关键词： Cancer   Cancer therapy   Head and neck cancer   Oncogenes  

摘要： Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo-TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5- dimethylthiazol- 2- yl]- 2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo-TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.

关键词： ATF3   MMP13   Smad4   TGF-beta 1  

摘要： We previously reported that transforming growth factor-beta 1 (TGF-beta 1) stimulated the sustained and prolonged expression of activating transcription factor 3 (ATF3) in highly metastatic and invasive human breast cancer cells (MDA-MB231), in contrast to normal human mammary epithelial cells. However, the mechanism behind the stability of ATF3 expression is not yet known. Based on an in silico approach with co-immunoprecipitation and mass spectrometric analyses, we identified a number of proteins, including Smad4, that interacted with ATF3 after TGF-beta 1 treatment in MDA-MB231 cells. The knockdown of Smad4 using the siRNA technique resulted in a significant loss of ATF3 expression in these cells. Chromatin immunoprecipitation was then used to identify the formation of an ATF3 and Smad4 complex at the matrix metalloproteinase 13 (MMP13) promoter upon TGF-beta 1-treatment and the knockdown of Smad4 decreased MMP13 promoter activity in MDA-MB231 cells. Our findings indicate that Smad4 is a pre-requisite for providing stability to ATF3 via TGF-beta 1 in human breast cancer cells. The targeting of Smad4 may thus provide the sustainable loss of ATF3 expression that is needed to control breast cancer progression. (C) 2019 Elsevier B.V. All rights reserved.

关键词： ZnO nanoparticle   ATF3   DNA repair   Apoptosis   p53  

摘要： ZnO nanoparticle (ZnO NP) exposure causes oxidative stress in the respiratory system, leading to pulmonary damage. Activating transcription factor 3 (ATF3) participates in a variety of cellular stress responses. However, the role of ATF3 in ZnO NP genotoxicity and cytotoxicity remains to be explored. Here we reported that ZnO NP treatment dramatically induced the expression of ATF3 in human bronchial epithelial (HBE) cells, which was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2). ATF3 was required for the repair of ZnO NP-induced DNA damage as gamma foci number increased when endogenous ATF3 was silenced. Moreover, ATF3 also contributed to ZnO NP-induced cell apoptosis. Mechanistic study revealed that ATF3 interacted with the p53 protein and upregulated its expression under ZnO NP treatment. Collectively, our findings demonstrated ATF3 as an important regulator of epithelial homeostasis by promoting both DNA repair and the death of damaged cells under ZnO NP-induced genotoxic stress.

关键词： Cancer genetics   Cancer microenvironment  

摘要： The activating transcription factor 3 (ATF3) and the c-Jun dimerization protein 2 (JDP2) are members of the basic leucine zipper (bZIP) family of transcription factors. These proteins share a high degree of homology and both can activate or repress transcription. Deficiency of either one of them in the non-cancer host cells was shown to reduce metastases. As ATF3 and JDP2 compensate each other's function, we studied the double deficiency of ATF3 and JDP2 in the stromal tumor microenvironment. Here, we show that mice with ATF3 and JDP2 double deficiency (designated thereafter dKO) developed larger tumors with high vascular perfusion and increased cell proliferation rate compared to wild type (WT) mice. We further identify that the underlying mechanism involves tumor associated fibroblasts which secrete high levels of stromal cell-derived factor 1 (SDF-1) in dKO fibroblasts. SDF-1 depletion in dKO fibroblasts dampened tumor growth and blood vessel perfusion. Furthermore, ATF3 and JDP2 were found to regulate SDF-1 transcription and secretion in fibroblasts, a phenomenon that is potentiated in the presence of cancer cells. Collectively, our results suggest that ATF3 and JDP2 regulate the expression of essential tumor promoting factors expressed by fibroblasts within the tumor microenvironment, and thus restrain tumor growth.

关键词： Quercetin   Sepsis   Macrophage polarization   TRPM2   AMPK   ATF3  

摘要： M2 macrophage polarization plays a crucial role in counteracting inflammatory disorders such as sepsis. Quercetin is a dietary flavonoid that possesses robust anti-inflammatory properties. However, it is not known whether quercetin takes effects by directly promoting M2 polarization in macrophages. In this study, we observed that quercetin enhanced macrophage M2 polarization and exerted anti-inflammatory activity in LPS stimulated murine peritoneal macrophages. Moreover, quercetin triggered TRPM2 dependent calcium influx and induced calcium dependent activation of AMPKa and ATF3, both were required to mediate M2 macrophage polarization and facilitate the anti-inflammatory activity by quercetin. In a murine endotoxaemia model, quercetin improved survival and ameliorated acute lung injury. Quercetin also induced AMPKa phosphorylation, upregulated ATF3 expression and promoted M2 macrophage polarization in model mice. In conclusion, our results suggest that quercetin promotes macrophage M2 polarization and confers protection of murine sepsis by inducing calcium dependent activation of the AMPK-ATF3 pathway.

摘要： Su1549

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  

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  

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  

摘要： For nearly a half century, the primary focus of pharmacological development for the treatment of heart failure with reduced ejection fraction (HFrEF) has been the canonical receptor-G protein-adenylyl cyclase signaling system (1–4)and the accessory proteins that modify signaling by hydrolyzing cyclic adenosine monophosphate (cAMP) (phosphodiesterase), desensitizing the receptor to further catecholamine stimuli (G protein receptor kinases, or GRKs)(5), uncoupling the phosphorylated receptor from the G protein, and targeting it for internalization (β-arrestin)(6)or coupling the β-adrenergic receptor (β-AR) and the L-type Ca2+channel (Bcl2-associated anthanogene 3, or BAG3)(7)(Figure 1). Maladaptive changes in the constituents of this signaling pathway are pathognomonic for HFrEF: a decrease in both β1-AR density and mRNA(8); uncoupling of β1-AR and β2-AR from downstream signaling; diminished G protein function(9); diminished levels of BAG3(10); and an increase in GRK2 mRNA and in kinase activity(11,12).