关键词： 抗肿瘤中药注射液   转录激活因子3(ATF3)   卵巢癌细胞  

摘要： 目的考察消癌平注射液、艾迪注射液、华蟾素注射液、复方苦参注射液、斑蝥酸钠维生素B_6注射液、参芪扶正注射液对卵巢癌细胞A2780、SK-OV-3中转录激活因子3(ATF3)mRNA表达的影响。方法 6种不同浓度中药注射液作用于卵巢癌细胞24 h后,MTT法、RT-PCR法分别检测细胞增殖率、ATF3 mRNA表达。结果各中药注射液均有抑制卵巢癌细胞增殖的作用,并呈浓度依赖性。其中,华蟾素注射液可在抑制细胞增殖的同时抑制ATF3 mRNA表达,斑蝥酸钠维生素B_6注射液显著上调该因子mRNA表达,一定浓度消癌平注射液、艾迪注射液、复方苦参注射液、参芪扶正注射液对其mRNA表达也呈下调作用。结论 6种抗肿瘤中药注射液对卵巢癌细胞中ATF3 mRNA表达有抑制或诱导作用,其机制可能与中药活性成分影响肿瘤发展和转移有关。

关键词： activating transcription factor 3   follicular helper T cell   Peyer's patches   intestinal mucosal immunity   colitis   NEGATIVE REGULATOR   PATHOGENESIS   MICROBIOTA   BACTERIA   BCL6  

摘要： Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (TFH) cells in the gut. The expression of ATF3 in CD4(+) T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4(+) T cells (CD4(cre)Atf3(fl/f)l) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of T-FH cells, not other T cell subsets, were dramatically decreased in Peyer's patches from CD4(cre)Atf3(fl/fl) mice compared with Atf3(fl/fl) littermate controls. The defective T-FH cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of TFH or IgA(+) B cells caused significant remission of colitis in CD4(cre)Atf3(fl/fl) mice, indicating the T-FH-IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4(+) T cells. In summary, we demonstrated ATF3 as a regulator of T-FH cells in the gut, which may represent a potential immunotherapeutic target in colitis.

关键词： ATF3   beta-adrenergic receptors   heart failure   PDE3A   polymorphism   transcription regulation   CONGESTIVE-HEART-FAILURE   INOTROPIC THERAPY   DOWN-REGULATION   MILRINONE   MORTALITY   TERM   CONTRACTILITY   TACHYPHYLAXIS   INHIBITOR   AMRINONE  

摘要： BACKGROUND The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit. OBJECTIVES The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF. METHODS PDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis. RESULTS The authors identified a 29-nucleotide (nt) insertion (INS)/ deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF. CONCLUSIONS A 29-nt INS/ DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF. (J Am Coll Cardiol 2019; 73: 1173-84) (c) 2019 by the American College of Cardiology Foundation.

关键词： ATF3   beta-adrenergic receptors   heart failure   PDE3A   polymorphism   transcription regulation   G-PROTEIN   CARDIAC-FUNCTION   ORAL MILRINONE   POLYMORPHISM   BAG3   CARDIOMYOPATHY   EXPRESSION   RECEPTORS   MORTALITY   EVOLUTION  

摘要： Corresponding Author

关键词： β-adrenergic receptors   ATF3   heart failure   PDE3A   polymorphism   transcription regulation  

摘要： Corresponding Author [ABSTRACT FROM AUTHOR]

关键词： ATF3   cholangiocarcinoma   EMT   p53 signalling pathway   ACTIVATING TRANSCRIPTION FACTOR-3   TUMOR-SUPPRESSOR   PROLIFERATION   EXPRESSION   APOPTOSIS   INVASION  

摘要： The aim of this research was to determine the underlying mechanism of activating transcription factor 3 (ATF3) on cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT). The differentially expressed mRNAs in cholangiocarcinoma (CC) and its adjacent tissues were screened by microarray analysis, and the expression of ATF3 was detected through Quantitative real time polymerase chain reaction (qRT-PCR) and Western blot. The expression of EMT markers and p53-related proteins was analysed by Western blot. Analyses using the Cell Counting Kit-8 and TUNEL were performed to assess the rate of apoptosis and cell proliferation. Scratch wound and transwell assays were performed to study cell migration and invasion. Activating transcription factor 3 was restrained in CC cell lines and tissues and inhibited EMT while activating the p53 signalling pathway. Knockdown of ATF3 promoted cell proliferation but reduced the rate of apoptosis by inhibiting p53 signalling. Cell migration and invasion can be strengthened by ATF3 through activating the p53 signalling pathway.

关键词： β-adrenergic receptors   ATF3   heart failure   PDE3A   polymorphism   transcription regulation  

摘要： Background: The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit.Objectives: The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.Methods: PDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis.Results: The authors identified a 29-nucleotide (nt) insertion (INS)/deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF.Conclusions: A 29-nt INS/DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF. [ABSTRACT FROM AUTHOR]

关键词： ACTIVATING TRANSCRIPTION FACTOR-3   JUN DIMERIZATION PROTEIN-2   ATF3-DEPENDENT CROSS-TALK   CARDIOMYOCYTES   REPRESSOR   DIFFERENTIATION   HYPERTROPHY   MACROPHAGES   PROTECTS   GENE  

摘要： c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease.

关键词： ENDOPLASMIC-RETICULUM STRESS   NUCLEAR FACTOR   GENE ATF3   CANCER   APOPTOSIS   PATHWAY   PROLIFERATION   CARCINOMA   ONCOGENE   GROWTH  

摘要： Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-beta 1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant Delta Zip2 in TGF-beta 1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express Delta Zip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-beta 1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated Delta Zip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and Delta Zip2 in response to Nrf2 and TGF-beta 1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent Delta Zip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, Delta Zip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, Delta Zip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and Delta Zip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed Delta Zip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the Delta Zip2 expression is induced in response to electrophile/oxidative (here

关键词： ATF3   Mitochondrial dynamics   Nerve injury   Neurodegenerative disease   Axonal transport   DRP1   MULTIPLE-SCLEROSIS   MOTOR-NEURONS   C-JUN   TRANSPORT   FISSION   MYELIN   DYNAMICS   PROTEIN   FUSION   REGENERATION  

摘要： Over the last decade, mitochondrial dynamics beyond function during axon regeneration/degeneration have received attention. Axons have an effective delivery system of mitochondria shuttling between soma and axonal terminals, due to their polarized structure. The proper axonal transport of mitochondria, coordinated with mitochondrial fission/fusion and clearance, is vital for supplying high power energy in injured axons. Many researchers have studied mitochondrial dynamics using in vitro cultured cells with significant progress reported. However, the in vitro culture system is missing a physiological environment including glial cells, immune cells, and endothelial cells, whose communications are indispensable to nerve regeneration/degeneration. In line with this, the understanding of mitochondrial behavior in injured axon in vivo is necessary for promoting the physiological understanding of damaged axons and the development of a therapeutic strategy. In this review, we focus on recent insights into in vivo mitochondrial dynamics during axonal regeneration/degeneration, and introduce the advances of mouse strains to visualize mitochondria in a neuron-specific or an injury-specific manner, which are extremely useful for nerve regeneration/degeneration studies. (C) 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.