Fos-related Antigen Research Articles

Memory regulation in feeding habit transformation to dead prey fish of Chinese perch (Siniperca chuatsi).

Memory drove a critical process of feeding habit transformation in Chinese perch when they re-trained to eat dead prey fish. To investigate the regulatory mechanism of cAMP-response element-binding protein (CREB) signaling pathway on the memory of Chinese perch during feeding habit transformation, the phosphorylation levels of upstream signal proteins of CREB between the control group (trained once) and the experimental group (trained twice) were measured. The results illustrated that the re-training was correlated to phosphorylation of extracellular regulated protein kinase (ERK1/2) and calcium/calmodulin-dependent protein kinase II (CaMKII), and dephosphorylation of protein kinase A (PKA) of Chinese perch. Inhibition of ERK1/2-CREB pathway decreased the mRNA levels of memory-related genes ((fos-related antigen 2 (fra2), CCAAT enhancer-binding protein delta (c/ebpb), immediate-early gene zif268 (zif268), proto-oncogenes c-fos (c-fox) and synaptotagmin-IV (sytIV)) and mRNA levels of appetite-related genes (agouti-related peptide (agrp) and ghrelin), and activation of PP1-CREB pathway increased the phosphorylated levels of CREB, the mRNA levels of memory-related genes (fra2, c/ebpb, zif268, and c-fox), and the mRNA levels of appetite-related genes (pro-opiomelanocortin (pomc) and leptin) in primary brain cells of Chinese perch. The memory in Chinese perch feeding habit transformation was associated with the ERK1/2-CREB and PP1-CREB pathways, which could regulate the transcription of memory-related genes and appetite-related genes.

Syndecan-1 shedding by meprin β impairs keratinocyte adhesion and differentiation in hyperkeratosis

Dysregulation of proteolytic enzymes has huge impact on epidermal homeostasis, which can result in severe pathological conditions such as fibrosis or Netherton syndrome. The metalloprotease meprin β was found to be upregulated in hyperproliferative skin diseases. AP-1 transcription factor complex has been reported to induce Mep1b expression. Since AP-1 and its subunit fos-related antigen 2 (fra-2) are associated with the onset and progression of psoriasis, we wanted to investigate if this could partially be attributed to increased meprin β activity. Here, we demonstrate that fra-2 transgenic mice show increased meprin β expression and proteolytic activity in the epidermis. To avoid influence by other fra-2 regulated genes, we additionally generated a mouse model that enabled tamoxifen-inducible expression of meprin β under the Krt5-promotor to mimic the pathological condition. Interestingly, induced meprin β expression in the epidermis resulted in hyperkeratosis, hair loss and mottled pigmentation of the skin. Employing N-terminomics revealed syndecan-1 as a substrate of meprin β in skin. Shedding of syndecan-1 at the cell surface caused delayed calcium-induced differentiation and impaired adhesion of keratinocytes, which was blocked by the meprin β inhibitor fetuin-B.

PFOA Exposure Prior to Hepatocyte Differentiation Leads to Gene Expression Changes Implicated in Non-Alcoholic Fatty Liver Disease

Background: Perfluorooctanoic acid (PFOA), is a persistent fluorinated compound with oil and water repelling properties found in cookware, food packaging and municipal water systems. Adult animals exposed to PFOA develop hepatomegaly, fatty liver, peroxisome proliferation, and immunotoxicity. Rodents exposed to PFCs in utero have altered hepatic lipid metabolism, increased hepatic de novo lipogenesis and susceptibility to non-alcoholic fatty liver disease (NAFLD), but underlying molecular mechanisms remain unknown. With increasing rates of obesity, diabetes, and NAFLD it is critical to examine the mechanisms by which in utero exposure to PFOA contributes to the development of metabolic syndrome in offspring. Objective: To determine mechanism by which PFOA alters gene expression in undifferentiated hepatic progenitor cells. Design/methods: HepaRG cells, a human derived hepatocyte progenitor cell line, was treated with 0.5uM PFOA or vehicle for 48 hours followed by differentiation into hepatocytes. Total RNA was extracted using the RNeasy (Qiagen) [total RNA A260/280>2 and RNA integrity number >7 (Agilent Bioanalyzer)] to generate libraries with the Illumina TruSeq stranded total RNA kit. RNA-Seq was performed using 85 bp single-end read sequencing to generate >20 million reads per sample. RNAseq data was aligned to hg38 using STAR v2.6.1a and then quantified with featureCounts v1.6.2. DESeq2 identified differentially expressed genes via FDR (false discovery rate) after Bonferroni correction. Differentially expressed gene lists were used for Ingenuity Pathway Analysis (IPA) to identify pathways of biological significance.Results: PFOA treatment resulted in increased expression of transcription factors EGR1 (early growth response protein 1), NR4A1 (nuclear receptor Nur77), EGR2 (early growth response protein 2), KLF10 (Krueppel-like factor 10) and FOSL1 (Fos-related antigen 1), key genes linked to impaired hepatic insulin signaling, hepatic lipid metabolism, steatosis and fibrosis (fold change > 1.5; q <0.05). IPA identified enrichment of canonical pathways with biological relevance including hepatic fibrosis signaling, stellate cell activation, VDR/RXR/TR activation, and Type 2 diabetes mellitus signaling (p<0.01). Conclusion: Hepatocyte progenitor cells exposed to low dose PFOA for 48 hours prior to differentiation results in changes in expression of key metabolic genes linked to the development of NAFLD and enrichment of biologically relevant pathways associated with hepatic fibrosis and hepatocellular carcinoma. These results suggest that PFOA exposure in utero may have lasting effects on hepatic glucose and lipid metabolism after differentiation. Further studies are needed to characterize the longstanding metabolic effects of in utero PFOA exposure in offspring and the mechanisms driving the persistence of these changes.

Preclinical analysis of novel prognostic transcription factors and immune-related gene signatures for bladder cancer via TCGA-based bioinformatic analysis.

Bladder cancer (BLCA) is a common malignancy of human urinary tract, whose prognosis is influenced by complex gene interactions. Immune response activity can act as a potential prognostic factor in BLCA. The present study established a prognostic model, based on the identification of tumor transcription factors (TFs) and immune-related genes (IRGs), and further explored their therapeutic potential in BLCA. The enrichment scores of 29 IRG sets, identified in The Cancer Genome Atlas BLCA tumor samples, were quantified by single-sample Gene Set Enrichment Analysis. The abundance of infiltrated immune cells in tumor tissues was determined using the Estimating Relative algorithm. Tumor-related TFs and IRGs signatures were retrieved using Least Absolute Shrinkage and Selection Operator Cox regression analysis. A prognostic gene network was built using Pearson's correlation analysis as a means of predicting the regulatory relationship between prognostic TFs and IRGs. A nomogram was devised to also predict the overall survival (OS) rate of patients with BLCA. Based on the Genomics of Drug Sensitivity in Cancer data, potential therapeutic drugs were identified upon analyzing the relationship between the expression level of prognostic genes and respective IC50 values. In vitro experiments were implemented for further validation. Respective TF binding profiles were acquired from the JASPAR 2020 database. The elevated infiltration of CD8+ T Cells was correlated with an improved OS of patients with BLCA. An innovative prognostic model for BLCA was then constructed that composed of nine putative gene markers: CXCL13, prepronociceptin, microtubule-associated protein tau, major histocompatibility class I polypeptide-related sequence B, prostaglandin E2 receptor EP3 subtype, IL20RA, proepiregulin, early growth response protein 1 and FOS-related antigen 1 (FOSL1). Furthermore, a theoretical basis for the correlation between the prognostic TFs and IRGs was reported. For this, 10 potentially effective drugs targeting the TFs in the present model for patients with BLCA were identified. It was then verified that downregulation of FOSL1 can lead to an enhanced sensitivity of the TW37 in T24 bladder cancer cells. Overall, the present prognostic model demonstrated a robust capability of predicting OS of patients with BLCA. Hence, the gene markers identified could be applied for targeted therapies against BLCA.

Pulmonary fibrosis in Fra-2 transgenic mice is associated with decreased numbers of alveolar macrophages and increased susceptibility to pneumococcal pneumonia.

Idiopathic pulmonary fibrosis (IPF) is a deadly condition characterized by progressive respiratory dysfunction. Exacerbations due to airway infections are believed to promote disease progression, and presence of Streptococcus in the lung microbiome has been associated with the progression of IPF and mortality. The aim of this study was to analyze the effect of lung fibrosis on susceptibility to pneumococcal pneumonia and bacteremia. The effects of subclinical (low dose) infection with Streptococcus pneumoniae were studied in a well characterized fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of spontaneous, progressive pulmonary fibrosis. Forty-eight hours after transnasal infection with S. pneumoniae, bacterial load was assessed in lung tissue, bronchoalveolar lavage (BAL), blood, and spleen. Leukocyte subsets and cytokine levels were analyzed in BAL and blood. Lung compliance and arterial blood gases were assessed. In contrast to wildtype mice, low dose lung infection with S. pneumoniae in Fra-2 TG mice resulted in substantial pneumonia including weight loss, increased lung bacterial load, and bacteremia. BAL alveolar macrophages were reduced in Fra-2 TG mice compared to the corresponding WT mice. Proinflammatory cytokines and chemokines (IL-1β, IL-6, TNF-α, and CXCL1) were elevated upon infection in BAL supernatant and plasma of Fra-2 TG mice. Lung compliance was decreased in Fra-2 TG mice following low dose infection with S. pneumoniae. Pulmonary fibrosis increases susceptibility to pneumococcal pneumonia and bacteremia possibly via impaired alveolar bacterial clearance.

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis.

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

FRA-1 suppresses apoptosis of Helicobacter pylori infected MGC-803 cells.

Previous research has demonstrated a correlation between elevated expression of Fos-related antigen 1 (FRA-1) and malignancies. Nevertheless, the role of FRA-1 in Helicobacter pylori infected gastric cancer cells remains vague. Our study aims to investigate whether FRA-1 plays a role in the apoptosis of MGC-803 induced by H. pylori and possible mechanisms. MGC-803 cells were used in vitro to establish a cell model of H. pylori infection. After stimulation with H. pylori, the expression of FRA-1 was increased in MGC-803 cells. H. pylori infection promoted the apoptosis of MGC-803 cells, and led to cell cycle arrest and increased oxidative stress levels. Furthermore, the knockdown of FRA-1 reinforced these changes. H. pylori decreased the expression of Bcl2, Caspase3 and Caspase9, while increased the level of BAX, Cleaved-Caspase3 and Cleaved-Caspase9; in addition, it led to the decrease of major proteins in Ras/Erk and PI3K/AKT signaling pathway. As expected, these changes were augmented by FRA-1 knockdown. Our results demonstrated that high expression of FRA-1 induced by H. pylori suppresses apoptosis in MGC-803 cells which may be regulated by oxidative stress and cycle arrest through caspase family, Ras/Erk and PI3K/AKT signaling pathway.

Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway.

The oncogenesis of cervical cancer is a multi-factor and multi-step process, and major risk factors include oncogene activation with tumor suppressor gene inactivation, viral factors, and immune factors. For example, the human papillomavirus (HPV) has been linked to the occurrence of cervical cancer. At present, the pathogenesis of cervical cancer remains unclear. Fra-1 (Fos-related antigen 1, also known as FOSL1) is a member of the Fos family and an important nuclear transcription factor that regulates normal cell growth, differentiation, and apoptosis. In the present study, we found that Fra-1 inhibited the proliferation of cervical cancer cells while also promoting apoptosis and affecting cell cycle distribution. Moreover, Fra-1 up-regulated STAT1 expression and modulated p53 signal pathway activity in cervical cancer cells. Overexpression of Fra-1 inhibited cell senescence by altering sirtuin 1 (SIRT1) expression in HeLa cells, and Fra-1 overexpression restored mitochondrial disorder and suppressed metabolic reprogramming in HeLa cells. Silencing of STAT1 impaired the inhibitory effect of Fra-1 on cervical cancer cell growth, while knock-down of STAT1 reversed the effect on cell senescence and mitochondrial dysfunction caused by Fra-1 in HeLa cells. Silencing of STAT1 also recovered metabolic reprogramming in cervical cancer cells. In summary, our results show that Fra-1 inhibited cervical cancer cell growth and the Warburg effect via STAT1-mediated regulation of the p53 signaling pathway.

Silencing circRNA_001937 may inhibit cutaneous squamous cell carcinoma proliferation and induce apoptosis by preventing the sponging of the miRNA‑597‑3p/FOSL2 pathway.

Circular RNAs (circRNAs) are reported to be aberrantly expressed and perform different functions in numerous types of tumor; however, their expression levels in cutaneous squamous cell carcinoma (CSCC) remain largely unclear. Thus, the purpose of the present study was to investigate the function of circRNA_001937 in CSCC. Differential circRNA expression profiles of CSCC were analyzed using the Arraystar Human circRNAs chip and reverse transcription-quantitative PCR (RT-qPCR); and the effects of circRNA_001937 on cell behavior, in particular its regulation over the microRNA (miRNA)-597-3p/Fos-related antigen 2 (FOSL2) pathway, was investigated using a dual-luciferase reporter assay, and verified using RT-qPCR and western blotting. circRNA_001937 expression levels were significantly increased in CSCC tissues and cell lines compared with the corresponding adjacent tissues and control cells (P<0.05). The genetic silencing of circRNA_001937 with small interfering RNA significantly inhibited cell proliferation, and induced cell apoptosis (P<0.05). circRNA_001937 was observed to directly bind to miRNA-597-3p and serve as a sponge, which indirectly increased the expression levels of FOSL2, a miRNA-597-3p target gene. In conclusion, circRNA_001937 expression was increased in CSCC and silencing circRNA_001937 gene expression may inhibit CSCC progression by sponging the miRNA-597-3p/FOSL2 pathway.

MicroRNA-143-3p contributes to inflammatory reactions by targeting FOSL2 in PBMCs from patients with autoimmune diabetes mellitus

Autoimmune diabetes mellitus (defined as ADM) comprises classical type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). In this study, microRNAs (miRNAs) expression profiles and functions in peripheral blood mononuclear cells (PBMCs) of ADM patients were mapped and used to explore epigenetic regulation of the pathogenesis of ADM. PBMCs samples from T1DM patients, LADA patients, and type 2 diabetes mellitus (T2DM) patients, as well as age- and sex-matched healthy controls for T1DM and T2DM, respectively, were collected and were sequenced to screen the miRNAs expression profiles. The target genes were verified by dual-luciferase reporter assay. Silencing or overexpressing of the differentially expressed miRNAs, or simultaneously silencing the miRNAs and it's target gene, and then levels of the mRNAs, protein and cytokines were detected. miR-143-3p expression was upregulated in ADM patients. The target gene of miR-143-3p was identified as Fos-related antigen 2 (FOSL2). Transfection of a miR-143-3p inhibitor into PBMCs upregulated FOSL2 expression, resulting in a downregulated expression of the IL-2, TNF-α, and IFN-γ, and an upregulated expression of IL-6. Transfection of a miR-143-3p mimic into PBMCs downregulated FOSL2 expression, leading to an upregulation of IL-2 and TNF-α expression and a downregulation of IL-6 expression. When silencing FOSL2 while inhibiting miR-143-3p in PBMCs, there was no significant change in expression of the FOSL2 mRNA, protein and cytokines. The expression of miR-143-3p in PBMCs from ADM patients is upregulated. miR-143-3p could function in the pathogenesis of ADM by modulating the inflammatory reaction through FOSL2.

NCAPG Dynamically Coordinates the Myogenesis of Fetal Bovine Tissue by Adjusting Chromatin Accessibility.

NCAPG is a subunit of condensin I that plays a crucial role in chromatin condensation during mitosis. NCAPG has been demonstrated to be associated with farm animal growth traits. However, its role in regulating myoblast differentiation is still unclear. We used myoblasts derived from fetal bovine tissue as an in vitro model and found that NCAPG was expressed during myogenic differentiation in the cytoplasm and nucleus. Silencing NCAPG prolonged the mitosis and impaired the differentiation due to increased myoblast apoptosis. After 1.5 days of differentiation, silencing NCAPG enhanced muscle-specific gene expression. An assay for transposase-accessible chromatin- high throughput sequencing (ATAC-seq) revealed that silencing NCAPG altered chromatin accessibility to activating protein 1 (AP-1) and its subunits. Knocking down the expression of the AP-1 subunits fos-related antigen 2 (FOSL2) or junB proto-oncogene (JUNB) enhanced part of the muscle-specific gene expression. In conclusion, our data provide valuable evidence about NCAPG’s function in myogenesis, as well as its potential role in gene expression.

Circular RNA hsa_circ_0056836 functions an oncogenic gene in hepatocellular carcinoma through modulating miR-766-3p/FOSL2 axis.

Background: Circular RNA (circRNA) remains a tumour-related factor in various biological cells and plays regulatory roles in gene expression. It is a type of non-coding RNA, whereas the function of human circRNA in hepatocellular carcinoma (HCC) is still not clear yet. Our investigation used the HCC cell line to uncover the biological function of hsa_circ_0056836 in the development and progression of hepatocellular carcinoma.Results: The present study showed that hsa_circ_0056836 revealed high expressions in HCC cell lines and tissues compared with corresponding controls. Silencing of Hsa_circ_0056836 decreased cell migration, proliferation and invasion. Silencing of hsa_circ_0056836 inhibited the development of HCC in xenograft nude mice. Mechanistically, we found that hsa_circ_0056836 directly bound to miR-766-3p, thereby alleviating the targeted inhibition of Fos-related antigen 2 (FOSL2). The results of this study indicated that hsa_circ_0056836 is a novel oncogenic RNA of vast potential as a tumor biomarker.Conclusion: In summary, the hsa_circ_0056836 / miR-766-3p / FOSL2 axis may serve as a promising strategy for HCC treatment.Method: First, the expressions of hsa_circ_0056836 in HCC tissues and corresponding para-cancerous tissues as well as in HCC cell lines and normal hepatocytes THLE-3 were detected by RT-PCR. Subcellular localization of hsa_circ_0056836 was confirmed by FISH. To detect the association between hsa_circ_0056836 and miR-766-3p, AGO2-RIP and Luciferase reporter assay were adopted. Loss of function study was applied to assess the role of hsa_circ_0056836 in HCC and to determine tumorigenesis in nude mice.

Nitrogen mustard prevents transport of Fra-1 into the nucleus to promote c-Fos- and FosB-dependent IL-8 induction in injured mouse epidermis

Transcription factor activator protein (AP)-1 can be activated in nitrogen-mustard-injured mouse skin, and is thought to participate in the inflammatory response. AP-1 consists of homo- or heterodimers of Fos [c-Fos, Fos-B, fos-related antigen (Fra)-1 and Fra-2] and Jun (c-Jun, JunB and JunD) family members, and information about their expression, location and function are still unclear. In nitrogen-mustard-exposed mouse skin, we found p-ERK activation increased Fra-1 and FosB. Unlike the nucleus location of c-Fos and FosB, Fra-1 and Fra-2 were mainly expressed in the cytoplasm. In nitrogen-mustard-exposed cultured immortalized human keratinocytes (HaCaT cells), Fra-1 in the nucleus functioned as an inhibitor of inflammatory cytokine interleukin (IL)-8. Co-immunoprecipitation showed that Fra-1 formed dimers with IL-8 transcription factors c-Jun, JunB and JunD. Fra-1 depletion increased c-Fos and FosB in the nucleus, accompanied by increased heterodimers of c-Fos/c-Jun, c-Fos/JunB, c-Fos/JunD, and FosB/JunB. In conclusion, Fra-1 trapped in the cytoplasm after nitrogen mustard exposure might be a driving force for IL-8 over-expression in injured skin.

Expression and function of FRA1 protein in tumors.

AP-1 is a dimeric complex that is composed of JUN, FOS, ATF and MAF protein families. FOS-related antigen 1 (FRA1) which encoded by FOSL1 gene, belongs to the FOS protein family, and mainly forms an AP-1 complex with the protein of the JUN family to exert an effect. Regulation of FRA1 occurs at levels of transcription and post-translational modification, and phosphorylation is the major post-translational modification. FRA1 is mainly regulated by the mitogen-activated protein kinases signaling pathway and is degraded by ubiquitin-independent proteasomes. FRA1 can affect biological functions, such as tumor proliferation, differentiation, invasion and apoptosis. Studies have demonstrated that FRA1 is abnormally expressed in many tumors and plays a relevant role, but the specific condition varies from the target organs. FRA1 is overexpressed in breast cancer, lung cancer, colorectal cancer, prostate cancer, nasopharyngeal cancer, thyroid cancer and other tumors. However, the expression of FRA1 is decreased in cervical cancer, and the expression of FRA1 in ovarian cancer and oral squamous cell carcinoma is still controversial. In this review, we present a detailed description of the regulatory factors and functions of FRA1, also, the expression of FRA1 in various tumors and its function in relative tumor.

Cloning and characterisation of the mouse fra-2 gene.

Transcription factor AP-1 is comprised of multiple protein complexes that include members of a family of genes related to the proto-oncogene c-fos. In this report, we have extended the analysis of one member of this family, fos-related antigen-2 (fra-2), by isolating and characterising genomic and cDNA clones encoding the mouse fra-2 homolog. The overall gene structure (number and positions of introns) was similar to that of both the chicken fra-2 gene and other members of the fos family, and the relative positions of putative enhancers in the 5' regulatory region were well conserved between the mouse and chicken fra-2 genes. High levels of fra-2 mRNA were detected in ovary, stomach, small and large intestine, brain, lung and heart. The mouse Fra-2 protein showed 94% and 87.5% conservation with human and chicken Fra-2, respectively, and mouse Fra-2, like the chicken homolog, induced transformation of chicken embryo fibroblasts. The characterisation of the mouse fra-2 gene provides a basis for analysis of Fra-2 function in the whole animal.

IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1β in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1β were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg−1·day−1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitro.Fra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1β was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis.

The polarization of macrophages is regulated by transcription factors such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1- or Fra-2-deficient macrophages revealed a central role of Fra-1, but not of Fra-2 in orchestrating the expression of genes related to wound response, toll-like receptor activation and interleukin signaling. Chromatin-immunoprecipitation (ChIP)-sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 down-regulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2- deficient mice, we observed an enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-L-arginine, while ʟ-arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1-deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active RA showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared to RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.

Neuro-behavioral effects after systemic administration of MK-801 and disinhibition of the anterior thalamic nucleus in rats: Potential relevance in schizophrenia

Non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonists have been suggested to evoke psychotomimetic-like behaviors by selectively targeting GABAergic elements in cortical and thalamic circuits. In previous studies, we had reported the involvement of the reticular and anterior thalamic nuclei (ATN) in the MK-801-evoked hyperactivity and other motor alterations. Consistent with the possibility that these responses were mediated by thalamic disinhibition, we examined the participation of cortical and hippocampal areas innervated by ATN in the responses elicited by the systemic administration of MK-801 (0.2 mg/kg) and compared them to the effects produced by the microinjection of a subconvulsive dose of bicuculline (GABAA receptor antagonist) in the ATN. We used the expression of Fos related antigen 2 (Fra-2) as a neuronal activity marker in the ATN and its projection areas such as hippocampus (HPC), retrosplenial cortex (RS), entorhinal cortex (EC) and medial prefrontal cortex (mPFC). Dorsal (caudate-putamen, CPu) and ventral striatum (nucleus accumbens, core and shell, NAc,co and NAc,sh) were also studied.Behavioral and brain activation results suggest a partial overlap after the effect of MK-801 administration and ATN disinhibition. MK-801 and ATN disinhibition increases locomotor activity and disorganized movements, while ATN disinhibition also reduces rearing behavior. A significant increase in Fra-2 immunoreactivity (Fra-2-IR) in the ATN, mPFC (prelimbic area, PrL) and NAc,sh was observed after MK-801, while a different pattern of Fra-2-IR was detected following ATN disinhibition (e.g., increase in DG and NAc,sh, and decrease in PrL cortex). Overall, our data may contribute to the understanding of dysfunctional neural circuits involved in schizophrenia.

Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Vascular aging has a strong relationship with cardiovascular disease. Fos-related antigen 1 (Fra-1), also referred to as Fos-like antigen 1, is a transcription factor and has been reported to be involved in many pathologic processes. Here, we demonstrate that Fra-1 plays a critical role in angiotensin II (Ang II)-induced vascular senescence. Fra-1 expression is increased significantly in Ang II-induced rat aortic endothelial cell (RAEC) senescence and the arteries from Ang II-infused mice. Interestingly, silencing Fra-1 blocks Ang II-induced senescence phenotypes in RAECs, including decreased senescence-associated β-galactosidase staining, and mitigated proliferation suppression and senescence-associated secretory phenotype. Further, knocking down Fra-1 inhibits vascular aging phenotypes in an Ang II-infused mice model. The up-regulated Fra-1 also exists in human atherosclerotic plaques and Ang II-induced vascular smooth muscle cells as well as in replicated senescence RAECs. Mechanistic studies reveal that Fra-1 preferentially associates with c-Jun and binds to the cyclin-dependent kinase inhibitor 1a (p21) and cyclin-dependent kinase inhibitor 2a (p16) promoter region, leading to elevated gene expression, which causes senescence-related phenotypes. In conclusion, our results identify that Fra-1 plays a novel and key role in promoting vascular aging by directly binding and transcriptionally activating p21 and p16 signaling, suggesting intervention of Fra-1 is a potential strategy for preventing aging-associated cardiovascular disorders.-Yang, D., Xiao, C., Long, F., Wu, W., Huang, M., Qu, L., Liu, X., Zhu, Y. Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

The expression, significance and function of cancer susceptibility candidate9 in lung squamous cell carcinoma: A bioinformatics and invitro investigation.

The cancer susceptibility candidate 9 (CASC9) gene has been reported to exert an oncogenic effect in several types of cancer. However, its role in lung squamous cell carcinoma (LUSC) is unknown. Therefore, the present study examined the expression of CASC9 in LUSC and non-cancer tissues by reverse transcription-quantitative polymerase chain reaction assays and by data mining of high-throughput public databases, including The Cancer Genome Atlas, the Gene Expression Omnibus, ArrayExpress and the Cancer Cell Line Encyclopedia. In vitro experiments were conducted to investigate the effects of CASC9 on the viability and the proliferation of LUSC cells. Furthermore, consulting the alteration status of CASC9 in LUSC from cBioPortal, functional enrichment analysis of co-expressed genes, prediction of potential transcription factors, and inspection of adjacent protein-coding genes were conducted to explore the potential molecular mechanism of CASC9 in LUSC. The results revealed that CASC9 was overexpressed in LUSC tissue, and significantly associated with the malignant progression of LUSC. In vitro experiments demonstrated that CASC9 knockdown by RNA interference attenuated the viability and proliferation of LUSC cells. Multiple copies of CASC9 gene were detected in 4 of 179 available sequenced LUSC cases. A functional enrichment analysis of 200 co-expressed genes indicated that these genes were significantly associated with terms, including 'cell-cell junction organization', 'desmosome organization', 'epidermis development', 'Hippo signaling pathway', 'pathogenic Escherichia coli infection' and 'PID HIF1 TF pathway'. Three genes, Fos-related antigen 2 (FOSL2), SWI/SNF complex subunit SMARCC2, and transcription factor COE1 (EBF1), were predicted by lncRNAMap to be associated with CASC9. Among these, the expression of FOSL2 and EBF1 was positively and negatively correlated with the expression of CASC9, respectively. Two adjacent protein-coding genes, cysteine-rich secretory protein LCCL domain-containing 1 and hepatocyte nuclear factor 4-γ, were also positively correlated with CASC9 expression. In conclusion, the present data suggest that CASC9 serves as an oncogene in LUSC and may be a promising target for alternative therapeutic options for patients with this condition.