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International Journal of Molecular... Aug 2021In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty... (Review)
Review
In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.
Topics: Acyl-CoA Oxidase; Animals; Fatty Acids; Humans; Liver; Oxidation-Reduction; Oxidoreductases; PPAR alpha; Peroxisome Proliferators; Peroxisomes; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Response Elements; Retinoid X Receptors; Transcriptional Activation
PubMed: 34445672
DOI: 10.3390/ijms22168969 -
Endocrine Journal Jun 2022Glucose is not only the energy fuel for most cells, but also the signaling molecule which affects gene expression via carbohydrate response element binding protein... (Review)
Review
Glucose is not only the energy fuel for most cells, but also the signaling molecule which affects gene expression via carbohydrate response element binding protein (ChREBP), a Mondo family transcription factor. In response to high glucose conditions, ChREBP regulates glycolytic and lipogenic genes by binding to carbohydrate response elements (ChoRE) in the regulatory region of its target genes, thus elucidating the role of ChREBP for converting excessively ingested carbohydrates to fatty acids as an energy storage in lipogenic tissues such as the liver and adipose tissue. While the pathophysiological roles of ChREBP for fatty liver and obesity in these tissues are well known, much of the physiological and pathophysiological roles of ChREBP in other tissues such as the kidney remains unclear despite its high levels of expression in them. This review will thus highlight the roles of ChREBP in the kidney and briefly introduce the latest research results that have been reported so far.
Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Glucose; Kidney; Liver; Response Elements; Transcription Factors
PubMed: 35474028
DOI: 10.1507/endocrj.EJ22-0083 -
Molecular Metabolism Jul 2022Tamoxifen is widely used for inducible Cre-LoxP systems but has several undesirable side effects for researchers investigating metabolism or energy balance, including...
OBJECTIVE
Tamoxifen is widely used for inducible Cre-LoxP systems but has several undesirable side effects for researchers investigating metabolism or energy balance, including weight loss, lipoatrophy, and drug incorporation into lipid stores. For this reason, we sought to determine whether a doxycycline-inducible system would be more advantageous for adipocyte-specific Cre mouse models, but serendipitously discovered widespread ectopic tetracycline response element Cre (TRE-Cre) recombinase activity.
METHODS
Adipocyte-specific tamoxifen- and doxycycline-inducible Cre mice were crossed to fluorescent Cre reporter mice and visualized by confocal microscopy to assess efficiency and background activity. TRE-Cre mice were crossed to stop-floxed diphtheria toxin mice to selectively ablate cells with background Cre activity.
RESULTS
Tamoxifen- and doxycycline-inducible systems performed similarly in adipose tissues, but ectopic Cre recombination was evident in numerous other cell types of the latter, most notably neurons. The source of ectopic Cre activity was isolated to the TRE-Cre transgene, driven by the pTet (tetO7) tetracycline-inducible promoter. Ablation of cells with ectopic recombination in mice led to stunted growth, diminished survival, and reduced brain mass.
CONCLUSIONS
These results indicate that tamoxifen- and doxycycline-inducible adipocyte-specific Cre mouse models are similarly efficient, but the TRE-Cre component of the latter is inherently leaky. TRE-Cre background activity is especially pronounced in the brain and peripheral nerve fibers, and selective ablation of these cells impairs mouse development and survival. Caution should be taken when pairing TRE-Cre with floxed alleles that have defined roles in neural function, and additional controls should be included when using this model system.
Topics: Animals; Anti-Bacterial Agents; Doxycycline; Integrases; Mice; Mice, Transgenic; Recombination, Genetic; Response Elements; Tamoxifen; Trans-Activators
PubMed: 35452876
DOI: 10.1016/j.molmet.2022.101501 -
International Journal of Molecular... Aug 2023Spermatogenesis is a very complex process with an intricate transcriptional regulation. The transition from the diploid to the haploid state requires the involvement of... (Review)
Review
Spermatogenesis is a very complex process with an intricate transcriptional regulation. The transition from the diploid to the haploid state requires the involvement of specialized genes in meiosis, among other specific functions for the formation of the spermatozoon. The transcription factor cAMP-response element modulator (CREM) is a key modulator that triggers the differentiation of the germ cell into the spermatozoon through the modification of gene expression. CREM has multiple repressor and activator isoforms whose expression is tissue-cell-type specific and tightly regulated by various factors at the transcriptional, post-transcriptional and post-translational level. The activator isoform CREMτ controls the expression of several relevant genes in post-meiotic stages of spermatogenesis. In addition, exposure to xenobiotics negatively affects expression, which is linked to male infertility. On the other hand, antioxidants could have a positive effect on expression and improve sperm parameters in idiopathically infertile men. Therefore, expression could be used as a biomarker to detect and even counteract male infertility. This review examines the importance of CREM as a transcription factor for sperm production and its relevance in male fertility, infertility and the response to environmental xenobiotics that may affect expression and the downstream regulation that alters male fertility. Also, some health disorders in which expression is altered are discussed.
Topics: Male; Humans; Xenobiotics; Semen; Spermatogenesis; Cyclic AMP Response Element-Binding Protein; Infertility, Male; Meiosis; Response Elements; Fertility; Cyclic AMP Response Element Modulator
PubMed: 37628737
DOI: 10.3390/ijms241612558 -
BMC Biology Jun 2021Epigenetic memory plays a critical role in the establishment and maintenance of cell identities in multicellular organisms. Polycomb and trithorax group (PcG and TrxG)...
BACKGROUND
Epigenetic memory plays a critical role in the establishment and maintenance of cell identities in multicellular organisms. Polycomb and trithorax group (PcG and TrxG) proteins are responsible for epigenetic memory, and in flies, they are recruited to specialized DNA regulatory elements termed polycomb response elements (PREs). Previous transgene studies have shown that PREs can silence reporter genes outside of their normal context, often by pairing sensitive (PSS) mechanism; however, their silencing activity is non-autonomous and depends upon the surrounding chromatin context. It is not known why PRE activity depends on the local environment or what outside factors can induce silencing.
RESULTS
Using an attP system in Drosophila, we find that the so-called neutral chromatin environments vary substantially in their ability to support the silencing activity of the well-characterized bxdPRE. In refractory chromosomal contexts, factors required for PcG-silencing are unable to gain access to the PRE. Silencing activity can be rescued by linking the bxdPRE to a boundary element (insulator). When placed next to the PRE, the boundaries induce an alteration in chromatin structure enabling factors critical for PcG silencing to gain access to the bxdPRE. When placed at a distance from the bxdPRE, boundaries induce PSS by bringing the bxdPREs on each homolog in close proximity.
CONCLUSION
This proof-of-concept study demonstrates that the repressing activity of PREs can be induced or enhanced by nearby boundary elements.
Topics: Animals; Chromatin; Drosophila; Drosophila Proteins; Polycomb Repressive Complex 1; Response Elements
PubMed: 34078365
DOI: 10.1186/s12915-021-01047-8 -
Archives of Pharmacal Research Mar 2020A constant improvement in understanding of mitochondrial biology has provided new insights into mitochondrial dysfunction in human disease pathogenesis. Impaired... (Review)
Review
A constant improvement in understanding of mitochondrial biology has provided new insights into mitochondrial dysfunction in human disease pathogenesis. Impaired mitochondrial dynamics caused by various stressors are characterized by structural abnormalities and leakage, compromised turnover, and reactive oxygen species overproduction in mitochondria as well as increased mitochondrial DNA mutation frequency, which leads to modified energy production and mitochondria-derived cell signaling. The mitochondrial dysfunction in airway epithelial, smooth muscle, and endothelial cells has been implicated in diseases including chronic obstructive lung diseases and acute lung injury. Increasing evidence indicates that the NRF2-antioxidant response element (ARE) pathway not only enhances redox defense but also facilitates mitochondrial homeostasis and bioenergetics. Identification of functional or potential AREs further supports the role for Nrf2 in mitochondrial dysfunction-associated airway disorders. While clinical reports indicate mixed efficacy, NRF2 agonists acting on respiratory mitochondrial dynamics are potentially beneficial. In lung cancer, growth advantage provided by sustained NRF2 activation is suggested to be through increased cellular antioxidant defense as well as mitochondria reinforcement and metabolic reprogramming to the preferred pathways to meet the increased energy demands of uncontrolled cell proliferation. Further studies are warranted to better understand NRF2 regulation of mitochondrial functions as therapeutic targets in airway disorders.
Topics: Animals; Antioxidant Response Elements; Humans; Mitochondria; NF-E2-Related Factor 2; Oxidation-Reduction; Respiration Disorders
PubMed: 31486024
DOI: 10.1007/s12272-019-01182-5 -
Steroids Mar 2011Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have... (Review)
Review
Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as "vitamin D or estrogen response element-binding proteins", behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements.
Topics: Animals; Estrogens; Humans; Mutation; Platyrrhini; Receptors, Calcitriol; Receptors, Steroid; Response Elements; Transcriptional Activation; Vitamin D; Vitamin D Response Element
PubMed: 21236284
DOI: 10.1016/j.steroids.2011.01.002 -
The Journal of Biological Chemistry May 2009A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which... (Review)
Review
A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed.
Topics: Adaptor Proteins, Signal Transducing; Animals; Antioxidants; Cell Line, Tumor; Cytoskeletal Proteins; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; Mice; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species; Response Elements; Signal Transduction; Transcription, Genetic
PubMed: 19182219
DOI: 10.1074/jbc.R900010200 -
Current Molecular Medicine Aug 2008Redox balance is particularly important in the airways because they are the first points of contact with environmental pollutants such as ozone, particles, and cigarette... (Review)
Review
Redox balance is particularly important in the airways because they are the first points of contact with environmental pollutants such as ozone, particles, and cigarette smoke, as well as pathogens such as bacteria and viruses. However, an imbalance between toxicant-induced reactive oxygen (ROS) and nitrogen (RNS) species and the antioxidant defense system leads to oxidative stress, which has been implicated in the development and/or perpetuation of airway diseases, including malignancy. Various antioxidant enzymes and proteins are critical to maintaining the reducing environment of the cell and preventing the damage to various biomolecules that is elicited by ROS/RNS. Emerging evidence indicates that transcriptional activation of the antioxidant response element (ARE) plays a crucial role in modulating oxidative stress and providing cytoprotection against prooxidant stimuli. This review focuses on the regulation and functional roles of key effectors that bind to the ARE and differentially (up- or down-) regulate gene expression in lung tissue/cell types in response to respiratory toxicants. It also provides a perspective on whether boosting ARE-mediated gene expression with dietary plants and synthetic plant products will offer a better therapeutic strategy for mitigating oxidative stress and respiratory pathogenesis.
Topics: Animals; Antioxidants; Humans; NF-E2-Related Factor 2; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Respiration Disorders; Response Elements
PubMed: 18691064
DOI: 10.2174/156652408785160925 -
Chromosoma Jun 2016A long-standing mystery in the field of Polycomb and Trithorax regulation is how these proteins, which are highly conserved between flies and mammals, can regulate... (Review)
Review
A long-standing mystery in the field of Polycomb and Trithorax regulation is how these proteins, which are highly conserved between flies and mammals, can regulate several hundred equally highly conserved target genes, but recognise these targets via cis-regulatory elements that appear to show no conservation in their DNA sequence. These elements, termed Polycomb/Trithorax response elements (PRE/TREs or PREs), are relatively well characterised in flies, but their mammalian counterparts have proved to be extremely difficult to identify. Recent progress in this endeavour has generated a wealth of data and raised several intriguing questions. Here, we ask why and to what extent mammalian PREs are so different to those of the fly. We review recent advances, evaluate current models and identify open questions in the quest for mammalian PREs.
Topics: Animals; Chromosomal Proteins, Non-Histone; CpG Islands; DNA-Binding Proteins; Drosophila Proteins; Drosophila melanogaster; Genes, Homeobox; Histones; Humans; Mice; Polycomb Repressive Complex 1; Polycomb Repressive Complex 2; Polycomb-Group Proteins; Protein Processing, Post-Translational; Response Elements; Transcription Factors
PubMed: 26453572
DOI: 10.1007/s00412-015-0539-4