关键词： Chaetocin   SUV39H1   CHOP   ATF3   DR5   Apoptosis   5 EXPRESSION   IN-VITRO   INHIBITOR   CHOP   TRIMETHYLATION   MODULATION   SUV39H1   TARGETS   AGENT  

摘要： Epigenetic abnormalities are associated with non-small cell lung cancer (NSCLC) initiation and progression. Epigenetic drugs are being studied and in clinical trials. However, the molecular mechanism underlying the apoptosis by the epigenetic agents remains unclear. SUV39H1 is an important methyl-transferase for lysine 9 on histone H3 and usually related to gene transcriptional suppression, and chaetocin acts as the inhibitor of SUV39H1. We demonstrated here that chaetocin effectively suppressed the growth of multiple lung cancer cells through inducing apoptosis in a death receptor 5 (DR5)-dependent manner. Chaetocin treatment activated endoplasmic reticulum (ER) stress which gave rise to the up-regulation of ATF3 and CHOP. Furthermore, ATF3 and CHOP contributed to the induction of DR5 and subsequent apoptosis. When SUV39H1 was silenced with siRNA, the expression of ATF3, CHOP and DR5 was elevated. Thereafter, knockdown of SUV39H1 induced apoptosis in NSCLC cells. In summary, chaetocin pharmacologically inhibits the activity of SUV39H1 which provokes ER stress and results in up-regulation of ATF3 and CHOP, leading to DR5-dependent apoptosis eventually. These findings provide a novel interpretation on the anti-neoplastic activity of epigenetic drugs as a new therapeutic approach in NSCLC.

关键词： hypertrophy   remodeling   ventricular dysfunction   fibrosis   inflammation   ISCHEMIA-REPERFUSION INJURY   NITRIC-OXIDE SYNTHASE   MYOCARDIAL-ISCHEMIA   DEFICIENT MICE   P-SELECTIN   OVEREXPRESSION   ATF3   PROTECTS   DYSFUNCTION   EXPRESSION  

摘要： Numerous fibrotic and inflammatory changes occur in the failing heart. Recent evidence indicates that certain transcription factors, such as activating transcription factor 3 (ATF3), are activated during heart failure. Because ATF3 may be upregulated in the failing heart and affect inflammation, we focused on the potential role of ATF3 on postinfarct heart failure. We subjected anesthetized, wild-type mice to nonreperfused myocardial infarction and observed a significant induction in ATF3 expression and nuclear translocation. To test whether the induction of ATF3 affected the severity of heart failure, we subjected wild-type and ATF3-null mice to nonreperfused infarct-induced heart failure. There were no differences in cardiac function between the two genotypes, except at the 2-wk time point; however, ATF3-null mice survived the heart failure protocol at a significantly higher rate than the wild-type mice. Similar to the slight favorable improvements in chamber dimensions at 2 wk, we also observed greater cardiomyocyte hypertrophy and more fibrosis in the noninfarcted regions of the ATF3-null hearts compared with the wild-type. Nevertheless, there were no significant group differences at 4 wk. Furthermore, we found no significant differences in markers of inflammation between the wild-type and ATF3-null hearts. Our data suggest that ATF3 suppresses fibrosis early but not late during infarct-induced heart failure. Although ATF3 deficiency was associated with more fibrosis, this did not occur at the expense of survival, which was higher in the ATF3-null mice. Overall, ATF3 may serve a largely maladaptive role during heart failure.

关键词： Leukemia   Molt4   ER stress   Apoptosis   Gene expression   ENDOPLASMIC-RETICULUM STRESS   UNFOLDED PROTEIN RESPONSE   LUNG-CARCINOMA CELLS   CYTOCHROME-C   SACCHAROMYCES-CEREVISIAE   SIGNALING PATHWAY   PERILLYL ALCOHOL   RISK-FACTORS   MOUSE MODEL   DEATH  

摘要： In this study, we demonstrate that treatment of T lymphoblastic leukemic Molt4 cells with farnesol activates the apoptosome via the intrinsic pathway of apoptosis. This induction was associated with changes in the level of intracellular potassium and calcium, the dissipation of the mitochondria] and plasma membrane potential, release of cytochrome c, activation of several caspases, and PARP cleavage. The induction of apoptosis by farnesol was inhibited by the addition of the pan-caspase inhibitor Z-VAD-fmk and by the exogenous expression of the anti-apoptotic protein Bcl2. Analysis of the gene expression profiles by microarray analysis revealed that farnesol increased the expression of several genes related to the unfolded protein response (UPR), including CHOP and CHAC1. This induction was associated with the activation of the PERK-eIF2 alpha-ATF3/4 cascade, but not the XBP-1 branch of the UPR. Although farnesol induced activation of the ERK1/2, p38, and JNK pathways, inhibition of these MAPKs had little effect on farnesol-induced apoptosis or the induction of UPR-related genes. Our data indicate that the induction of apoptosis in leukemic cells by farnesol is mediated through a pathway that involves activation of the apoptosome via the intrinsic pathway and induction of the PERK-eIF2 alpha-ATF3/4 cascade in a manner that is independent of the farnesol-induced activation of MAPKs. Published by Elsevier Inc.

关键词： stress response   adenylate-uridylate-rich mRNA   reactivation   CAMP-RESPONSE ELEMENT   HOST SHUTOFF RNASE   ORGAN-CULTURES   MESSENGER-RNAS   AU-RICH   REACTIVATION   TYPE-1   ATF3   GENE   HSV-1  

摘要： A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSVs express a long noncoding RNA, a latency-associated transcript (LAT), which plays a key role in maintaining latently infected neurons, but not viral proteins. To investigate the events leading to reactivation, we examined the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to nerve growth factor (NGF) or delayed reactivation in medium containing NGF and epidermal growth factor (EGF). Here we report the discovery that activating transcription factor 3 (ATF3), a stress response protein, profoundly affects the interaction of HSV with its host. Specifically, (i) ATF3 is induced by stress, such as inhibition of protein synthesis or infection; (ii) in infected cells, ATF3 enhances the accumulation of LAT by acting on the response elements in the promoter of the LAT precursor RNA; (iii) ATF3 is induced nearly 100-fold in ganglionic organ cultures; and (iv) ATF3 plays a key role in the maintenance of the latent state, inasmuch as expression of ATF3 bereft of the C-terminal activation domain acts as a dominant negative factor, inducing HSV gene expression in ganglionic organ cultures harboring latent virus and incubated in medium containing NGF and EGF. Thus, ATF3 is a component of a cluster of cellular proteins that together with LAT maintain the integrity of the neurons harboring latent virus.

关键词： TOLL-LIKE RECEPTORS   SIGNAL-TRANSDUCTION   ATF3   PROTEINS   FAMILY   CANCER   PROTECTS   INSIGHTS   IMMUNITY   BIOLOGY  

摘要： Activating transcription factor 3 (ATF3) is induced by inflammatory responses, cell death, cytokines, and oxidative stress conditions. ATF3 is a negative regulator in the Toll-like receptor 4 signalling pathway. The principal molecule in this pathway is nuclear factor.B (NF-kappa B) that translocates into the nucleus to initiate the transcription of inflammatory mediators. However, scarce data are available regarding the interaction of ATF3 and p65, a part of the NF-kappa B dimer. Therefore, we studied the mechanism of regulation of p65 by ATF3 in RAW 264.7 cells. First, LPS-mediated NF-kappa B activation was confirmed, and then the direct interaction of ATF3 and p65 was observed through immunoprecipitation (IP). The presence of histone deacetylase 1 (HDAC1) was also detected in the complex. In ATF3 deficient cells, NF-kappa B activity was up-regulated and HDAC1 was not detected by IP. These observations suggest that p65 is attenuated by ATF3 such that ATF3 recruits HDAC1 to the ATF3/p65 complex and facilitates the deacetylation of p65. Likewise, inflammatory response genes were induced by translocated NF-kappa B in ATF3-deficient cells. Cumulatively, we uncovered a novel mechanism for the negative regulation of NF-kappa B by ATF3 via direct interaction with p65.

关键词： NF-KAPPA-B   TRANSCRIPTION FACTOR-3   GENE-EXPRESSION   ADAPTIVE-RESPONSE   TUMOR-SUPPRESSOR   METASTASIS   KINASE   TRANSACTIVATION   ADENOCARCINOMA   REPRESSION  

摘要： Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.

关键词： 转录激活因子3   心血管疾病   研究进展  

摘要： 转录激活因子3(activating transcription factor 3,ATF3)是一种应激快反应基因,属于ATF/CREB家族成员,在大部分细胞中能够稳定表达。ATF3广泛参与机体内各种生理病理过程,如调节细胞周期、影响凋亡、抑制炎性因子表达等,其活性异常甚至与多种肿瘤的形成密切相关。近年研究发现,ATF3与多种心血管疾病的发生、发展有关,已成为心血管疾病的研究热点之一。

关键词： TRANSCRIPTION factors   EXTRACELLULAR matrix   OBSTRUCTIVE lung diseases  

摘要： A retraction of the article 'ATF3 and Extracellular Matrix-Related Genes Associated With the Process of Chronic Obstructive Pulmonary' by Jia Ye and colleagues in the 2014 issue is presented.

关键词： 心肌缺血再灌注损伤   转录激活因子3   TLR4  

摘要： 冠心病是危害人类健康的疾病,近几十年来其发病率和病死率呈上升趋势。再灌注治疗是挽救心肌梗死的有效手段,同时也可能对心脏产生更大的损伤,即心肌缺血再灌注损伤(myocardial ischemia reperfusion injury,MIRI)。大量研究表明,ATF/CERB家族成员ATF3在缺血再灌注损伤中发挥负性调控作用。本文将对ATF3的表达特点和其在MIRI中的负性调控作用进行综述。这将为ATF3过表达治疗MIRI这一基因治疗策略提供理论基础。

关键词： Toll-like receptors (TLRs)   Myddosome   ATF3   Innate immunity   Signalling   NF-KAPPA-B   NLRP3 INFLAMMASOME ACTIVATION   HIGH-DENSITY-LIPOPROTEIN   DOMAIN-CONTAINING ADAPTER   PATTERN-RECOGNITION RECEPTORS   CHOLESTEROL EFFLUX CAPACITY   PRION-LIKE POLYMERIZATION   CUTTING EDGE   IRAK-M   STERILE INFLAMMATION  

摘要： Families of innate immune receptors serve as the bodies primary defence system by recognising and rapidly responding to infection by microorganisms or to endogenous danger signals and initiating inflammatory processes. Whilst Toll-like receptors (TLRs) were the first family to be discovered, important and exciting discoveries continue to emerge into the molecular mechanisms that control their activation and regulation. Herein, I will provide an overview of TLR activation and their downstream signalling cascades, and discuss some of the recent findings concerning the assembly of a TLR oligomeric signalling platform, known as the Myddosome. Further, a brief examination of the importance of crosstalk between multiple TLRs or between TLRs and other innate immune receptors for appropriate and coordinated immune responses will be presented. Finally, I will discuss the importance of mechanisms that regulate TLRs with a focus on the role of activating transcription factor 3 (ATF3) in modulating transcriptional responses downstream of TLRs. (C) 2015 Elsevier Ltd. All rights reserved.