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Biochimica Et Biophysica Acta.... May 2018Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered... (Review)
Review
Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription. In the present review we briefly introduce the Nrf2-Keap1 system and describe Nrf2 functions, illustrate the Nrf2-NF-κB cross-talk, and highlight the effects of the Nrf2-Keap1 system in the physiology and pathophysiology of striated muscle tissue taking into account its role(s) in oxidative stress and reductive stress.
Topics: Cell Nucleus; Humans; Kelch-Like ECH-Associated Protein 1; Maf Transcription Factors; NF-E2-Related Factor 2; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Signal Transduction
PubMed: 29499228
DOI: 10.1016/j.bbamcr.2018.02.010 -
Cell Stem Cell Apr 2022The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We...
The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.
Topics: Animals; Capillaries; Endothelial Cells; Endothelium; Liver; Liver Cirrhosis; Liver Regeneration; Mice; Proto-Oncogene Proteins c-maf
PubMed: 35364013
DOI: 10.1016/j.stem.2022.03.002 -
Physiological Reviews Jul 2018The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and... (Review)
Review
The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor of redox insults, whereas NRF2 is a transcription factor that robustly transduces chemical signals to regulate a battery of cytoprotective genes. KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1-mediated repression on exposure to stresses. The rapid inducibility of a response based on a derepression mechanism is an important feature of the KEAP1-NRF2 system. Recent studies have unveiled the complexities of the functional contributions of the KEAP1-NRF2 system and defined its broader involvement in biological processes, including cell proliferation and differentiation, as well as cytoprotection. In this review, we describe historical milestones in the initial characterization of the KEAP1-NRF2 system and provide a comprehensive overview of the molecular mechanisms governing the functions of KEAP1 and NRF2, as well as their roles in physiology and pathology. We also refer to the clinical significance of the KEAP1-NRF2 system as an important prophylactic and therapeutic target for various diseases, particularly aging-related disorders. We believe that controlled harnessing of the KEAP1-NRF2 system is a key to healthy aging and well-being in humans.
Topics: Amino Acid Sequence; Carcinogenesis; Cytoprotection; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Kelch-Like ECH-Associated Protein 1; Maf Transcription Factors; NF-E2-Related Factor 2; Oxidation-Reduction
PubMed: 29717933
DOI: 10.1152/physrev.00023.2017 -
Archives of Insect Biochemistry and... Jun 2020Insects have evolved resistance to almost all insecticides developed for their control. Multiple mechanisms of resistance, including enhanced metabolism and excretion of... (Review)
Review
Insects have evolved resistance to almost all insecticides developed for their control. Multiple mechanisms of resistance, including enhanced metabolism and excretion of insecticides, target-site insensitivity, reduced penetration of insecticides, and avoidance behavior, have been reported. The genes coding for proteins involved in resistance have been identified in numerous insects. The enzymes and transporters required for all three phases of insecticide metabolism and excretion including cytochrome P450 monooxygenases, glutathione S-transferases, UDP-glucuronosyltransferases, carboxylesterases, and ATP-binding cassette transmembrane transporters have been identified. Recent research in multiple insect species identified CNC-bZIP transcription factor superfamily members as regulators of genes coding for enzymes and transporters involved in insecticide metabolic resistance. The information on the pathway including reactive oxygen species, cap "n" collar isoform-C, and its heterodimer partner, muscle aponeurosis fibromatosis transcription factors involved in overexpression of enzymes and transporters involved insecticide resistance will be summarized.
Topics: Animals; Inactivation, Metabolic; Insect Proteins; Insecta; Insecticide Resistance; Insecticides; Oncogene Protein v-maf; Transcription Factors
PubMed: 32281173
DOI: 10.1002/arch.21674 -
Human Molecular Genetics Mar 2023Maf-family basic motif leucine zipper protein NRL specifies rod photoreceptor cell fate during retinal development and, in concert with homeodomain protein CRX and other...
Maf-family basic motif leucine zipper protein NRL specifies rod photoreceptor cell fate during retinal development and, in concert with homeodomain protein CRX and other regulatory factors, controls the expression of most rod-expressed genes including the visual pigment gene Rhodopsin (Rho). Transcriptional regulatory activity of NRL is modulated by post-translational modifications, especially phosphorylation, and mutations at specific phosphosites can lead to retinal degeneration. During our studies to elucidate NRL-mediated transcriptional regulation, we identified protein kinase CK2 in NRL-enriched complexes bound to Rho promoter-enhancer regions and in NRL-enriched high molecular mass fractions from the bovine retina. The presence of CK2 in NRL complexes was confirmed by co-immunoprecipitation from developing and adult mouse retinal extracts. In vitro kinase assay and bioinformatic analysis indicated phosphorylation of NRL at Ser117 residue by CK2. Co-transfection of Csnk2a1 cDNA encoding murine CK2 with human NRL and CRX reduced the bovine Rho promoter-driven luciferase expression in HEK293 cells and mutagenesis of NRL-Ser117 residue to Ala restored the reporter gene activity. In concordance, overexpression of CK2 in the mouse retina in vivo by electroporation resulted in reduction of Rho promoter-driven DsRed reporter expression as well as the transcript level of many phototransduction genes. Thus, our studies demonstrate that CK2 can phosphorylate Ser117 of NRL. Modulation of NRL activity by CK2 suggests intricate interdependence of transcriptional and signaling pathways in maintaining rod homeostasis.
Topics: Animals; Cattle; Mice; Humans; Casein Kinase II; HEK293 Cells; Eye Proteins; Basic-Leucine Zipper Transcription Factors; Retina; Rhodopsin; Retinal Rod Photoreceptor Cells; Mammals; Proto-Oncogene Proteins c-maf
PubMed: 36226585
DOI: 10.1093/hmg/ddac256 -
Frontiers in Immunology 2020Beyond its well-admitted role in development and organogenesis, it is now clear that the transcription factor c-Maf has owned its place in the realm of immune-related... (Review)
Review
Beyond its well-admitted role in development and organogenesis, it is now clear that the transcription factor c-Maf has owned its place in the realm of immune-related transcription factors. Formerly introduced solely as a Th2 transcription factor, the role attributed to c-Maf has gradually broadened over the years and has extended to most, if not all, known immune cell types. The influence of c-Maf is particularly prominent among T cell subsets, where c-Maf regulates the differentiation as well as the function of multiple subsets of CD4 and CD8 T cells, lending it a crucial position in adaptive immunity and anti-tumoral responsiveness. Recent research has also revealed the role of c-Maf in controlling Th17 responses in the intestine, positioning it as an essential factor in intestinal homeostasis. This review aims to present and discuss the recent advances highlighting the particular role played by c-Maf in T lymphocyte differentiation, function, and homeostasis.
Topics: Cell Differentiation; Humans; Immune Tolerance; Interleukin-10; Intestines; Nuclear Receptor Subfamily 1, Group F, Member 3; Proto-Oncogene Proteins c-maf; T-Lymphocytes
PubMed: 32117317
DOI: 10.3389/fimmu.2020.00206 -
Genes Sep 2023Large musculoaponeurotic fibrosarcoma (MAF) transcription factors contain acidic, basic, and leucine zipper regions. Four types of MAF have been elucidated in mice and... (Review)
Review
Large musculoaponeurotic fibrosarcoma (MAF) transcription factors contain acidic, basic, and leucine zipper regions. Four types of MAF have been elucidated in mice and humans, namely c-MAF, MAFA, MAFB, and NRL. This review aimed to elaborate on the functions of MAF transcription factors that have been studied in vivo so far, as well as describe the pathology of human patients and corresponding mouse models with c-MAF, MAFA, and MAFB point mutations. To identify the functions of MAF transcription factors in vivo, we generated genetically modified mice lacking c-MAF, MAFA, and MAFB and analyzed their phenotypes. Further, in recent years, c-MAF, MAFA, and MAFB have been identified as causative genes underpinning many rare diseases. Careful observation of human patients and animal models is important to examine the pathophysiological mechanisms underlying these conditions for targeted therapies. Murine models exhibit phenotypes similar to those of human patients with c-MAF, MAFA, and MAFB mutations. Therefore, generating these animal models emphasizes their usefulness for research uncovering the pathophysiology of point mutations in MAF transcription factors and the development of etiology-based therapies.
Topics: Humans; Mice; Animals; Transcription Factors; Maf Transcription Factors, Large; MafB Transcription Factor; Insulin; Point Mutation
PubMed: 37895232
DOI: 10.3390/genes14101883 -
Cell Reports Apr 2023Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons...
Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-Maf) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-Maf neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-Maf neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-Maf neuron activation. Our study identifies c-Maf neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.
Topics: Animals; Mice; Spinal Cord Dorsal Horn; Spinal Cord; Posterior Horn Cells; Neuralgia; Synaptic Transmission; Interneurons; Proto-Oncogene Proteins c-maf
PubMed: 36947543
DOI: 10.1016/j.celrep.2023.112295 -
Biomolecules Jul 2021MAF is a transcription factor that may act either as a tumor suppressor or as an oncogene, depending on cell type. We have shown previously that the overexpressed...
MAF is a transcription factor that may act either as a tumor suppressor or as an oncogene, depending on cell type. We have shown previously that the overexpressed miR-1290 influences MAF protein levels in LSCC (laryngeal squamous cell carcinoma) cell lines. In this study, we shed further light on the interaction between miR-1290 and , as well as on cellular MAF protein localization in LSCC. We confirmed the direct interaction between miR-1290 and 3'UTR by a dual-luciferase reporter assay. In addition, we used immunohistochemistry staining to analyze MAF protein distribution and observed loss of MAF nuclear expression in 58% LSCC samples, of which 10% showed complete absence of MAF, compared to nuclear and cytoplasmatic expression in 100% normal mucosa. Using TCGA data, bisulfite pyrosequencing and CNV analysis, we excluded the possibility that loss-of-function mutations, promoter region DNA methylation or CNV are responsible for MAF loss in LSCC. Finally, we identified genes involved in the regulation of apoptosis harboring the MAF binding motif in their promoter region by applied FIMO and DAVID GO analysis. Our results highlight the role of miR-1290 in suppressing MAF expression in LSCC. Furthermore, MAF loss or mislocalization in FFPE LSCC tumor samples might suggest that MAF acts as a LSCC tumor suppressor by regulating apoptosis.
Topics: 3' Untranslated Regions; Aged; Cell Line, Tumor; Cell Nucleus; DNA Methylation; Female; Gene Dosage; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Male; MicroRNAs; Middle Aged; Mutation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-maf; Squamous Cell Carcinoma of Head and Neck
PubMed: 34356658
DOI: 10.3390/biom11071035 -
Cell Reports Apr 2023Myofibers are broadly characterized as fatigue-resistant slow-twitch (type I) fibers and rapidly fatiguing fast-twitch (type IIa/IIx/IIb) fibers. However, the molecular...
Myofibers are broadly characterized as fatigue-resistant slow-twitch (type I) fibers and rapidly fatiguing fast-twitch (type IIa/IIx/IIb) fibers. However, the molecular regulation of myofiber type is not entirely understood; particularly, information on regulators of fast-twitch muscle is scarce. Here, we demonstrate that the large Maf transcription factor family dictates fast type IIb myofiber specification in mice. Remarkably, the ablation of three large Mafs leads to the drastic loss of type IIb myofibers, resulting in enhanced endurance capacity and the reduction of muscle force. Conversely, the overexpression of each large Maf in the type I soleus muscle induces type IIb myofibers. Mechanistically, a large Maf directly binds to the Maf recognition element on the promoter of myosin heavy chain 4, which encodes the type IIb myosin heavy chain, driving its expression. This work identifies the large Maf transcription factor family as a major regulator for fast type IIb muscle determination.
Topics: Mice; Animals; Myosin Heavy Chains; Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Maf Transcription Factors, Large; Proto-Oncogene Proteins c-maf
PubMed: 36952339
DOI: 10.1016/j.celrep.2023.112289