关键词： JDP2   Cardiac remodeling   AP-1   ATF3   CARDIOMYOCYTES   HYPERTROPHY  

关键词： 慢性阻塞性肺疾病   肺组织   ATF3   ATF4   γ-GCS  

摘要： 目的探究慢性阻塞性肺疾病(COPD)患者肺组织中转录活化因子3(ATF3)与转录活化因子4(ATF4)对γ-谷氨酰半胱氨酸合成酶(γ-GCS)表达的影响。方法本研究采用回顾性分析方法,选择2014~2016年收治的160例肺部疾病患者作为研究对象,将经胸部X线或CT检查确诊为COPD者列为观察组(80例),将非COPD者列为对照组(80例)。观察两组光镜下肺病理形态学改变、肺功能指标和吸烟史。经原位杂交分析两组肺组织中的ATF3、ATF4、γ-GCS-HS水平,采用免疫组化法检测肺组织中的ATF3、ATF4、γ-GCS-HS蛋白表达,并采用直线相关法,分析肺组织ATF3、ATF4蛋白与γ-GCS-HS表达的相关性及肺组织ATF3、ATF4、γ-GCS-HS蛋白与肺功能之间的关系。结果经HE法,光镜下可见观察组肺组织标本有病理形态学改变,而对照组无形态学变化;观察组肺功能指标低于对照组(P<0.05),观察组吸烟史多于对照组(P<0.05)。经原位杂交法检验,观察组中的ATF3、ATF4、γ-GCSHS的mRNA表达水平高于对照组,差异有统计学意义(P<0.05)。经免疫组化检测,观察组中的ATF3、ATF4、γ-GCS-HS蛋白的表达水平高于对照组,差异有统计学意义(P<0.05)。经直线相关法分析,ATF3、ATF4蛋白表达与γ-GCS-HSmRNA及其蛋白呈正相关关系(P<0.01);ATF3、ATF4、γ-GCS-HS蛋白与肺功能各指标呈正相关关系(P<0.01)。结论 COPD患者的ATF3、ATF4表达明显上调可影响调控γ-GCS表达,从而使γ-GCS表达上调,以发挥抗氧化作用。

关键词： activating transcription factor 3   aging   ER stress   idiopathic pulmonary fibrosis   mitochondrial dysfunction   PTEN-induced putative kinase 1   IDIOPATHIC PULMONARY-FIBROSIS   INDUCED PREMATURE SENESCENCE   ADAPTIVE-RESPONSE   STRESS   PTEN   MUTATIONS   PROTEINS   FACTOR-3  

摘要： PINK1 (PTEN-induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promoter is located in the first 150 bp upstream of the transcription start site. Induction of ER stress or overexpression of ATF3 inhibited the activity of the PINK1 promoter. Importantly, overexpression of ATF3 causes accumulation of depolarized mitochondria, increased production of mitochondrial ROS, and loss of cell viability. Furthermore, conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin-induced lung fibrosis. Finally, we observed that ATF3 expression increases in the lung with age and, specially, in lung epithelial cells from IPF lungs. These data provide a unique link between ATF3 and PINK1 expression suggesting that persistent stress, driven by ATF3, can dysregulate mitochondrial homeostasis by repression of PINK1 mRNA synthesis.

关键词： 人参   大黄芪汤   肺癌   ATF3   B7-H3  

摘要： 目的:研究大黄芪汤抑制化疗所致lewis肿瘤肺转移的作用及机制。方法:40只C57BL/6小鼠随机分为对照组、中药组、化疗组、联合中药组,每组各10只。对照组单予生理盐水腹腔注射,中药组用生理盐水腹腔注射联合大黄芪汤灌胃,化疗组小鼠予顺铂腹腔注射,联合中药组予顺铂腹腔注射联合大黄芪汤灌胃。化疗末次后4 d,对所有小鼠尾静脉注射lewis细胞。20 d后检测小鼠肺内转移病灶数、瘤重,并分析瘤周肺组织ATF3、瘤体B7-H3表达。结果:1.肺内转移病灶数:对照组、中药组、化疗组、联合中药组、分别为4.7、4.9、7.6、5.5个,化疗组与其余三组分别比较显著升高,P<0.01。2.瘤重:对照组、中药组、化疗组、联合中药组分别为1.41、1.47、1.92、1.43g,化疗组与其余三组分别比较显著升高,P<0.01。3.瘤周正常肺组织ATF3、瘤体B7-H3表达:化疗组均高于对照组,联合中药后其表达均降低。结论:大黄芪汤可以抑制化疗所致的lewis肿瘤肺转移,其机制可能与其降低正常肺组织ATF3及肿瘤组织B7-H3表达有关。

关键词： ACTIVATING TRANSCRIPTION FACTOR-3   SIGNALING PATHWAY   TUMOR SUPPRESSION   DROSOPHILA   JUNCTIONS   CANCER   GROWTH   EXPRESSION   NETWORK   PROTEIN  

摘要： Interplay between apicobasal cell polarity modules and the cytoskeleton is critical for differentiation and integrity of epithelia. However, this coordination is poorly understood at the level of gene regulation by transcription factors. Here, we establish the Drosophila activating transcription factor 3 (atf3) as a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the tumor suppressors Scribble or DIg1 induces atf3 expression via aPKC but independent of Jun-N-terminal kinase (JNK) signaling. Strikingly, removal of Atf3 from DIg1 deficient cells restores polarized cytoarchitecture, levels and distribution of endosomal trafficking machinery, and differentiation. Conversely, excess Atf3 alters microtubule network, vesicular trafficking and the partition of polarity proteins along the apicobasal axis. Genomic and genetic approaches implicate Atf3 as a regulator of cytoskeleton organization and function, and identify Lamin C as one of its bona fide target genes. By affecting structural features and cell morphology, Atf3 functions in a manner distinct from other transcription factors operating downstream of disrupted cell polarity.

关键词： Atf3   D3R   Methamphetamine   Pde4b   Sensitization   INCENTIVE-SENSITIZATION THEORY   D-3 RECEPTOR   DORSAL STRIATUM   COCAINE-SEEKING   PSYCHOTIC SYMPTOMS   DRUG-ADDICTION   RAT-BRAIN   USERS   SCHIZOPHRENIA   MICE  

摘要： The role of the D3 dopamine receptor (D3R) and the specific molecular mechanisms underlying the regulation of D3R via the CAMP signaling pathway in methamphetamine (METH) addiction are still unclear. Here, we measured changes in Pde4b and Atf3 in the cAMP signaling pathway of dopaminergic system components, including the nucleus accumbens (NAc), caudate putamen (CPu) and hippocampus (Hip), in D3R knockout mice(D3R-/-) 1 h and 24 h after METH-induced behavioral sensitization. We found that knocking out D3R attenuated METH induced behavioral sensitization, and Pde4b and Atf3 exhibited different expression patterns in brain regions in response to METH. Knocking out D3R suppressed the METH-induced increase in Pde4b in the Hip of mice 24 h after the final METH injection and augmented the METH-induced increase in Atf3 in the CPu of mice 1 h after the final METH injection. Our study suggests that D3R knockout controls METH-induced behavioral sensitization via regulation of Pde4b and Atf3 in different brain regions. Furthermore, the responses of Pde4b and Atf3 to METH exposure depend on the specific region of the brain involved.

关键词： Indoxyl sulfate   Cannabinoid type 1 receptor   ATF3   C-Jun   Oxidative stress   Uremic cardiomyopathy   ENDOCANNABINOID SYSTEM   DYSFUNCTION   AP-1   FIBROSIS   DISEASE  

摘要： Background: The risk of cardiovascular disease is notably increased in patients with chronic kidney disease (CKD) and cannabinoid receptor type 1 (CB1R) plays an important role in the development of uremic cardiomyopathy. However, the molecular mechanism underlying the uremic toxin-induced upregulation of CBI R remains elusive. Methods: The expression of the ATF3/c-Jun complex and CB1R in both in vivo and in vitro models of CKD were measured. We also determined the impact of the ATF3/c-Jun complex on CB1R expression by transfecting H9c2 cells with dominant negative mutants of ATF3 or c-Jun. Inhibitors of organic anion transport, specific MAPK pathways and oxidative DNA damage were also used to assess the pathways mediating the effects of indoxyl sulfate (IS). Results: CB1R upregulation was associated with increased ATF3 expression and c-Jun phosphorylation in CKD both in vivo and in vitro. Expression of dominant-negative ATF3 or c-Jun mutants in IS-treated cells significantly reduced CB1R mRNA levels. Moreover, Co-IP revealed that the ATF3/c-Jun complex is formed and ChIP confirmed its binding to the CB1R promoter, suggesting that this complex directly stimulates CB1R transcription in CKD. Blocking the cellular entry of IS using an organic anion transport inhibitor, as well as inhibiting the ERK1/2 and/or JNK pathways, abrogated the effects of IS on CB1R, ATF3, and c Jun expression. The IS-induced reactive oxygen species (ROS) was observed in the mitochondria. Conclusions: We demonstrate that uremic toxins induce ATF3/c-Jun complex-mediated CBIR expression both in vivo and in vitro, possibly by modulating the ERK1/2 and JNK signaling pathways and ROS. (C) 2017 Elsevier B.V. All rights reserved.

关键词： liver   ATF4 transcription   histone modification   AAR   UPR   RNA-POLYMERASE-II   ACTIVATING TRANSCRIPTION FACTOR-3   UNFOLDED PROTEIN RESPONSE   MESSENGER-RNA   COMPOSITE SITE   HEPG2 CELLS   EXPRESSION   DEPRIVATION   LIMITATION   BINDING  

摘要： Activating transcription factor 3 (ATF3) is a highly regulated protein that is implicated in a wide range of pathological conditions including inflammation and transformation. Transcription from the ATF3 gene is induced by several stress-induced signaling pathways, including amino acid limitation (amino acid response, AAR) and ER stress (unfolded protein response, UPR). Induction of ATF3 transcription by these pathways is mediated by ATF4 and cJUN recruitment to enhancer elements within the ATF3 gene. Although a canonical promoter (promoter A) has been studied by numerous laboratories, a second promoter activity (promoter Al), 43 kb upstream of the first, has been reported to respond to stress-induced signaling and to be critical for ATF3 expression in certain transformed cells. The results of the present study show that in normal human hepatocytes and HepG2 human hepatoma cells both basal as well as AAR- and UPR-induced transcription occurs almost exclusively from promoter A. This selectivity between the two promoters correlated with increased binding of ATF4, recruitment of RNA polymerase II, and the expected histone modifications in the promoter A region of the gene. Time course studies of ATF3 transcription activity revealed that the temporal kinetics for ATF3 induction differ between the AAR and UPR, with the former being more transient than the latter. Collectively, the results document that ATF3 expression in normal and transformed human liver originates from the canonical promoter A that responds to multiple stress signals.

关键词： Anticancer   ATF3   Cinnamomum cassia   Cyclin D1   Human colorectal cancer   NF-kappa B   ROS   Twigs of Cinnamomum cassia   SYNTHASE KINASE 3-BETA   CYCLIN D1 GENE   OXIDATIVE STRESS   NUCLEAR EXPORT   PHOSPHORYLATION   TARGET   BARK   COMBINATIONS   PREVENTS   DRUGS  

摘要： Background: Because twigs of Cinnamomum cassia (TC) have been reported to exert anti-cancer activity, the mechanistic study for TC's anti-cancer activity is required. Thus, we elucidated the potential molecular mechanism of TC's anti-proliferative effect and the induction of apoptosis in human colorectal cancer cells. Methods: How water extracts form TC (TC-HW) was used in this study. Anti-cell proliferative effect of TC-HW was evaluated by MTT assay. The change of protein or mRNA level by TC-HW was evaluated by Western blot and RT-RCR, respectively. The promoter construct for ATF3, NF-kappa B, TOP-FLASH or FOP-FLASH was used for the investigation of the transcriptional activity for ATF3, NF-kappa B or Wnt. siRNA for ATF3 or p65 was used for the knockdown of ATF3 and p65. Results: TC-HW reduced the cell viability in human colorectal cancer cells. TC-HW decreased cyclin D1 protein level through cyclin D1 degradation via GSK3 beta-dependent threonine-286 (T286) phosphorylation of cyclin D1, indicating that cyclin D1 degradation may contribute to TC-HW-mediated decrease of cyclin D1 protein level. TC-HW downregulated the expression of cyclin D1 mRNA level and inhibited Wnt activation through the downregulation of beta-catenin and TCF4 expression, indicating that inhibition of cyclin D1 transcription may also result in TC-HW-mediated decrease of cyclin D1 protein level. In addition, TC-HW was observed to induce apoptosis through ROS-dependent DNA damage. TC-HWinduced ROS increased NF-kappa B and ATF3 activation, and inhibition of NF-kappa B and ATF3 activation attenuated TC- HWmediated apoptosis. Conclusions: Our results suggest that TC-HW may suppress cell proliferation through the downregulation of cyclin D1 via proteasomal degradation and transcriptional inhibition, and may induce apoptosis through ROSdependent NF-kappa B and ATF3 activation. These effects of TC-HW may contribute to the reduction of cell viability in human colorectal cancer cells. From these findings