scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals Hypoxia-induced PTTG3P contributes to colorectal cancer glycolysis and M2 phenotype of macrophage

2021 ◽  
Author(s):  
Yue Wang ◽  
Guilin Yu ◽  
Yiyang Liu ◽  
Longfei Xie ◽  
Jinnian Ge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Malignant Tumors ◽  
Macrophage Polarization ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Mice Model ◽  
Atp Assay ◽  
Dismal Prognosis ◽  
Novel Approach ◽  
M2 Phenotype

Long noncoding RNAs (lncRNAs) play critical factors in tumor progression and are ectopically expressed in malignant tumors. Until now, lncRNA PTTG3P biological function in colorectal cancer (CRC) needs further to be clarified. qRT-PCR was used to measure the PTTG3P level and CCK-8, glucose uptake, lactate assay, ATP assay, ECAR assay, and xenograft mice model were adopted to evaluate the glycolysis and proliferation, and macrophage polarization were determined in CRC cells. Xenograft experiments were utilized to analyze tumor growth. Ectopic expression of PTTG3P was involved in CRC and related to dismal prognosis. Through gain-of-function and loss-of-function approaches, PTTG3P enhanced cell proliferation and glycolysis through YAP1. Further, LDHA knockdown or glycolysis inhibitor (2-DG,3-BG) recovered PTTG3P-induced proliferation. And PTTG3P overexpression could facilitate M2 polarization of macrophages. Silenced PTTG3P decreased the level of inflammatory cytokines TNF-α, IL-1β, and IL-6, and low PTTG3P expression related with CD8+ T, NK, and TFH cell infiltration. Besides, HIF1A could increase PTTG3P expression by binding to the PTTG3P promoter region. Hypoxia-induced PTTG3P contributes to glycolysis and M2 phenotype of macrophage, which proposes a novel approach for clinical treatment.

scholarly journals Hypoxia-Induced PTTG3P Contributes to Colorectal Cancer Glycolysis and M2 Phenotype of Macrophage

2021 ◽  
Author(s):  
yue wang ◽  
guilin yu ◽  
yiyang liu ◽  
longfei xie ◽  
jinnian ge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Malignant Tumors ◽  
Macrophage Polarization ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Mice Model ◽  
Atp Assay ◽  
Dismal Prognosis ◽  
Novel Approach ◽  
M2 Phenotype

Abstract Background Long noncoding RNAs (lncRNAs) play critical factors in tumor progression and are ectopically expressed in malignant tumors. Until now, lncRNA PTTG3P biological function in colorectal cancer (CRC) needs further to be clarified. Methods qRT-PCR was used to measure the PTTG3P level and CCK-8, glucose uptake, lactate assay, ATP assay, ECAR assay, and xenograft mice model were adopted to evaluate the glycolysis and proliferation, and macrophage polarization were determined in CRC cells. Xenograft experiments were utilized to analyze tumor growth. Results Ectopic expression of PTTG3P was involved in CRC and related to dismal prognosis. Through gain-of-function and loss-of-function approaches, PTTG3P enhanced cell proliferation and glycolysis through YAP1. Further, LDHA knockdown or glycolysis inhibitor (2-DG,3-BG) recovered PTTG3P-induced proliferation. And PTTG3P overexpression could facilitate M2 polarization of macrophages. Silenced PTTG3P decreased the level of inflammatory cytokines TNF-α, IL-1β, and IL-6, and low PTTG3P expression related with CD8+ T, NK, and TFH cell infiltration. Besides, HIF1A could increase PTTG3P expression by binding to the PTTG3P promoter region. Conclusions Hypoxia-induced PTTG3P contributes to glycolysis and M2 phenotype of macrophage, which proposes a novel approach for clinical treatment.

scholarly journals Increased Uptake of Zinc in Malignant Cells is Associated with Enhanced Activation of MAPK Signalling and P53-Dependent Cell Injury

2008 ◽  
Vol 51 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Emil Rudolf
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Injury ◽  
Cell Damage ◽  
Zinc Homeostasis ◽  
Malignant Cells ◽  
Intracellular Zinc ◽  
Free Zinc ◽  
Dependent Cell ◽  
Zinc Levels

Excess intracellular zinc has been demonstrated to be responsible for cell injury and cell death in various experimental as well as clinical models. While the cells possess a system of mechanisms regulating intracellular zinc homeostasis, their saturation by acutely increased zinc levels or by a sustained exposure to elevated zinc levels results in liberation of free zinc stores within the cells and ultimate cell damage and cell death. Here we report that in Hep-2 malignant cells enhanced uptake of zinc causes activation of mitogen-activated protein kinase (MAPK) signaling with resulting p53-dependent cell injury which can be significantly prevented by specific p53 inhibition and by prevention of oxidative stress. Our observations are consistent with the view that subacutely increased intracellular free zinc levels stimulate via oxidative stress p53-dependent pathways which are responsible for the final cell damage in tumor cells.

scholarly journals Synaptic Zinc: An Emerging Player in Parkinson’s Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4724
Author(s):  
Joanna Sikora ◽  
Abdel-Mouttalib Ouagazzal
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cortical Neurons ◽  
Zinc Homeostasis ◽  
Glutamatergic System ◽  
Cellular Functions ◽  
Intracellular Zinc ◽  
Glutamatergic Neurons ◽  
Zinc Levels ◽  
The Brain

Alterations of zinc homeostasis have long been implicated in Parkinson’s disease (PD). Zinc plays a complex role as both deficiency and excess of intracellular zinc levels have been incriminated in the pathophysiology of the disease. Besides its role in multiple cellular functions, Zn2+ also acts as a synaptic transmitter in the brain. In the forebrain, subset of glutamatergic neurons, namely cortical neurons projecting to the striatum, use Zn2+ as a messenger alongside glutamate. Overactivation of the cortico-striatal glutamatergic system is a key feature contributing to the development of PD symptoms and dopaminergic neurotoxicity. Here, we will cover recent evidence implicating synaptic Zn2+ in the pathophysiology of PD and discuss its potential mechanisms of actions. Emphasis will be placed on the functional interaction between Zn2+ and glutamatergic NMDA receptors, the most extensively studied synaptic target of Zn2+.

scholarly journals Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model

F1000Research ◽  
2018 ◽  
Vol 4 ◽  
pp. 214 ◽  
Author(s):  
Mark Brenneman ◽  
Amanda Field ◽  
Jiandong Yang ◽  
Gretchen Williams ◽  
Leslie Doros ◽  
...  
Keyword(s):  
Temporal Order ◽  
De Novo ◽  
Lung Tumor ◽  
Malignant Tumors ◽  
Early Adulthood ◽  
Pleuropulmonary Blastoma ◽  
Neoplastic Disease ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Clinical Phenotypes

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.

scholarly journals Kupyaphores are counter regulatory zinc homeostatic metallophores required for Mycobacterium tuberculosis colonization

2021 ◽  
Author(s):  
Kritee Mehdiratta ◽  
Shubham Singh ◽  
Sachin Sharma ◽  
Rashmi Bhosale ◽  
Rahul Choudhury ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Studies ◽  
Covalent Modification ◽  
Zinc Homeostasis ◽  
Macrophage Infection ◽  
Intracellular Zinc ◽  
Nutritional Deprivation ◽  
Zinc Release ◽  
Metabolic Imbalance ◽  
And Function

Abstract Tuberculosis (TB) patients suffer from progressive and debilitating loss of muscle mass and function, referred to as cachexia. Though a multifactorial condition, cachexia in cancer is promoted by systemic zinc redistribution and accumulation in muscles. Clinical studies with TB patients indeed show zinc dyshomeostasis. We therefore set out to understand mechanisms by which Mycobacterium tuberculosis (Mtb) govern zinc metallostasis at the host-pathogen interface. Here, we report a novel zinc metallophore from Mtb that restores zinc metabolic imbalance. These diisonitrile lipopeptides, named kupyaphores are transiently induced early-on during macrophage infection and also in infected mice lungs. Kupyaphores protects bacteria from host-mediated nutritional deprivation and intoxication. Kupyaphore Mtb mutant strain cannot mobilize zinc and shows reduced fitness in mice. Further, we characterize Mtb encoded isonitrile hydratase that could mediate intracellular zinc release through covalent modification of kupyaphores. Our studies could provide a molecular link between TB-induced altered zinc homeostasis and associated cachexia.

Biallelic Loss-of-Function Variants in AIMP1 Cause a Rare Neurodegenerative Disease

2018 ◽  
Vol 34 (2) ◽  
pp. 74-80 ◽  
Author(s):  
Andrea Accogli ◽  
Kether Guerrero ◽  
Maria Daniela D’Agostino ◽  
Luan Tran ◽  
Cécile Cieuta-Walti ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Neurodegenerative Disorder ◽  
Cerebral Atrophy ◽  
Trna Synthetase ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
The Central Nervous System ◽  
And Function

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

scholarly journals Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality

2020 ◽  
pp. jmedgenet-2020-106873
Author(s):  
Marilena Elpidorou ◽  
Sunayna Best ◽  
James A Poulter ◽  
Verity Hartill ◽  
Emma Hobson ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Stop Codon ◽  
Neurodevelopmental Disorder ◽  
Premature Stop Codon ◽  
Homozygous Deletion ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Functional Characterisation ◽  
Mitochondrial Functions ◽  
And Function

BackgroundThe HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype.Methods and resultsWe ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA.ConclusionThis study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders.

scholarly journals Engaging chromatin: PRC2 structure meets function

2019 ◽  
Vol 122 (3) ◽  
pp. 315-328 ◽  
Author(s):  
Paul Chammas ◽  
Ivano Mocavini ◽  
Luciano Di Croce
Keyword(s):  
Regulation Of Gene Expression ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Core Complex ◽  
Methyltransferase Activity ◽  
Facultative Heterochromatin ◽  
Developmental Defects ◽  
Polycomb Repressive Complex 2 ◽  
And Function ◽  
The Impact

Abstract Polycomb repressive complex 2 (PRC2) is a key epigenetic multiprotein complex involved in the regulation of gene expression in metazoans. PRC2 is formed by a tetrameric core that endows the complex with histone methyltransferase activity, allowing it to mono-, di- and tri-methylate histone H3 on lysine 27 (H3K27me1/2/3); H3K27me3 is a hallmark of facultative heterochromatin. The core complex of PRC2 is bound by several associated factors that are responsible for modulating its targeting specificity and enzymatic activity. Depletion and/or mutation of the subunits of this complex can result in severe developmental defects, or even lethality. Furthermore, mutations of these proteins in somatic cells can be drivers of tumorigenesis, by altering the transcriptional regulation of key tumour suppressors or oncogenes. In this review, we present the latest results from structural studies that have characterised PRC2 composition and function. We compare this information with data and literature for both gain-of function and loss-of-function missense mutations in cancers to provide an overview of the impact of these mutations on PRC2 activity.

scholarly journals Natural variation in the sequestosome-related gene, sqst-5, underlies zinc homeostasis in Caenorhabditis elegans

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1008986
Author(s):  
Kathryn S. Evans ◽  
Stefan Zdraljevic ◽  
Lewis Stevens ◽  
Kimberly Collins ◽  
Robyn E. Tanny ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Recombinant Inbred Lines ◽  
Cellular Growth ◽  
Zinc Homeostasis ◽  
Related Gene ◽  
Intracellular Zinc ◽  
Increased Sensitivity ◽  
Chromosome Iii ◽  
Zinc Levels ◽  
Zinc Resistance

Zinc is an essential trace element that acts as a co-factor for many enzymes and transcription factors required for cellular growth and development. Altering intracellular zinc levels can produce dramatic effects ranging from cell proliferation to cell death. To avoid such fates, cells have evolved mechanisms to handle both an excess and a deficiency of zinc. Zinc homeostasis is largely maintained via zinc transporters, permeable channels, and other zinc-binding proteins. Variation in these proteins might affect their ability to interact with zinc, leading to either increased sensitivity or resistance to natural zinc fluctuations in the environment. We can leverage the power of the roundworm nematode Caenorhabditis elegans as a tractable metazoan model for quantitative genetics to identify genes that could underlie variation in responses to zinc. We found that the laboratory-adapted strain (N2) is resistant and a natural isolate from Hawaii (CB4856) is sensitive to micromolar amounts of exogenous zinc supplementation. Using a panel of recombinant inbred lines, we identified two large-effect quantitative trait loci (QTL) on the left arm of chromosome III and the center of chromosome V that are associated with zinc responses. We validated and refined both QTL using near-isogenic lines (NILs) and identified a naturally occurring deletion in sqst-5, a sequestosome-related gene, that is associated with resistance to high exogenous zinc. We found that this deletion is relatively common across strains within the species and that variation in sqst-5 is associated with zinc resistance. Our results offer a possible mechanism for how organisms can respond to naturally high levels of zinc in the environment and how zinc homeostasis varies among individuals.

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