关键词： ATF3   ChIP-seq   Enhancer   p300   H3K27ac   p53  

摘要： Background: Dysregulation of the common stress responsive transcription factor ATF3 has been causally linked to many important human diseases such as cancer, atherosclerosis, infections, and hypospadias. Although it is believed that the ATF3 transcription activity is central to its cellular functions, how ATF3 regulates gene expression remains largely unknown. Here, we employed ATF3 wild-type and knockout isogenic cell lines to carry out the first comprehensive analysis of global ATF3-binding profiles in the human genome under basal and stressed (DNA damage) conditions. Results: Although expressed at a low basal level, ATF3 was found to bind a large number of genomic sites that are often associated with genes involved in cellular stress responses. Interestingly, ATF3 appears to bind a large portion of genomic sites distal to transcription start sites and enriched with p300 and H3K27ac. Global gene expression profiling analysis indicates that genes proximal to these genomic sites were often regulated by ATF3. While DNA damage elicited by camptothecin dramatically altered the ATF3 binding profile, most of the genes regulated by ATF3 upon DNA damage were pre-bound by ATF3 before the stress. Moreover, we demonstrated that ATF3 was co-localized with the major stress responder p53 at genomic sites, thereby collaborating with p53 to regulate p53 target gene expression upon DNA damage. Conclusions: These results suggest that ATF3 likely bookmarks genomic sites and interacts with other transcription regulators to control gene expression.

关键词： 肝细胞癌   转录激活因子3   蛋白质类  

摘要： 目的筛选及验证肝癌细胞中与转录激活因子3（ATF3）相互结合的蛋白质，初步探讨在肝癌发生发展中协助ATF3发挥生物学功能的相关分子机制。方法应用免疫沉淀法沉淀出HepG2细胞中与ATF3相互结合的蛋白，经变性聚丙烯凝胶分析，与空载体组比对，挑选出差异性的电泳条带进行蛋白质谱分析，筛选出候选蛋白；再经免疫共沉淀验证二者是否相互结合；应用免疫组织化学及Westernblot检测并分析ATF3和候选蛋白在肝癌中的表达模式。结果过表达ATF3的HepG2实验组呈现出差异性表达的电泳条带；经质谱检测，Mascot软件分析及NCBI数据库检索，得到候选蛋白肽段信息，结合前期实验结果，PubMed文献报道，从中筛选出与ATF3最可能相关的蛋白gelsolin（GSN）；免疫共沉淀结果验证了ATI^3与GSN相互结合的关系，免疫组织化学及Westernblot检测出肝癌组织中ATF3与GSN的表达模式一致。结论ATF3可能通过与GSN蛋白之间的相互作用，在肝癌形成过程中协同发挥抑癌作用。

关键词： Activating transcription factor 3 (ATF3)   Staphylococcus aureus   Listeria monocytogenes   bacterial infection   cytokine  

摘要： Activating transcription factor 3 (ATF3) is a stress-induced transcriptional regulator in eukaryote. The role of ATF3 in cancer has been well defined, but how ATF3 functions in bacterial infection is not well understood. Pneumococcal infection has been shown to induce ATF3 expression, which subsequently enhances cytokine production and provides protection from lethal Streptococcus pneumoniae infection, but the role of ATF3 in other Gram-positive (G⁺) infections remains unclear. Here, we report that infection with other G⁺ bacteria (Staphylococcus aureus and Listeria monocytogenes) and with G^? bacteria (uropathogenic Escherichia coli) also significantly induced ATF3 expression. Moreover, the production of cytokines (tumor necrosis factor alpha [TNF]-α, interleukin [IL]-1β, IL-6 and interferon [IFN]-γ) was enhanced by ATF3 in S.?aureus and L. monocytogenes infection, but decreased in uropathogenic E. coli (UPEC) infection. In addition, in S.?aureus and L. monocytogenes infections, ATF3 WT mice cleared bacteria more efficiently and had higher survival rates than ATF3 knockout mice. However, in UPEC infection, no significant difference was found in survival rate. Taken together, these data suggest that ATF3 provides protection from S.?aureus and L. monocytogenes infections; however, the role of ATF3 in UPEC infection is more complicated and should be further elucidated.

关键词： brain ischemia   MCAO   ATF3   lentiviral overexpression   glutamate neurotoxicity   reporter assay  

摘要： This study evaluates the pathological role of the stress sensor activating transcription factor-3 (ATF3) in ischemic neurotoxicity. Upregulation of the transcript and protein for ATF3 was seen 2-10 hr after reperfusion in the ipsilateral cerebral hemisphere of mice with transient middle cerebral artery occlusion for 2 hr. Immunohistochemical analysis confirmed the expression of ATF3 by cells immunoreactive for a neuronal marker in neocortex, hippocampus, and striatum within 2 hr after reperfusion. In murine neocortical neurons previously cultured under ischemic conditions for 2 hr, transient upregulation of both Atf3 and ATF3 expression was similarly found during subsequent culture for 2-24 hr under normoxia. Lentiviral overexpression of ATF3 ameliorated the neurotoxicity of glutamate (Glu) in cultured murine neurons along with a slight but statistically significant inhibition of both Fluo-3 and rhodamine-2 fluorescence increases by N-methyl-D-aspartate. Similarly, transient upregulation was seen in Atf3 and ATF3 expression during the culture for 48 hr in neuronal Neuro2A cells previously cultured under ischemic conditions for 2 hr. Luciferase reporter analysis with ATF3 promoter together with immunoblotting revealed the possible involvement of several transcription factors responsive to extracellular and intracellular stressors in the transactivation of the Atf3 gene in Neuro2A cells. ATF3 could be upregulated to play a role in mechanisms underlying mitigation of the neurotoxicity mediated by the endogenous neurotoxin Glu at an early stage after ischemic signal inputs. (c) 2016 Wiley Periodicals, Inc.

关键词： STAPHYLOCOCCUS aureus   LISTERIA monocytogenes  

摘要： A correction to the article 'ATF3 provides protection from Staphylococcus aureus and Listeria monocytogenes infections' that was published in the April 19, 2016 issue is presented.

关键词： Transcription factors   B cells   Lymphomas   Genes   Immunoassay  

摘要： The article describes the expression pattern and the role of different members of the activating transcription factor (ATF) family in survival of diffuse large B-cell lymphoma (DLBCL) cell. The composition of AP-1 complexes determines the genes that are regulated, either positively or negatively. Immuno-histochemical analysis revealed strong nuclear ATF3 expression in tumors from ABC DLBCL patients.

关键词： Echinacoside   Parkinson＇s disease   1-Methyl-4-phenylpyridinium ion. Reactive oxygen species   ATF3   CHOP  

摘要： Echinacoside （ECH） is protective in a mouse model of Parkinson＇ s disease （PD） induced by 1-methyl-4- phenylpyridinium ion （MPP＋）. To investigate the mechanisms involved, SH-SYSY neuroblastoma ceils were treated with MPP＋ or a combination of MPP＋ and ECH, and the expression of ATF3 （activating transcription factor 3）, CHOP （C/EBP-homologous protein）, SCNA （synuclein alpha）, and GDNF （glial cell line-derived neurotrophic factor） was assessed. The results showed that ECH significantly improved cell survival by inhibiting the generation of MPP＋-induced reactive oxygen species （ROS）. In addition, ECH suppressed the ROS and MPP＋- induced expression of apoptotic genes （ATF3, CHOP, and SCNA）. ECH markedly decreased the MPP＋-induced cas- pase-3 activity in a dose-dependent manner. ATF3- knockdown also decreased the CHOP and cleaved caspase- 3 levels and inhibited the apoptosis induced by MPP＋. Interestingly, ECH partially restored the GDNF expression that was down-regulated by MPP＋. ECH also improved dopaminergic neuron survival during MPP＋ treatment and protected these neurons against the apoptosis induced by MPTP. Taken together, these data suggest that the ROS/ ATF3/CHOP pathway plays a critical role in mechanisms by which ECH protects against MPP＋-induced apoptosis in PD.

关键词： Activating transcription factor 3   Cardiac remodeling   Hypertrophy   Autophagy   Macrophages  

关键词： Bortezomib   CCL2   Allodynia   c-Jun   ATF3  

摘要： Bortezomib (BTZ) is a frequently used chemotherapeutic drug for the treatment of refractory multiple myeloma and hematological neoplasms. The mechanism by which the administration of BTZ leads to painful peripheral neuropathy remains unclear. In present study, we found that application of BTZ at 0.4 mg/kg for consecutive 5 days significantly increased the expression of CCL2 in DRG, and intrathecal administration of neutralizing antibody against CCL2 inhibited the mechanical allodynia induced by BTZ. We also found an increased expression of c-Jun in DRG, and that inhibition of c-Jun signaling prevented the CCL2 upregulation and mechanical allodynia in the rats treated with BTZ. Furthermore, the results with luciferase assay in vitro and ChIP assay in vivo showed that c-Jun might be essential for BTZ-induced CCL2 upregulation via binding directly to the specific position of the ccl2 promoter. In addition, the present results showed that an upregulated expression of ATF3 was co-expressed with c-Jun in the DRG neurons, and the enhanced interaction between c-Jun and ATF3 was observed in DRG in the rats treated with BTZ. Importantly, pretreatment with ATF3 siRNA significantly inhibited the recruitment of c-Jun to the ccl2 promoter in the rats treated with BTZ. Taken together, these findings suggested that upregulation of CCL2 resulting from the enhanced interaction between c-Jun and ATF3 in DRG contributed to BTZ-induced mechanical allodynia. (C) 2015 Published by Elsevier Inc.

关键词： Activating transcription factor 3   Endoplasmic reticulum stress   Reactive oxygen species   Liver cancer  

摘要： Background: Hepatocellular carcinoma (HCC) is one of most common and aggressive human malignancies in the world, especially, in eastern Asia, and its mortality is very high at any phase. We want to investigate mechanism of niclosamide inducing cell apoptosis in HCC. Methods: Two hepatoma cell lines were used to evaluate activity of niclosamide inducing cell apoptosis and study its mechanism. Quantitative real-time PCR and western blotting were used in analysis of genes expression or protein active regulated by niclosamide. Results: Niclosamide remarkably induced cell apoptosis in hepatoma cells. Furthermore, our study revealed that RNA-dependent protein kinase-like kinase (PERK) is activated and its expression is up-regulated in HCC cells which are exposed to niclosamide. niclosamide also significantly increase activating transcription factor 3 (ATF3), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP) expression in HCC cells. It's suggested that the function of niclosamide was abrogated by PERK inhibitor or absent ATF3. Expression of PERK and CHOP is correlated with ATF3 level in the cells. Conclusion: Taken together, our results indicate that ATF3 plays an integral role in ER stress activated and cell apoptosis induced by niclosamide in HCC cells. In this study, the new mechanism of niclosamide as anti-cancer we investigated, too.