Ligand inducible transcription factors
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We review trialkyltin and triaryltin compounds, representing a class of organometallic compounds that function as nuclear retinoid X receptors (RXR) agonists due to their capability to bind to the ligand-binding domain of RXR subtypes and function as transcriptional activators. RXRs act predominantly as heterodimers with other nuclear receptors as permissive heterodimers with peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptor, pregnane X receptor and constitutive androstan receptor or as non-permissive heterodimer with vitamin D receptor, and as conditional heterodimers with retinoid receptors, and thyroid hormone receptors. RXR - "partner" receptor heterodimers are considered to be ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. Tributyltin at even pico- or nanomolar concentrations may cause the superimposition of male genitalia on female in several aquatic organisms, since they are DNA-targeted, mitotic, and their actions are occurring through target gene(s)-mediated pathways. They may cause molecular interactions with reproductive system in mammals, and as potent environmental obesogens, they promote adipocyte differentiation. Organotin compounds become known also for their immunotoxicity, neurotoxicity, for their effects on reproduction and/or development. We also review effects of organotins with respect to levels and activities of hepatic P450s and aromatase activity.
- MeSH
- genetická transkripce MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lidé MeSH
- organocínové sloučeniny toxicita MeSH
- retinoidní X receptory agonisté MeSH
- transkripční faktory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.
Osteoprotegerin a jeho ligand (tzv. RANKL) jsou působky, které ovlivňují významným způsobem kostní resorpci (OPG inhibuje osteoklastogenezi a jeho ligand ji stimuluje). Obě látky jsou produkovány osteoblastickou buněčnou linií, vyskytují se v oběhu ve volné formě, a lze je tudíž měřit. Účinky OPG/RANKL jsou v posledních letech intenzívně studovány. Na animálních modelech bylo prokázáno, že OPG deficitní myši mají osteoporózu a naopak, myši s defektním genem pro ligand OPG mají osteopetrózu. Také podle výsledků většiny klinických studií se zdá, že existuje negativní souvislost mezi OPG a kostní denzitou. Existují pokusy o uplatnění modelu OPG/RANKL při výzkumu maligních primárních i sekundárních kostních ložisek, myelomu, cévních kalcifikací atp. Terapeutické podávání osteoprotegerinu v experimentu se osvědčilo u jedinců s těžkou osteoporózou, destruktivními chorobami skeletu, u metastazujících karcinomů mamy, tlustého střeva a prostaty, osteosarkomu či po ovarektomii. U takto léčených jedinců došlo také k významné redukci experimentálně navozených cévních kalcifikací.
Osteoprotegerin and its ligand (so-called RANKL) are substances which influence in an important way bone resorption (OPG inhibits osteoclastogenesis and its ligand stimulates it). Both substances are produced by the osteoblastic cell line, they are found in the blond stream in the free form and they can thus be estimated. The effects of OPG/RANKL are intensely studied in retem years. On animal models evidence was provided tkat OPG deficient mice have osteoporosis and vice ýersa. Also according to the results of the majority of clinical studies it seems tkat there exists an invers relationship between OPG and bone density. There are attempts to apply the OPG/RANKL method in research of malignant primary and secondary osseous fotí, myelomas, vascular calcifications etc. Therapeutic administration of osteoprotegerin in experiments proved useful in individuals with severe osteoporosis, destructive skeletal disease, in metastatizing carcinomas of the mammary gland, large intestine and prostaty, osteosarcoma or after ovariectomy. In thus treated subjects also a significant reduction of experimentally induced calcifications occurred.
- MeSH
- Albers-Schönbergova nemoc etiologie farmakoterapie MeSH
- cytokiny fyziologie terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom etiologie farmakoterapie MeSH
- modely nemocí na zvířatech MeSH
- NF-kappa B fyziologie terapeutické užití MeSH
- osteoporóza etiologie farmakoterapie MeSH
- resorpce kosti MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells.
- MeSH
- apoptóza účinky léků MeSH
- cytotoxicita imunologická účinky léků MeSH
- genetická transkripce účinky léků MeSH
- leukemie genetika metabolismus patologie MeSH
- lidé MeSH
- ligand Fas farmakologie MeSH
- lymfom genetika metabolismus patologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protein bcl-X metabolismus MeSH
- protein TRAIL farmakologie MeSH
- proteosyntéza účinky léků MeSH
- protinádorové látky farmakologie MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus MeSH
- puriny farmakologie MeSH
- signální adaptorové proteiny receptorové domény smrti metabolismus MeSH
- TNF-alfa farmakologie MeSH
- tumor burden účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.
- MeSH
- aktivace enzymů účinky léků MeSH
- cytochrom P-450 CYP1A1 genetika MeSH
- hepatocyty metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- orgánová specificita MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- promotorové oblasti (genetika) účinky léků MeSH
- receptory aromatických uhlovodíků agonisté chemie metabolismus MeSH
- simulace molekulového dockingu MeSH
- střevní sliznice metabolismus MeSH
- sulfonamidy farmakologie MeSH
- transkripční faktory bHLH agonisté chemie metabolismus MeSH
- tryptaminy farmakologie MeSH
- upregulace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A major outcome of the canonical Wnt/beta-catenin-signalling pathway is the transcriptional activation of a specific set of target genes. A typical feature of the transcriptional response induced by Wnt signalling is the involvement of Tcf/Lef factors that function in the nucleus as the principal mediators of signalling. Vertebrate Tcf/Lef proteins perform two well-characterized functions: in association with beta-catenin they activate gene expression, and in the absence of Wnt ligands they bind TLE/Groucho proteins to act as transcriptional repressors. Although the general characteristics of Tcf/Lef factors are well understood, the mechanisms that control their specific roles in various cellular backgrounds are much less defined. In this report we reveal that the evolutionary conserved Dazap2 protein functions as a TCF-4 interacting partner. We demonstrate that a short region proximal to the TCF-4 HMG box mediates the interaction and that all Tcf/Lef family members associate with Dazap2. Interestingly, knockdown of Dazap2 not only reduced the activity of Wnt signalling as measured by Tcf/beta-catenin reporters but additionally altered the expression of Wnt-signalling target genes. Finally, chromatin immunoprecipitation studies indicate that Dazap2 modulates the affinity of TCF-4 for its DNA-recognition motif.
- MeSH
- beta-katenin metabolismus MeSH
- buněčné linie MeSH
- DNA vazebné proteiny chemie metabolismus MeSH
- genetická transkripce MeSH
- genový knockdown MeSH
- lidé MeSH
- myši MeSH
- promotorové oblasti (genetika) MeSH
- proteiny vázající RNA antagonisté a inhibitory genetika metabolismus MeSH
- proteiny Wnt metabolismus MeSH
- regulace genové exprese MeSH
- transkripční faktory BHLH-Zip MeSH
- transkripční faktory chemie metabolismus MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
