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Journal of Hematology & Oncology Aug 2018Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and... (Review)
Review
Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer.
Topics: Carcinogenesis; Humans; Metallothionein; Neoplasms
PubMed: 30139373
DOI: 10.1186/s13045-018-0645-x -
IUBMB Life Apr 2017Metallothioneins (MTs) are a class of low molecular weight and cysteine-rich metal binding proteins present in all the branches of the tree of life. MTs efficiently bind... (Review)
Review
Metallothioneins (MTs) are a class of low molecular weight and cysteine-rich metal binding proteins present in all the branches of the tree of life. MTs efficiently bind with high affinity several essential and toxic divalent and monovalent transition metals by forming characteristic polynuclear metal-thiolate clusters within their structure. MTs fulfil multiple biological functions related to their metal binding properties, with essential roles in both Zn(II) and Cu(I) homeostasis as well as metal detoxification. Depending on the organism considered, the primary sequence, and the specific physiological and metabolic status, Cu(I)-bound MT isoforms have been isolated, and their chemistry and biology characterized. Besides the recognized role in the biochemistry of divalent metals, it is becoming evident that unique biological functions in selectively controlling copper levels, its reactivity as well as copper-mediated biochemical processes have evolved in some members of the MT superfamily. Selected examples are reviewed to highlight the peculiar chemical properties and biological functions of copper MTs. © 2016 IUBMB Life, 69(4):236-245, 2017.
Topics: Amino Acid Sequence; Carrier Proteins; Copper; Humans; Metallothionein; Zinc
PubMed: 28296007
DOI: 10.1002/iub.1618 -
International Journal of Molecular... Sep 2016Mammalian metallothionein-2A (MT2A) has received considerable attention in recent years due to its crucial pathophysiological role in anti-oxidant, anti-apoptosis,... (Review)
Review
Mammalian metallothionein-2A (MT2A) has received considerable attention in recent years due to its crucial pathophysiological role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation. For many years, most studies evaluating the effects of MT2A have focused on reactive oxygen species (ROS), as second messengers that lead to oxidative stress injury of cells and tissues. Recent studies have highlighted that oxidative stress could activate mitogen-activated protein kinases (MAPKs), and MT2A, as a mediator of MAPKs, to regulate the pathogenesis of various diseases. However, the molecule mechanism of MT2A remains elusive. A deeper understanding of the functional, biochemical and molecular characteristics of MT2A would be identified, in order to bring new opportunities for oxidative stress therapy.
Topics: Animals; Cardiovascular Diseases; Humans; MAP Kinase Signaling System; Metallothionein; Neoplasms; Nervous System Diseases; Oxidative Stress
PubMed: 27608012
DOI: 10.3390/ijms17091483 -
Metal Ions in Life Sciences Apr 2017Heavy metal exposure has long been associated with metallothionein (MT) regulation and its functions. MT is a ubiquitous, cysteine-rich protein that is involved in... (Review)
Review
Heavy metal exposure has long been associated with metallothionein (MT) regulation and its functions. MT is a ubiquitous, cysteine-rich protein that is involved in homeostatic metal response for the essential metals zinc and copper, as well as detoxification of heavy metals; the most commonly proposed being cadmium. MT binds in vivo to a number of metals in addition to zinc, cadmium and copper, such as bismuth. In vitro, metallation with a wide range of metals (especially mercury, arsenic, and lead) has been reported using a variety of analytical methods. To fully understand MT and its role with lead metabolism, we will describe how MT interacts with a wide variety of metals that bind in vitro. In general, affinity to the metal-binding cysteine residues of MT follows that of metal binding to thiols: Zn(II) < Pb(II) < Cd (II) < Cu(I) < Ag(I) < Hg(II) < Bi(III). To introduce the metal binding properties that we feel directly relate to the metallation of metallothionein by Pb(II), we will explore MT's interactions with metals long known as toxic, particularly, Cd(II), Hg(II), and As(III), along with xenobiotic metals, and how these metal-binding studies complement those of lead binding. Lead's effects on an organism's physiological functions are not fully understood, but it is known that chronic exposure inflicts amongst other factors pernicious anemia and developmental issues in the brain, especially in children who are more vulnerable to its toxic effects. Understanding the interaction of lead with metallothioneins throughout the biosphere, from bacteria, to algae, to fish, to humans, is important in determining pathways for lead to enter and damage physiologically significant protein function, and thereby its toxicity.
Topics: Animals; Humans; Lead; Lead Poisoning; Metallothionein; Protein Binding
PubMed: 28731302
DOI: 10.1515/9783110434330-009 -
Oxidative Medicine and Cellular... 2017Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential... (Review)
Review
Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential metals. There are 4 major isoforms of MTs (I-IV), three of which have been localized in the central nervous system. MT-I and MT-II have been localized in the spinal cord and brain, mainly in astrocytes, whereas MT-III has been found mainly in neurons. MT-I and MT-II have been considered polyvalent proteins whose main function is to maintain cellular homeostasis of essential metals such as zinc and copper, but other functions have also been considered: detoxification of heavy metals, regulation of gene expression, processes of inflammation, and protection against free radicals generated by oxidative stress. On the other hand, the MT-III has been related in events of pathogenesis of neurodegenerative diseases such as Parkinson and Alzheimer. Likewise, the participation of MTs in other neurological disorders has also been reported. This review shows recent evidence about the role of MT in the central nervous system and its possible role in neurodegenerative diseases as well as in brain disorders.
Topics: Animals; Brain Diseases; Metallothionein; Rats
PubMed: 29085556
DOI: 10.1155/2017/5828056 -
Biomolecular Concepts Apr 2013Metallothioneins (MTs) are a family of universal, small proteins, sharing a high cysteine content and an optimal capacity for metal ion coordination. They take part in a... (Review)
Review
Metallothioneins (MTs) are a family of universal, small proteins, sharing a high cysteine content and an optimal capacity for metal ion coordination. They take part in a plethora of metal ion-related events (from detoxification to homeostasis, storage, and delivery), in a wide range of stress responses, and in different pathological processes (tumorigenesis, neurodegeneration, and inflammation). The information on both intracellular and extracellular interactions of MTs with other proteins is here comprehensively reviewed. In mammalian kidney, MT1/MT2 interact with megalin and related receptors, and with the transporter transthyretin. Most of the mammalian MT partners identified concern interactions with central nervous system (mainly brain) proteins, both through physical contact or metal exchange reactions. Physical interactions mainly involve neuronal secretion multimers. Regarding metal swap events, brain MT3 appears to control the metal ion load in peptides whose aggregation leads to neurodegenerative disorders, such as Aβ peptide, α-synuclein, and prion proteins (Alzheimer's and Parkinson's diseases, and spongiform encephalopathies, respectively). Interaction with ferritin and bovine serum albumin are also documented. The intercourse of MTs with zinc-dependent enzymes and transcription factors is capable to activate/deactivate them, thus conferring MTs the role of metabolic and gene expression regulators. As some of these proteins are involved in cell cycle and proliferation control (p53, nuclear factor κB, and PKCμ), they are considered in the context of oncogenesis and tumor progression. Only one non-mammalian MT interaction, involving Drosophila MtnA and MtnB major isoforms and peroxiredoxins, has been reported. The prospective use for biomedical applications of the MT-interaction information is finally discussed.
Topics: Animals; Brain; Gene Expression Regulation; Humans; Kidney; Metallothionein; Neoplasms; Neurodegenerative Diseases; Protein Aggregates; Protein Binding; Protein Conformation; Reactive Oxygen Species; Synaptic Transmission
PubMed: 25436572
DOI: 10.1515/bmc-2012-0049 -
Ageing Research Reviews Jan 2011Metallothionein (MT) is a low molecular weight protein with anti-apoptotic properties that has been demonstrated to scavenge free radicals in vitro. MT has not been... (Review)
Review
Metallothionein (MT) is a low molecular weight protein with anti-apoptotic properties that has been demonstrated to scavenge free radicals in vitro. MT has not been extensively investigated within the context of aging biology. The purpose of this review, therefore, is to discuss findings on MT that are relevant to basic aging mechanisms and to draw attention to the possible role of MT in pro-longevity interventions. MT is one of just a handful of proteins that, when overexpressed, has been demonstrated to increase mouse lifespan. MT also protects against development of obesity in mice provided a high fat diet as well as diet-induced oxidative stress damage. Abundance of MT is responsive to caloric restriction (CR) and inhibition of the insulin/insulin-like signaling (IIS) pathway, and elevated MT gene expression has been observed in tissues from fasted and CR-fed mice, long-lived dwarf mice, worms maintained under CR conditions, and long-lived daf-2 mutant worms. The dysregulation of MT in these systems is likely to have tissue-specific effects on aging outcomes. Further investigation will therefore be needed to understand how MT contributes to the response of invertebrates and mice to CR and the endocrine mutations studied by aging researchers.
Topics: Aging; Animals; Caenorhabditis elegans; Endocrine Glands; Energy Intake; Humans; Longevity; Metallothionein; Mice
PubMed: 20933613
DOI: 10.1016/j.arr.2010.09.007 -
International Journal of Molecular... Mar 2016Around 3000 proteins are thought to bind zinc in vivo, which corresponds to ~10% of the human proteome. Zinc plays a pivotal role as a structural, catalytic, and... (Review)
Review
Around 3000 proteins are thought to bind zinc in vivo, which corresponds to ~10% of the human proteome. Zinc plays a pivotal role as a structural, catalytic, and signaling component that functions in numerous physiological processes. It is more widely used as a structural element in proteins than any other transition metal ion, is a catalytic component of many enzymes, and acts as a cellular signaling mediator. Thus, it is expected that zinc metabolism and homeostasis have sophisticated regulation, and elucidating the underlying molecular basis of this is essential to understanding zinc functions in cellular physiology and pathogenesis. In recent decades, an increasing amount of evidence has uncovered critical roles of a number of proteins in zinc metabolism and homeostasis through influxing, chelating, sequestrating, coordinating, releasing, and effluxing zinc. Metallothioneins (MT) and Zrt- and Irt-like proteins (ZIP) and Zn transporters (ZnT) are the proteins primarily involved in these processes, and their malfunction has been implicated in a number of inherited diseases such as acrodermatitis enteropathica. The present review updates our current understanding of the biological functions of MTs and ZIP and ZnT transporters from several new perspectives.
Topics: Acrodermatitis; Animals; Cation Transport Proteins; Epigenesis, Genetic; Gene Expression Regulation; Genetic Predisposition to Disease; Homeostasis; Humans; Metallothionein; Phylogeny; Polymorphism, Single Nucleotide; Repressor Proteins; Zinc
PubMed: 26959009
DOI: 10.3390/ijms17030336 -
Folia Histochemica Et Cytobiologica 2015Metallothioneins (MTs) are low weight proteins involved in several key cellular processes such as metal ions homeostasis, detoxification and scavenging of free radicals.... (Review)
Review
Metallothioneins (MTs) are low weight proteins involved in several key cellular processes such as metal ions homeostasis, detoxification and scavenging of free radicals. Four groups of MTs are distinguished: MT-1, MT-2, MT-3 and MT-4. Regardless of the type, MTs are characterized by high content of cysteine, responsible for their biological properties such as binding of relevant zinc and copper ions, as well as toxic ions such as lead and cadmium. MTs were additionally shown to protect cells against oxidative stress damage and participate in differentiation, proliferation and/or apoptosis of normal and cancer cells. Many studies of different neoplasms showed association of elevated MTs levels with occurrence of chemo- and radiotherapy resistance and poor patients' outcome. In this review, we summarize and discuss the potential mechanism of action of metallotioneins in lung physiology and pathology.
Topics: Animals; Biomarkers, Tumor; Carcinoma; Humans; Lung Neoplasms; Metallothionein
PubMed: 25815626
DOI: 10.5603/FHC.a2015.0009 -
Aging Jan 2022
Topics: Animals; Cadmium; Gene Expression Regulation; Longevity; Metallothionein
PubMed: 35027505
DOI: 10.18632/aging.203831