关键词： Leukemia   Molt4   ER stress   Apoptosis   Gene expression  

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： 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： TRANSCRIPTION factors   PROSTATE cancer research   CELL proliferation   PROTEIN-protein interactions   MICE as laboratory animals   GENE expression  

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： 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  

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.

关键词： autism   dendiritic spines   mTOR   protein synthesis   translation  

摘要： Hyperactivation of the mechanistic target of rapamycin (mTOR) kinase, as a result of loss-of-function mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulation, increased cell size, and aberrant neuronal connectivity. Dys-regulated synthesis of synaptic proteins has been implicated in the pathophysiology of autism spectrum disorder (ASD) associated with TSC and fragile X syndrome. However, cell type-specific translational profiles in these disease models remain to be investigated. Here, we used high-fidelity and unbiased Translating Ribosome Affinity Purification (TRAP) methodology to purify ribosome-associated mRNAs and identified translational alterations in a rat neuronal culture model of TSC. We find that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed. Importantly, transcripts for the activating transcription factor-3 (Atf3) and mitochondrial uncoupling protein-2 (Ucp2) are highly induced in Tsc2-deficient neurons, as well as in a neuron-specific Tsc1 conditional knock-out mouse model, and show differential responses to the mTOR inhibitor rapamycin. Gelsolin, a known target of Atf3 transcriptional activity, is also upregulated. shRNA-mediated block of Atf3 induction suppresses expression of gelsolin, an actin-severing protein, and rescues spine deficits found in Tsc2-deficient neurons. Together, our data demonstrate that a cell-autonomous program consisting of a stress-induced Atf3-gelsolin cascade affects the change in dendritic spine morphology following mTOR hyperactivation. This previously unidentified molecular cascade could be a therapeutic target for treating mTORopathies.

关键词： TRANSCRIPTION factors   INFLAMMATION   AORTIC valve -- Diseases   CALCIFICATION   MEDICAL research  

关键词： apoptosis   DNA transcription   DNA-protein interaction   endoplasmic reticulum stress (ER stress)   oxidative stress   unfolded protein response (UPR)   ATF3   ATF4   CEBP   CHAC1  

摘要： Using an unbiased systems genetics approach, we previously predicted a role for CHAC1 in the endoplasmic reticulum stress pathway, linked functionally to activating transcription factor 4 (ATF4) following treatment with oxidized phospholipids, a model for atherosclerosis. Mouse and yeast CHAC1 homologs have been shown to degrade glutathione in yeast and a cell-free system. In this report, we further defined the ATF4-CHAC1 interaction by cloning the human CHAC1 promoter upstream of a luciferase reporter system for in vitro assays in HEK293 and U2OS cells. Mutation and deletion analyses defined two major cis DNA elements necessary and sufficient for CHAC1 promoter-driven luciferase transcription under conditions of ER stress or ATF4 coexpression: the -267 ATF/cAMP response element (CRE) site and a novel -248 ATF/CRE modifier (ACM) element. We also examined the ability of the CHAC1 ATF/CRE and ACM sequences to bind ATF4 and ATF3 using immunoblot-EMSA and confirmed ATF4, ATF3, and CCAAT/enhancer-binding protein binding at the human CHAC1 promoter in the proximity of the ATF/CRE and ACM using ChIP. To further validate the function of CHAC1 in a human cell model, we measured glutathione levels in HEK293 cells with enhanced CHAC1 expression. Overexpression of CHAC1 led to a robust depletion of glutathione, which was alleviated in a CHAC1 catalytic mutant. These results suggest an important role for CHAC1 in oxidative stress and apoptosis with implications for human health and disease.