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  

摘要： EAS-0425

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.

关键词： 子宫颈肿瘤   鳞癌   病理学   激活转录因子3   免疫组织化学  

摘要： 目的探讨激活转录因子3(activating transcription factor 3,ATF3)在子宫颈鳞癌组织的表达及其临床意义。方法采用免疫组化SP法分别检测72例子宫颈鳞癌组织和48例子宫颈正常组织中ATF3的表达。结果 ATF3在子宫颈鳞癌组织中的阳性率(77.8%,56/72)明显高于正常子宫颈组织(25.0%,12/48),二者比较差异有统计学意义(P<0.05)。ATF3表达与子宫颈鳞癌临床分期、浸润深度和淋巴结转移相关(P<0.05),与患者年龄、鳞癌分化程度无关(P>0.05)。结论 ATF3在子宫颈鳞癌组织中高表达,并且与临床分期、浸润深度和淋巴结转移密切相关,可能作为反映子宫颈鳞癌生物行为的有效指标之一。

关键词： stem   cell   ATF  

摘要： One of the major problems of modern neurobiology is how to replace dead or damaged neurons in the human brain or spinal cord after injury or as a consequence of neurodegenerative dis- eases. In fact, because adult mammalian neurons are post-mi- totic cells that cannot divide to replace dead cells, loss due to lesion or disease is permanent. Furthermore, surviving neurons have modest capacity to regenerate their damaged axons and re-establish functional connections. Thus, a gradual neurode- generative scenario with certain similarities in stroke, brain or spinal cord injuries and neurological diseases like Alzheimer＇s disease is produced. These conditions represent the major disease burden of the modern world in terms of mortality, dis- ability, productivity loss and health-care costs （World Health Organization, 2008）. While much effort has been directed to understand the molecular and cellular mechanisms involved in the pathology of these diseases to set new effective treatments, many neuroprotective and regenerative approaches, although showing positive results in preclinical studies, have so far failed to provide strong benefit to patients.

关键词： NSC-169780   Second Primary Cancer   ATF3 gene   Circulating Neoplastic Cells   cancer cell   DNA damage response   DNA Breaks   cancer patient   Catalysis  

摘要： Background and PurposeThe catalytic topoisomerase II inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response. Experimental ApproachWe investigated the DNA damage response and the role of the activating transcription factor 3 (ATF3) accumulation in tumour cells exposed to dexrazoxane. Key ResultsDexrazoxane exposure induced topoisomerase II (TOP2A)-dependent cell death, -H2AX accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA damage responses, shown by enhanced levels of -H2AX/53BP1 foci, ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), Chk1 and Chk2 phosphorylation, and by p53 accumulation. Dexrazoxane-induced -H2AX accumulation was dependent on ATM. ATF3 protein was induced by dexrazoxane in a concentration- and time-dependent manner, which was abolished in TOP2A-depleted cells and in cells pre-incubated with ATM inhibitor. Knockdown of ATF3 gene expression by siRNA triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane -treated cells. This was accompanied by increased -H2AX accumulation. ATF3 knockdown also delayed the repair of dexrazoxane -induced DNA double-strand breaks. Conclusions and ImplicationsAs with other TOP2A poisons, dexrazoxane induced DNA double-strand breaks followed by activation of the DNA damage response. The DNA damage-triggered ATF3 controlled p53 accumulation and generation of double-strand breaks and is proposed to serve as a switch between DNA damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane.