关键词： FATTY LIVER-DISEASE   HEPATIC INSULIN-RESISTANCE   ATF3   STEATOSIS   BIOSYNTHESIS   INFLAMMATION   MECHANISM   STRESS   CHAIN  

摘要： Background and Aims NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. Approach and Results Here, we discovered that CRLS1 was significantly down-regulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA-mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte-specific Crls1-knockout (Crls1-HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol diet-induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. Conclusions In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3.

关键词： Breast cancer   ATF3   miRNA   lncRNA   circRNA   EPITHELIAL-MESENCHYMAL TRANSITION   GENE-REGULATION   EXPRESSION   ATF3   PREDICTION   DATABASE   SPONGE   CERNA  

摘要： We previously reported that activating transcription factor 3 (ATF3), an adaptive response gene, plays a dichotomous role in regulating several molecular processes during breast cancer progression. ATF3 promoted the expression of runt-related transcription factor 2 (Runx2, a metastatic gene) and activated matrix metalloproteinase 13 (MMP13, an invasive gene), thereby fostering proliferation and bone-metastasis of the breast cancer cells. Targeting ATF3 may mitigate the metastatic spread of breast cancer and improve the patient's lifespan. Non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are the new-era regimens that are currently utilized for diagnosis and treatment of a variety of malignancies including cancer. mir-3674 putatively targets ATF3, but its expression was significantly increased in human breast cancer cells (MDA-MB231), compared to normal human mammary epithelial cells (MCF-10A). Our in silico analysis identified a few lncRNAs and circRNAs showing their putative binding sites for miR-3674. Thus, mir-3674, despite its abundance in the MDA-MB231 cells, could not effectively target ATF3, which could be due to the sponging mechanism of lncRNAs and circRNAs towards mir-3674. More extensive in vitro and in vivo studies are required to validate this and expand the diagnostic and therapeutic perspectives of breast cancer.

关键词： ATF3   Atherosclerosis   CREB   Indoxyl sulfate   Neointimal formation   Uremia   ACTIVATING TRANSCRIPTION FACTOR-3   ELEMENT-BINDING PROTEIN   GENE-EXPRESSION   ATF3 EXPRESSION   HEART-FAILURE   CYCLIN D1   DISEASE   CREB   CARDIOMYOCYTES   CALCIFICATION  

摘要： Background and aims: Uremic patients are characterized by an increased risk of atherosclerotic cardiovascular diseases. Vascular smooth muscle cell (VSMC) proliferation contributes to neointimal formation, a main pathological feature in atherosclerosis. Activation of CREB/ATF3 signaling is pivotal in VSMC proliferation, yet its role in uremic atherosclerosis is unknown. This study aimed to explore whether CREB/ATF3 signaling is involved in the molecular mechanism underlying neointimal formation in uremia. Methods and results: Treatment of VSMCs with uremic toxin (indoxyl sulfate [IS]) activated cAMP/CREB/ATF3/cyclin D signaling, which was reflected by increased VSMC proliferation. Blocking cAMP/PKA/CREB/ATF3 signaling attenuated the promoting effect of IS on cyclin D1 expression and VSMC proliferation. Loss-of-function and time-dependent experiments showed that ATF3 lies downstream of the CREB signaling. Mutational analysis of cyclin D1 promoter along with chromatin immunoprecipitation assays showed that CREB/ATF3 signaling participated in IS-induced cyclin D transcription. In vivo, phosphorylated CREB (an active form of CREB) and ATF3 were prominently upregulated in the neointima of experimental uremic rats, the atherosclerotic plaques of uremic ApoE(-/-) mice, and the iliac arteries of uremic patients. Notably, the use of lentivirus to knock down ATF3 in the neointima of balloon-injured arteries could suppress the effect of uremia in vivo, including neointimal formation and cyclin D expression. Conclusions: In this study, we demonstrated that CREB/ATF3-related signaling may be involved in IS-induced VSMC proliferation and the pathogenesis of neointimal formation during uremia.

关键词： CYCLE ARREST   DNA-DAMAGE   KAPPA-B   POTENTIAL IMPACT   INDUCTION   APOPTOSIS   ATF3   EXPRESSION   ACID   PHYTOCHEMICALS  

摘要： Human colon cancer is the third leading cause of mortality in the United States and worldwide. Chemoprevention using diet is widely accepted as a promising approach for cancer management. Numerous population studies indicate a negative correlation between the incidence of colon cancer and consumption of whole grains with a high content of bioactive phenolic compounds. In the current study, we evaluated the anticancer properties of a high phenolic sorghum bran extract prepared using 70% ethanol with 5% citric acid solvent at room temperature. A significant dose-dependent suppression of cell proliferation was observed in human colon cancer cells treated with the high phenolic sorghum bran extract. Apoptosis and S phase growth arrest were induced, while cell migration and invasion were inhibited by this treatment; these effects were accompanied by altered expression of apoptosis, cell cycle, and metastasis-regulating genes. We also found that the high phenolic sorghum bran extract stimulated DNA damage in association with induction of extracellular signal-regulated kinase (ERK) and c-Jun-NH2-terminal kinase (JNK) and subsequent expression of activating transcription factor 3 (ATF3). The present study expands our understanding of the potential use of high phenolic sorghum bran to prevent human colon cancer.

关键词： breast cancer   endocrine therapy   drug-resistance   ATF3   RPPA   ACTIVATING TRANSCRIPTION FACTOR-3   PATIENT-LEVEL METAANALYSIS   GENE-EXPRESSION   AROMATASE INHIBITORS   ADJUVANT TAMOXIFEN   THERAPY   CELLS   MAPK   CLASSIFICATION   SUBTYPE  

摘要： Simple Summary Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express estrogen receptor alpha (ER alpha) are the vast majority and are mostly treated with targeted endocrine therapy. However, resistance development poses an urgent clinical problem and the mechanisms of this phenomenon are not fully understood. In this study we identified ATF3 as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. Our work adds a new piece to the complex puzzle of the molecular mechanisms at the basis of endocrine therapy resistance and proposes ATF3 and the downstream pathways as putative targets for novel combinatorial treatment strategies. Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor alpha account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, depending on the degree of severity of the disease at diagnosis, 10 to 40% of these tumors eventually relapse due to resistance development. Even though recent novel approaches as the combination with CDK4/6 inhibitors increased the overall survival of relapsing patients, this remains relatively short and there is a urgent need to find alternative targetable pathways. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle, and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed in vivo in a mouse model, and eleva

关键词： LEUCINE-ZIPPER   TRANSCRIPTION FACTORS   CPG METHYLATION   5-HYDROXYMETHYLCYTOSINE   5-METHYLCYTOSINE   RECOGNITION   TET   PROTEIN   SPECIFICITY   REVEALS  

摘要： In mammalian cells, 5-methylcytosine (5mC) occurs in genomic double-stranded DNA (dsDNA) and is enzymatically oxidized to 5-hydroxymethylcytosine (ShmC), then to 5-formylcy-tosine (SfC), and finally to 5-carboxylcytosine (ScaC). These cytosine modifications are enriched in regulatory regions of the genome. The effect of these oxidative products on five bZIP dimers (CREB1, ATF2, Zta, ATF3 vertical bar cJun, and cFos vertical bar cJun) binding to five types of dsDNA was measured using protein binding microarrays. The five dsDNAs contain either cytosine in both DNA strands or cytosine in one strand and either 5mC, 5hmC, 5fC, or 5caC in the second strand. Some sequences containing the CEBP half-site GCAA are bound more strongly by all five bZIP domains when dsDNA contains 5fC, 5hmC, or 5fC. dsDNA containing 5caC in some TRE (AP-1)-like sequences, e.g., TGACTAA, is better bound by Zta, ATF3 vertical bar cJun, and cFos vertical bar cJun.

关键词： 中国仓鼠卵巢细胞(CHO)   转录激活因子3(ATF3)   CRISPR/Cas9   DNMT3A  

摘要： 转录激活因子3(ATF3)是一种早期应激反应基因,能够影响细胞增殖、分化、转化和凋亡。中国仓鼠卵巢细胞(CHO)是重组蛋白、单克隆抗体等生物大分子药物生产的主要宿主细胞之一。ATF3能够促进肿瘤细胞的增殖及抗凋亡等作用,理论上可对CHO细胞发挥调节作用。因此本试验对CHO细胞中ATF3的甲基化水平进行深入研究,通过重亚硫酸盐测序法检测CHO-K1细胞中ATF3的甲基化水平,发现ATF3启动子区域的胞嘧啶-磷酸-鸟嘌呤(CpG)甲基化高达90%。为了进一步研究ATF3甲基化的上游调控机制,构建了敲除DNA甲基转移酶3A(DNMT3A)的CHO-K1来研究DNMT3A对ATF3甲基化水平的影响。结果表明,敲除DNMT3A后,CHO-K1细胞中的ATF3甲基化水平降低至0,这充分证明了DNMT3A对ATF3的甲基化的调控作用,为CHO细胞的ATF3基因调控研究以及后续CHO细胞株改造提供了理论依据。

关键词： Nanopillar   Deformation   Cytoskeleton   Physiology   ATF3   PANCREATIC-CANCER   SKELETAL-MUSCLE   ADHESION   FORCE   RIGIDITY   GROWTH   CYTOSKELETON   MODULATION   CONTRACTIONS   FABRICATION  

摘要： Architecture of cell correlates with the onset of disease. External factors as mechanical force and geometric constraint trigger physical deformation. In this study, we took advantage of nanopillar-based vertical array as a mechanobiological platform to quantitatively deconstruct the relationship between morphological deformation and cell behavior. Technically, this nanoscale platform enables us to make a comprehensive and detailed illustration on alternation of physiological behavior to mechanical stimuli. Morphologically, we found whole cell architecture and nuclear deformation were highly associated with cytoskeleton rearrangement. Mechanistically, we found that cell deformation induced translocation of activating transcription factor 3 (ATF3) into nucleus. Unraveling the signal responding networks associated with morphological deformation will not only increase our understanding of mechanotransduction, but may also encourage the development of a potential therapeutically target to treat diseases. (c) 2020 Elsevier Ltd. All rights reserved.

关键词： AT/RT   ALDH   Disulfiram   Cisplatin   Combination therapy   ATF3   ATF3 GENE-EXPRESSION   ALDEHYDE DEHYDROGENASE   MULTIMODAL THERAPY   INITIATING CELLS   CANCER CELLS   STEM-CELLS   RESISTANCE   SURVIVAL   MECHANISMS   CHILDREN  

摘要： Atypical teratoid/rhabdoid tumor (AT/RT) is the most malignant tumor of the central nervous system that generally occurs in young children. Despite the use of intensive multimodal therapy for AT/RT, the prognosis is still poor. The brain tumor initiating cells in AT/RT cells has been suggested as one of the challenges in AT/RT treatment. These cells have high expression of aldehyde dehydrogenase (ALDH). We investigated the combination effect of the ALDH inhibitor, disulfiram and cisplatin in the treatment of AT/RT cells. Isobologram analysis revealed that the combination therapy synergistically increases AT/RT cell death. The enzyme activity of ALDH AT/RT cells was effectively reduced by the combination therapy. We proposed that the synergistic augmentation occurs, at least partially through an increase in cleaved Poly (ADP-ribose) polymerase (PARP)-dependent apoptosis mediated by activating transcription factor 3 (ATF3). In the AT/RT mouse model, the combination therapy decreased tumor volume and prolonged survival. Immunofluorescence assay in mouse brain tissues were consistent with the expression of ATF3 and cleaved PARP. Our study demonstrates enhanced anti-cancer effect of combination therapy of disulfiram and cisplatin. This combination might provide a viable therapeutic strategy for AT/RT patients.

关键词： HISTONE DEACETYLASE 3   SET ENRICHMENT ANALYSIS   IN-VIVO   TRANSCRIPTION   INHIBITORS   MACROPHAGE   EXPRESSION   ATF3   METABOLISM   ACTIVATION  

摘要： During the activation of mouse macrophages by lipopolysaccharides, histone deacetylase 3 controls inflammatory responses by both repressing and activating gene transcription depending on its differential association with transcription factors. The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity(1-3). However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear(4-8). Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system.