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Cells Aug 2021Glucocorticoids (GCs) are essential in regulating functions and homeostasis in many biological systems and are extensively used to treat a variety of conditions... (Review)
Review
Glucocorticoids (GCs) are essential in regulating functions and homeostasis in many biological systems and are extensively used to treat a variety of conditions associated with immune/inflammatory processes. GCs are among the most powerful drugs for the treatment of autoimmune and inflammatory diseases, but their long-term usage is limited by severe adverse effects. For this reason, to envision new therapies devoid of typical GC side effects, research has focused on expanding the knowledge of cellular and molecular effects of GCs. GC-induced leucine zipper (GILZ) is a GC-target protein shown to mediate several actions of GCs, including inhibition of the NF-κB and MAPK pathways. GILZ expression is not restricted to immune cells, and it has been shown to play a regulatory role in many organs and tissues, including the cardiovascular system. Research on the role of GILZ on endothelial cells has demonstrated its ability to modulate the inflammatory cascade, resulting in a downregulation of cytokines, chemokines, and cellular adhesion molecules. GILZ also has the capacity to protect myocardial cells, as its deletion makes the heart, after a deleterious stimulus, more susceptible to apoptosis, immune cell infiltration, hypertrophy, and impaired function. Despite these advances, we have only just begun to appreciate the relevance of GILZ in cardiovascular homeostasis and dysfunction. This review summarizes the current understanding of the role of GILZ in modulating biological processes relevant to cardiovascular biology.
Topics: Cardiovascular System; Glucocorticoids; Humans; Leucine Zippers
PubMed: 34440924
DOI: 10.3390/cells10082155 -
Molecular Neurobiology Dec 2017The central nervous system (CNS) is a large network of intercommunicating cells that function to maintain tissue health and homeostasis. Considerable evidence suggests... (Review)
Review
The central nervous system (CNS) is a large network of intercommunicating cells that function to maintain tissue health and homeostasis. Considerable evidence suggests that glucocorticoids exert both neuroprotective and neurodegenerative effects on the CNS. Glucocorticoids act by binding two related receptors in the cytoplasm, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The glucocorticoid receptor complex mediates cellular responses by transactivating target genes and by protein: protein interactions. The paradoxical effects of glucocorticoids on neuronal survival and death have been attributed to the concentration and the ratio of mineralocorticoid to glucocorticoid receptor activation. Glucocorticoid-induced leucine zipper (GILZ) is a recently identified protein transcriptionally upregulated by glucocorticoids. Constitutively, expressed in many tissues including brain, GILZ mediates many of the actions of glucocorticoids. It mimics the anti-inflammatory and anti-proliferative effects of glucocorticoids but exerts differential effects on stem cell differentiation and lineage development. Recent experimental data on the effects of GILZ following induced stress or trauma suggest potential roles in CNS diseases. Here, we provide a short overview of the role of GILZ in CNS health and discuss three potential rationales for the role of GILZ in Alzheimer's disease pathogenesis.
Topics: Animals; Central Nervous System; Glucocorticoids; Humans; Leucine Zippers; Receptors, Glucocorticoid; Signal Transduction; Up-Regulation
PubMed: 27889894
DOI: 10.1007/s12035-016-0277-5 -
Frontiers in Immunology 2018Dendritic cells (DCs) are key antigen-presenting cells that control the induction of both tolerance and immunity. Understanding the molecular mechanisms regulating DCs... (Review)
Review
Dendritic cells (DCs) are key antigen-presenting cells that control the induction of both tolerance and immunity. Understanding the molecular mechanisms regulating DCs commitment toward a regulatory- or effector-inducing profile is critical for better designing prophylactic and therapeutic approaches. Initially identified in dexamethasone-treated thymocytes, the glucocorticoid-induced leucine zipper (GILZ) protein has emerged as a critical factor mediating most, but not all, glucocorticoids effects in both non-immune and immune cells. This intracellular protein exerts pleiotropic effects through interactions with transcription factors and signaling proteins, thus modulating signal transduction and gene expression. GILZ has been reported to control the proliferation, survival, and differentiation of lymphocytes, while its expression confers anti-inflammatory phenotype to monocytes and macrophages. In the past twelve years, a growing set of data has also established that GILZ expression in DCs is a molecular switch controlling their T-cell-priming capacity. Here, after a brief presentation of GILZ isoforms and functions, we summarize current knowledge regarding GILZ expression and regulation in DCs, in both health and disease. We further present the functional consequences of GILZ expression on DCs capacity to prime effector or regulatory T-cell responses and highlight recent findings pointing to a broader role of GILZ in the fine tuning of antigen capture, processing, and presentation by DCs. Finally, we discuss future prospects regarding the possible roles for GILZ in the control of DCs function in the steady state and in the context of infections and chronic pathologies.
Topics: Animals; Antigen Presentation; Antigens; Biomarkers; Dendritic Cells; Gene Expression Regulation; Glucocorticoids; Humans; Immune Tolerance; Immunomodulation; Leucine Zippers
PubMed: 29915587
DOI: 10.3389/fimmu.2018.01232 -
Annual Review of Cell and Developmental... Oct 2019The dual leucine zipper-bearing kinase (DLK) and leucine zipper-bearing kinase (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage kinase family. Acting... (Review)
Review
The dual leucine zipper-bearing kinase (DLK) and leucine zipper-bearing kinase (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage kinase family. Acting upstream of stress-responsive JNK and p38 MAP kinases, DLK and LZK have emerged as central players in neuronal responses to a variety of acute and traumatic injuries. Recent studies also implicate their function in astrocytes, microglia, and other nonneuronal cells, reflecting their expanding roles in the multicellular response to injury and in disease. Of particular note is the potential link of these kinases to neurodegenerative diseases and cancer. It is thus critical to understand the physiological contexts under which these kinases are activated, as well as the signal transduction mechanisms that mediate specific functional outcomes. In this review we first provide a historical overview of the biochemical and functional dissection of these kinases. We then discuss recent findings on regulating their activity to enhance cellular protection following injury and in disease, focusing on but not limited to the nervous system.
Topics: Animals; Axons; Humans; Leucine Zippers; MAP Kinase Kinase Kinases; Neurodegenerative Diseases; Neuroglia; Neurons; Regeneration; Stem Cells; Stress, Physiological; Wounds and Injuries
PubMed: 31590586
DOI: 10.1146/annurev-cellbio-100617-062644 -
Plant Signaling & Behavior Feb 2009Homeodomain-leucine zipper (HD-Zip) proteins are transcription factors unique to plants and are encoded by more than 25 genes in Arabidopsis thaliana. Based on sequence... (Review)
Review
Homeodomain-leucine zipper (HD-Zip) proteins are transcription factors unique to plants and are encoded by more than 25 genes in Arabidopsis thaliana. Based on sequence analyses these proteins have been classified into four distinct groups: HD-Zip I-IV. HD-Zip proteins are characterized by the presence of two functional domains; a homeodomain (HD) responsible for DNA binding and a leucine zipper domain (Zip) located immediately C-terminal to the homeodomain and involved in protein-protein interaction. Despite sequence similarities HD-ZIP proteins participate in a variety of processes during plant growth and development. HD-Zip I proteins are generally involved in responses related to abiotic stress, abscisic acid (ABA), blue light, de-etiolation and embryogenesis. HD-Zip II proteins participate in light response, shade avoidance and auxin signalling. Members of the third group (HD-Zip III) control embryogenesis, leaf polarity, lateral organ initiation and meristem function. HD-Zip IV proteins play significant roles during anthocyanin accumulation, differentiation of epidermal cells, trichome formation and root development.
Topics: Arabidopsis; Arabidopsis Proteins; Gene Expression Regulation, Plant; Homeodomain Proteins; Indoleacetic Acids; Leucine Zippers; Light; Transcription Factors
PubMed: 19649178
DOI: 10.4161/psb.4.2.7692 -
ASN Neuro 2022Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous... (Review)
Review
Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous system. Persistent inflammation due to chronic stress, age related accrual of free radicals, subclinical infections or other factors lead to reduced survival and increased neuronal death. Circadian abnormalities secondary to altered sleep/wake cycles is one of the earliest signs of neurodegenerative diseases. Brain specific or global deficiency of core circadian trans-activator brain and muscle ARNT (Arylhydrocarbon Receptor Nuclear Translocator)-like protein 1 (BMAL1) or that of the transrepressor REV-ERBα, impaired neural function and cognitive performance in rodents. Consistently, transcripts of inflammatory cytokines and host immune responses have been shown to exhibit diurnal variation, in parallel with the disruption of the circadian rhythm. Glucocorticoids that exhibit both a circadian rhythm similar to that of the core clock transactivator BMAL1 and tissue specific ultradian rhythm are critical in the control of neuroinflammation and re-establishment of homeostasis. It is widely accepted that the glucocorticoids suppress nuclear factor-kappa B (NF-κB) mediated transactivation and suppress inflammation. Recent mechanistic elucidations suggest that the core clock components also modulate NF-κB mediated transactivation in the brain and peripheral tissues. In this review we discuss evidence for interactions between the circadian clock components, glucocorticoids and NF-κB signaling responses in the brain and propose glucocorticoid induced leucine zipper (GILZ) encoded by Tsc22d3, as a molecular link that connect all three pathways in the maintenance of CNS homeostasis as well as in the pathogenesis of neuroinflammation-neurodegeneration.
Topics: Humans; NF-kappa B; Circadian Clocks; Glucocorticoids; ARNTL Transcription Factors; Leucine Zippers; Neuroinflammatory Diseases; Ultradian Rhythm; Inflammation
PubMed: 36317290
DOI: 10.1177/17590914221120190 -
The New Phytologist Jan 2017Homeodomain-leucine zipper proteins (HD-ZIPs) form a plant-specific family of transcription factors functioning as homo- or heterodimers. Certain members of all four... (Review)
Review
Homeodomain-leucine zipper proteins (HD-ZIPs) form a plant-specific family of transcription factors functioning as homo- or heterodimers. Certain members of all four classes of this family are involved in embryogenesis, the focus of this review. They support auxin biosynthesis, transport and response, which are in turn essential for the apical-basal patterning of the embryo, radicle formation and outgrowth of the cotyledons. They transcriptionally regulate meristem regulators to maintain the shoot apical meristem once it is initiated. Some members are specific to the protoderm, the outermost layer of the embryo, and play a role in shoot apical meristem function. Within classes, homeodomain-leucine zippers tend to act redundantly during embryo development, and there are many examples of regulation within and between classes of homeodomain-leucine zippers. This indicates a complex network of regulation that awaits future experiments to uncover.
Topics: Gene Expression Regulation, Developmental; Homeodomain Proteins; Indoleacetic Acids; Leucine Zippers; Meristem; Plants
PubMed: 27523393
DOI: 10.1111/nph.14132 -
International Journal of Molecular... Feb 2023Small heterodimer partner-interacting leucine zipper (SMILE) is a member of the CREB/ATF family of basic leucine zipper (bZIP) transcription factors. SMILE has two... (Review)
Review
Small heterodimer partner-interacting leucine zipper (SMILE) is a member of the CREB/ATF family of basic leucine zipper (bZIP) transcription factors. SMILE has two isoforms, a small and long isoform, resulting from alternative usage of the initiation codon. Interestingly, although SMILE can homodimerize similar to other bZIP proteins, it cannot bind to DNA. As a result, SMILE acts as a co-repressor in nuclear receptor signaling and other transcription factors through its DNA binding inhibition, coactivator competition, and direct repression, thereby regulating the expression of target genes. Therefore, the knockdown of SMILE increases the transactivation of transcription factors. Recent findings suggest that SMILE is an important regulator of metabolic signals and pathways by causing changes in glucose, lipid, and iron metabolism in the liver. The regulation of SMILE plays an important role in pathological conditions such as hepatitis, diabetes, fatty liver disease, and controlling the energy metabolism in the liver. This review focuses on the role of SMILE and its repressive actions on the transcriptional activity of nuclear receptors and bZIP transcription factors and its effects on liver metabolism. Understanding the importance of SMILE in liver metabolism and signaling pathways paves the way to utilize SMILE as a target in treating liver diseases.
Topics: Transcription Factors; Basic-Leucine Zipper Transcription Factors; Liver; Leucine Zippers
PubMed: 36769229
DOI: 10.3390/ijms24032907 -
Journal of Innate Immunity 2021Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is...
Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is implicated in neuropathic pain. We hypothesized that neuronal DLK is involved in the regulation of inflammation and nociceptive behavior in cystitis. Mice deficient in DLK in sensory neurons (cKO) were generated by crossing DLK floxed mice with mice expressing Cre recombinase under Advillin promoter. Cystitis was induced by cyclophosphamide (CYP) administration in mice. Nociceptive behavior, bladder inflammation, and pathology were assessed following cystitis induction in control and cKO mice. The role of DLK in CYP-induced cystitis was further determined by pharmacological inhibition of DLK with GNE-3511. Deletion of neuronal DLK attenuated CYP-induced pain-like nociceptive behavior and suppressed histamine release from mast cells, neuronal activation in the spinal cord, and bladder pathology. Mice deficient in neuronal DLK also showed reduced inflammation induced by CYP and reduced c-Jun activation in the dorsal root ganglia (DRG). Pharmacological inhibition of DLK with GNE-3511 recapitulated the effects of neuronal DLK depletion in CYP treatment mice. Our study suggests that DLK is a potential target for the treatment of neuropathic pain and bladder pathology associated with cystitis.
Topics: Animals; Cyclophosphamide; Cystitis; Ganglia, Spinal; Leucine Zippers; Mice; Nociception
PubMed: 34175846
DOI: 10.1159/000514545 -
Genes Mar 2022The basic leucine zipper (bZIP) is a widely found transcription factor family that plays regulatory roles in a variety of cellular processes including cell growth and...
The basic leucine zipper (bZIP) is a widely found transcription factor family that plays regulatory roles in a variety of cellular processes including cell growth and development and various stress responses. However, the bZIP gene family has not been well studied at a genome-wide scale in , a potent pathogen of cereal grains. In the present study, we conducted a genome-wide identification, characterization, and expression profiling of 22 bZIP () genes at different developmental stages and under various abiotic stresses. All identified were categorized into nine groups based on their sequence similarity and phylogenetic tree analysis. Furthermore, the gene structure analysis, conserved motif analysis, chromosomal localization, protein network studies, and synteny analysis were performed. The symmetry of the exon and intron varied with the phylogenetic groups. The post-translational modifications (PTMs) analysis also predicted several phosphorylation sites in FgbZIPs, indicating their functional diversity in cellular processes. The evolutionary study identified many orthogroups among eight species and also predicted several gene duplication events in . The protein modeling indicated the presence of a higher number of α-helices and random coils in their structures. The expression patterns of genes showed that 5 genes, including , , and , had high expression at different growth and conidiogenesis stages. Similarly, eight genes including , , , , , , and demonstrated their putative role in response to various abiotic stresses. In summary, these results provided basic information regarding FgbZIPs which are helpful for further functional analysis.
Topics: Basic-Leucine Zipper Transcription Factors; Chromosomes, Plant; Fusarium; Gene Expression Profiling; Gene Expression Regulation, Plant; Leucine Zippers; Multigene Family; Phylogeny
PubMed: 35456413
DOI: 10.3390/genes13040607