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Experimental Biology and Medicine... Mar 2015WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other... (Review)
Review
WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other alterations in a variety of different cancers. This chromosomal band also contains the FRA16D common fragile site (CFS). CFSs are chromosomal regions found in all individuals which are highly unstable. WWOX has also been demonstrated to function as a tumor suppressor that is involved in the development of many cancers. Two other highly unstable CFSs, FRA3B (3p14.2) and FRA6E (6q26), also span extremely large genes, FHIT and PARK2, respectively, and these two genes are also found to be important tumor suppressors. There are a number of interesting similarities between these three large CFS genes. In spite of the fact that they are derived from some of the most unstable chromosomal regions in the genome, they are found to be highly evolutionarily conserved and the chromosomal region spanning the mouse homologs of both WWOX and FHIT are also CFSs in mice. Many of the other CFSs also span extremely large genes and many of these are very attractive tumor suppressor candidates. WWOX is therefore a member of a very interesting family of very large CFS genes.
Topics: Animals; Carcinogenesis; Chromosome Fragile Sites; Disease Models, Animal; Genomic Instability; Humans; Mice; Neoplasms; Oxidoreductases; Signal Transduction; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25595185
DOI: 10.1177/1535370214565992 -
Experimental Biology and Medicine... Mar 2015Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell... (Review)
Review
Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies.
Topics: Apoptosis; Drug Resistance, Neoplasm; Humans; Neoplasms; Oxidoreductases; Signal Transduction; Stress, Physiological; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25595191
DOI: 10.1177/1535370214566747 -
Journal of Experimental & Clinical... Mar 2024A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol... (Review)
Review
A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol oxidoreductase, is confirmed to be highly upregulated in various cancer types and associated with a significantly worse prognosis. Of importance, under ER stress, the functional interplay of ERO1α/PDI axis plays a pivotal role to orchestrate proper protein folding and other key processes. Multiple lines of evidence propose ERO1α as an attractive potential target for cancer treatment. However, the unavailability of specific inhibitor for ERO1α, its molecular inter-relatedness with closely related paralog ERO1β and the tightly regulated processes with other members of flavoenzyme family of enzymes, raises several concerns about its clinical translation. Herein, we have provided a detailed description of ERO1α in human cancers and its vulnerability towards the aforementioned concerns. Besides, we have discussed a few key considerations that may improve our understanding about ERO1α in tumors.
Topics: Humans; Clinical Relevance; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Membrane Glycoproteins; Neoplasms; Oxidation-Reduction; Oxidoreductases
PubMed: 38454454
DOI: 10.1186/s13046-024-02990-4 -
Applied and Environmental Microbiology Jun 2022Bacteria coping with oxygen deficiency use alternative terminal electron acceptors for NADH regeneration, particularly fumarate. Fumarate is reduced by the domain of...
Bacteria coping with oxygen deficiency use alternative terminal electron acceptors for NADH regeneration, particularly fumarate. Fumarate is reduced by the domain of cytoplasmic fumarate reductase in many bacteria. The variability of the primary structure of this domain in homologous proteins suggests the existence of reducing activities with different specificities. Here, we produced and characterized one such protein encoded in the Vibrio harveyi genome (GenBank ID: AIV07243) and found it to be a specific NADH:acrylate oxidoreductase (ARD). This previously unknown enzyme is formed by the , , and domains and contains covalently bound flavin mononucleotide (FMN) and noncovalently bound flavin adenine dinucleotide (FAD) and FMN in a ratio of 1:1:1. The covalently bound FMN is absolutely required for activity and is attached by the specific flavin transferase, ApbE, to the domain. Quantitative reverse transcription PCR (RT-qPCR) and activity measurements indicated dramatic stimulation of ARD biosynthesis by acrylate in the V. harveyi cells grown aerobically. In contrast, the gene expression in the cells grown anaerobically without acrylate was higher than that in aerobic cultures and increased only 2-fold in the presence of acrylate. These findings suggest that the principal role of ARD in is energy-saving detoxification of acrylate coming from the environment. The benefits of the massive genomic information accumulated in recent years for biological sciences have been limited by the lack of data on the function of most gene products. Approximately half of the known prokaryotic genes are annotated as "proteins with unknown functions," and many other genes are annotated incorrectly. Thus, the functional and structural characterization of the products of such genes, including identification of all existing enzymatic activities, is a pressing issue in modern biochemistry. In this work, we have shown that the product of the V. harveyi gene exhibits a yet-undescribed NADH:acrylate oxidoreductase activity. This activity may allow acrylate detoxification and its use as a terminal electron acceptor in anaerobic or substrate in aerobic respiration of marine and other bacteria.
Topics: Acrylates; Amino Acid Sequence; FMN Reductase; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Fumarates; NAD; NADH Dehydrogenase; NADH, NADPH Oxidoreductases; Vibrio
PubMed: 35612301
DOI: 10.1128/aem.00519-22 -
Experimental Biology and Medicine... Mar 2015WWOX was cloned as a tumor suppressor gene mapping to chromosomal fragile site FRA16D. Loss of WWOX is closely related to tumorigenesis, cancer progression, and therapy... (Review)
Review
WWOX was cloned as a tumor suppressor gene mapping to chromosomal fragile site FRA16D. Loss of WWOX is closely related to tumorigenesis, cancer progression, and therapy resistance. Recent studies demonstrate the growing role of WWOX gene in other human pathologies such as metabolic and nervous system-related conditions. The neurologic phenotype of WWOX mutation includes seizures, ataxia, developmental delay, and spasticity of variable severity. WWOX is a ubiquitous protein with high expression in many tissues including brain, cerebellum, brain stem, and spinal cord. WWOX is highly expressed in different brain regions during murine fetal development and remained unchanged in the cortex and the corpus callosum in adult mice. The mechanism or the putative role of WWOX in the nervous system is still unclear but may include abnormal signaling protein, disruption of neuronal pathways, neuronal differentiation, mitochondrial dysfunction, or apoptosis. Homozygous mutations affecting WWOX in humans are likely to be more described in the future using exome sequencing. The described findings highlight that WWOX plays a critical role in normal central nervous system development and disease. The aim of this review is to summarize the roles of WWOX in the developing brain.
Topics: Animals; Brain; Brain Diseases; Chromosome Fragile Sites; Disease Models, Animal; Gene Expression Regulation, Developmental; Humans; Mice; Mutation; Oxidoreductases; Phenotype; Rats; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25416187
DOI: 10.1177/1535370214561952 -
Biomolecular Concepts Sep 2017Protein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron... (Review)
Review
Protein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron sulfur molybdoenzymes (CISM) requires use of a system specific chaperone - a redox enzyme maturation protein (REMP) - to help mediate final folding and assembly. The CISM dimethyl sulfoxide (DMSO) reductase is a bacterial oxidoreductase that utilizes DMSO as a final electron acceptor for anaerobic respiration. The REMP DmsD strongly interacts with DMSO reductase to facilitate folding, cofactor-insertion, subunit assembly and targeting of the multi-subunit enzyme prior to membrane translocation and final assembly and maturation into a bioenergetic catalytic unit. In this article, we discuss the biogenesis of DMSO reductase as an example of the participant network for bacterial CISM maturation pathways.
Topics: Bacterial Proteins; Iron-Sulfur Proteins; Models, Molecular; Molecular Chaperones; Oxidoreductases; Protein Folding; Protein Interaction Maps; Protein Transport
PubMed: 28688222
DOI: 10.1515/bmc-2017-0011 -
Nitric Oxide : Biology and Chemistry Feb 2017This perspective reviews single molecule and ensemble fluorescence spectroscopy studies of the three tissue specific nitric oxide synthase (NOS) isoenzymes and the... (Review)
Review
This perspective reviews single molecule and ensemble fluorescence spectroscopy studies of the three tissue specific nitric oxide synthase (NOS) isoenzymes and the related diflavin oxidoreductase cytochrome P450 reductase. The focus is on the role of protein dynamics and the protein conformational landscape and we discuss how recent fluorescence-based studies have helped in illustrating how the nature of the NOS conformational landscape relates to enzyme turnover and catalysis.
Topics: NADPH-Ferrihemoprotein Reductase; Nitric Oxide Synthase; Protein Conformation; Spectrometry, Fluorescence
PubMed: 27619338
DOI: 10.1016/j.niox.2016.09.002 -
Biochimica Et Biophysica Acta. Reviews... Jan 2024Endoplasmic reticulum oxidoreductin 1 (ERO1) alpha (ERO1A) is an endoplasmic reticulum (ER)-localized protein disulfide oxidoreductase, involved in the disulfide bond... (Review)
Review
Endoplasmic reticulum oxidoreductin 1 (ERO1) alpha (ERO1A) is an endoplasmic reticulum (ER)-localized protein disulfide oxidoreductase, involved in the disulfide bond formation of proteins. ERO1's activity in oxidative protein folding is redundant in higher eukaryotes and its loss is well compensated. Although it is dispensable in non-cancer cells, high ERO1 levels are seen with different cancers and predict their malignant phenotype. ERO1 fosters tumor aggressiveness and the response to drug therapy in hypoxic and highly metastatic tumors. It regulates vascular endothelial growth factor (VEGF) levels, oxidative folding and N-glycosylation in hypoxic conditions, boosting tumor fitness and angiogenesis on multiple levels. In addition, ERO1 regulates protein death ligand-1 (PD-L1) on tumors, interfering with the related immune surveillance mechanism, hence acting on the tumors' response to immune check-point inhibitors (ICI). This all points to inhibition of ERO1 as an effective pharmacological tool, selectively targeting tumors while sparing non-cancer cells from cytotoxicity. The critical discussion here closely examines the molecular basis for ERO1's involvement in tumors and ERO1 inhibition strategies for their treatment.
Topics: Humans; Vascular Endothelial Growth Factor A; Oxidoreductases; Neoplasms; Endoplasmic Reticulum; Disulfides
PubMed: 38007054
DOI: 10.1016/j.bbcan.2023.189027 -
Experimental Biology and Medicine... Mar 2015Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been...
Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation.
Topics: Humans; Mutation; Neoplasms; Nervous System Diseases; Oxidoreductases; Signal Transduction; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25802472
DOI: 10.1177/1535370215574226 -
Biochimica Et Biophysica Acta.... Dec 2017NAD is a dinucleotide cofactor with the potential to accept electrons in a variety of cellular reduction-oxidation (redox) reactions. In its reduced form, NADH is a... (Review)
Review
NAD is a dinucleotide cofactor with the potential to accept electrons in a variety of cellular reduction-oxidation (redox) reactions. In its reduced form, NADH is a ubiquitous cellular electron donor. NAD, NADH, and the NAD/NADH ratio have long been known to control the activity of several oxidoreductase enzymes. More recently, enzymes outside those participating directly in redox control have been identified that sense these dinucleotides, including the sirtuin family of NAD-dependent protein deacylases. In this review, we highlight examples of non-redox enzymes that are controlled by NAD, NADH, or NAD/NADH. In particular, we focus on the sirtuin family and assess the current evidence that the sirtuin enzymes sense these dinucleotides and discuss the biological conditions under which this might occur; we conclude that sirtuins sense NAD, but neither NADH nor the ratio. Finally, we identify future studies that might be informative to further interrogate physiological and pathophysiological changes in NAD and NADH, as well as enzymes like sirtuins that sense and respond to redox changes in the cell.
Topics: Biochemical Phenomena; Electron Transport; NAD; Oxidation-Reduction; Oxidoreductases; Sirtuins
PubMed: 28947253
DOI: 10.1016/j.bbabio.2017.09.005