domain. Given growing plant genetic resources, a large pool of copper biocatalysts remains to be characterized from plants as plant genomes contain on average more than 70 copper enzyme genes. A major challenge in characterization of copper biocatalysts from plant genomes is the identification of endogenous substrates and catalyzed reactions. We highlight some recent and future trends in filling these knowledge gaps in plant metabolism and the potential for genomic discovery of copper-based enzymology from plants.
| S-EPMC8672867 | biostudies-literature
Project description:Emerging studies show that melatonin promotes cashmere development through hypodermic implantation. However, the impact and underlying mechanisms are currently unknown. In vitro study has previously demonstrated that melatonin induces cashmere growth by regulating the proliferation of goat secondary hair follicle stem cells (gsHFSCs), but there is limited information concerning the effects of melatonin on cell pluripotency. It is also known that Wnt signaling may actively participate in regulating cell proliferation and stem cell pluripotency. Therefore, in the current investigation, goat hair follicle stem cells were exposed to multiple concentrations of melatonin and different culture times to reveal the relationship between melatonin and the activation of Wnt signaling. A proportionally high Catenin beta-1 (CTNNB1) response was induced by 500 ng/L of melatonin, but it was then suppressed with the dosages over 1,000 ng/L. Greater amounts of CTNNB1 entered the cell nuclei by extending the exposure time to 72 h, which activated transcription factor 4/lymphoid enhancer-binding factor 1 and promoted the expression of the proliferation-related genes C-MYC, C-JUN, and CYCLIND1. Moreover, nuclear receptor ROR-alpha (RORα) and bone morphogenetic protein 4 (BMP4) were employed to analyze the underlying mechanism. RORα presented a sluggish concentration/time-dependent rise, but BMP4 was increased dramatically by melatonin exposure, which revealed that melatonin might participate in regulating the pluripotency of hair follicle stem cells. Interestingly, NOGGIN, which is a BMP antagonist and highly relevant to cell stemness, was also stimulated by melatonin. These findings demonstrated that melatonin exposure and/or NOGGIN overexpression in hair follicle stem cells might promote the expression of pluripotency markers Homeobox protein NANOG, Organic cation/carnitine transporter 4, and Hematopoietic progenitor cell antigen CD34. Our findings here provided a comprehensive view of Wnt signaling in melatonin stimulated cells and melatonin mediated stemness of gsHFSCs by regulating NOGGIN, which demonstrates a regulatory mechanism of melatonin enhancement on the growth of cashmere.
| S-EPMC8212062 | biostudies-literature
Project description:To examine the roles of active hypusinated eIF5A (eukaryotic translation initiation factor 5A) and polyamines in cell proliferation, mouse mammary carcinoma FM3A cells were treated with an inhibitor of deoxyhypusine synthase, GC7 (N1-guanyl-1, 7-diaminoheptane), or with an inhibitor of ornithine decarboxylase, DFMO (a-difluoromethylornithine), or with DFMO plus an inhibitor of spermine synthase, APCHA [N1-(3-aminopropyl)-cyclohexylamine]. Treatment with GC7 decreased the level of active eIF5A on day 1 without affecting cellular polyamine content, and inhibition of cell growth occurred from day 2. This delay reflects the fact that eIF5A was present in excess and was very stable in these cells. Treatment with DFMO or with DFMO plus APCHA inhibited cell growth on day 1. DFMO considerably decreased the levels of putrescine and spermidine, and the formation of active eIF5A began to decrease when the level of spermidine fell below 8 nmol/mg of protein after 12 h of incubation with DFMO. The combination of DFMO and APCHA markedly decreased the levels of putrescine and spermine and significantly decreased the level of spermidine, but did not affect the level of active eIF5A until day 3 when spermidine level decreased to 7 nmol/mg of protein. The results show that a decrease in either active eIF5A or polyamines inhibits cell growth, indicating that eIF5A and polyamines are independently involved in cell growth
| S-EPMC1134754 | biostudies-other