关键词： HUMAN COLON-CANCER   FACTOR-KAPPA-B   TUMOR-METASTASIS   DOWN-REGULATION   MECHANISTIC INSIGHTS   PANCREATIC-CANCER   ALLELIC LOSS   CELL-LINES   SHORT ARM   EXPRESSION  

摘要： NDRG1 and KAI1 belong to metastasis suppressor genes, which impede the dissemination of tumor cells from primary tumors to distant organs. Previously, we identified the metastasis promoting transcription factor, ATF3, as a downstream target of NDRG1. Further analysis revealed that the KAI1 promoter contained a consensus binding motif of ATF3, suggesting a possibility that NDRG1 suppresses metastasis through inhibition of ATF3 expression followed by activation of the KAI1 gene. In this report, we found that ectopic expression of NDRG1 was able to augment endogenous KAI1 gene expression in prostate cancer cell lines, whereas silencing NDRG1 was accompanied with significant decrease in KAI1 expression in vitro and in vivo. In addition, our results of ChIP analysis indicate that ATF3 indeed bound to the promoter of the KAI1 gene. Importantly, our promoter-based analysis revealed that ATF3 modulated KAI1 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NF kappa B). Moreover, loss of KAI1 expression significantly abrogated NDRG1-mediated metastatic suppression in vitro as well as in a spontaneous metastasis animal model, indicating that KAI1 is a functional downstream target of the NDRG1 pathway. Our result of immunohistochemical analysis showed that loss of NDRG1 and KAI1 occurs in parallel as prostate cancer progresses. We also found that a combined expression status of these two genes serves as a strong independent prognostic marker to predict metastasis-free survival of prostate cancer patients. Taken together, our result revealed a novel regulatory network of two metastasis suppressor genes, NDRG1 and KAI1, which together concerted metastasis-suppressive activities through an intrinsic transcriptional cascade.

关键词： ATF3 gene   Gene association study   Polymorphism   C reactive protein   Haplotype   Interaction   ACTIVATING TRANSCRIPTION FACTOR-3   ENDOTHELIAL-CELLS   METABOLIC-SYNDROME   ADIPOSE-TISSUE   EXPRESSION   PROMOTER   DISEASE   ATHEROSCLEROSIS   POLYMORPHISMS   INFLAMMATION  

摘要： Objective: ATF3 has traditionally been related to various inflammatory processes. Our aim was to test the statistical association between variations in the ATF3 gene and levels of nine serum inflammatory markers, including C reactive protein (CRP), in a Taiwanese population using interaction analysis. Methods: A sample population of 604 Taiwanese subjects was enrolled. Five tagging single nucleotide polymorphisms of the ATF3 gene from the Han Chinese HapMap Database were selected and genotyped. Results: With or without adjustment for clinical covariates, ATF3 genotypes were found to be associated with CRP levels but not with other inflammatory marker levels. Minor alleles of 2 of the 5 ATF3 SNPs were associated with decreased CRP levels predominantly in non-obese subjects (Bonferoni P = 0.018, and P = 0.002 for rs11571530, and rs10475, respectively). Two haplotypes inferred from the 5 SNPs, GATTA and TACCA, were also associated with increased or decreased CRP levels, respectively, in non-obese subjects (Bonferoni P = 0.012 and P = 0.01, respectively) but not in obese subjects. Interaction analysis revealed interaction of obesity with an ATF3 genotype associated with a high CRP level (interaction P = 0.006 for SNP rs10475). An effect of obesity on CRP level was also noted in haplotype interaction analysis (interaction P = 0.019 for haplotype TACCA). Conclusions: ATF3 polymorphisms are independently associated with CRP levels in Taiwanese subjects. Further, ATF3 genotypes/haplotypes interact with obesity to set CRP levels. These findings may have implications for the prediction of atherosclerotic disease. (C) 2011 Elsevier B.V. All rights reserved.

关键词： 转录激活因子3   糖皮质激素   邻苯二甲酸二丁酯   尿道下裂  

摘要： 目的利用糖皮质激素与邻苯二甲酸二丁酯（DBP）联合作用致大鼠尿道下裂，观察转录激活因子3（ATF3）在正常大鼠生殖结节（GT）与不同严重程度尿道下裂大鼠生殖结节中的差异表达，并探讨ATF3在尿道下裂发生中的作用机制。方法将sD孕鼠40只随机均分为4组，在妊娠14～18d（GD14～18）分别给予：A组：大豆油灌胃2ml／d；B组：地塞米松（DXM）O．1mg／（kg·d）皮下注射；c组：DBP700mg／（kg·d）灌胃；D组：DXM0．1mg／（kg·d）皮下注射加DBP700mg／（kg·d）灌胃。GDl9将各组孕鼠处死剖腹统计雄性仔鼠出生体质量（BW）及肛门生殖器间距离（AGD），取雄性仔鼠生殖结节，运用免疫印迹法和免疫组织化学方法分析ATF3的表达。结果DXM单独作用于孕鼠仅表现为仔鼠BW下降，但与DBP组合作用却能显著增强DBP的致畸作用，导致雄性仔鼠BW及AGD／BW明显减少。ATF3在A组的蛋白相对表达量为0．351±0．012，B组为0．336±0．015，C组为0．603±0．014，D组为0．851±0．016，C组或D组与A组，以及C组与D组之间的差异均有统计学意义（P〈0．05）；免疫组织化学结果显示ATF3主要定位于生殖结节的尿道上皮和侧翼间质，C组和D组免疫组织化学染色强度明显强于A组，而D组染色强于C组。结论DXM联合DBP进一步增强了DBP的致畸作用，提示尿道下裂的发生是环境中多因素协同作用的结果，ATF3在对照组与实验组生殖结节中的表达有明显变化，且随着尿道下裂程度的加重而表达增高，ATF3的高表达影响了生殖结节的发育及尿生殖褶的融合，这可能是尿道下裂发生的机制之一。

关键词： Angiotensin II   Nrf2   ATF3   TCMK-1   Fibrosis   MESENCHYMAL TRANSITION   PROTEASOMAL DEGRADATION   MOLECULAR-MECHANISMS   OXIDATIVE STRESS   KIDNEY FIBROSIS   TGF-BETA   PATHWAY   OXIDASE   RATS   CONTRIBUTES  

摘要： Angiotensin II (ATII), a physiologically active mediator of the renin-angiotensin system, has been shown to be associated with renal fibrosis pathophysiology. In our current study with murine renal epithelial TCMK-1 cells, ATII inhibited the expression of NF-E2-related factor 2 (Nrf2)-target antioxidant genes such as NAD(P)H: quinone oxidoreductase-1 and gamma-glutamate cysteine ligase (GCL). In accord to the reduced expression of GCL, a GSH biosynthesis enzyme, ATII treatment reduced intracellular GSH content and increased the levels of reactive oxygen species (ROS). While, there was no significant changes in nuclear protein levels of Nrf2 following ATII treatment, implying the potential alterations in the expression of partner proteins of Nrf2. Our measurement of Nrf2 partner bZIP transcription factors, including Bach1, small Maf proteins, and activating transcription factor 3 (ATF3) showed that the expression level for ATF3 was enhanced in ATII-treated TCMK cells. Presumably through ATII-induced oxidative stress, ATII treatment was found to enhance the inducible level of TGF beta-mediated alpha-smooth muscle actin (alpha-SMA) expression, which is one of molecular markers of renal fibrosis. In conclusion, our results indicate that ATII suppresses Nrf2-GSH signaling in murine renal epithelial cells. Elevated ROS levels in ATII exposed epithelial cells might be a causing factor contributing to renal fibrosis pathology.

关键词： Epigenetic therapy   kidney injury   ATF3   deacetylation   ACUTE-RENAL-FAILURE   ACTIVATING TRANSCRIPTION FACTOR   ISCHEMIA-REPERFUSION INJURY   NF-KAPPA-B   ENDOTHELIAL-CELLS   ISCHEMIA/REPERFUSION INJURY   OXIDATIVE STRESS   ATF3   EXPRESSION   PROTECTS  

摘要： The incidence of mortality in acute renal failure (ARF) induced by ischemia-reperfusion (I/R) injury or septic shock is high. Previous studies using animal models of ARF reported that inflammation-induced macrophage recruitment in endothelial cells, along with I/R-induced production of inflammatory cytokines and chemokines in tubule epithelial cells, results in macrophage and neutrophil accumulation, and that both ultimately lead to irreversible kidney injury. Recent studies suggest that ARF may also induce a beneficial stress response program and express many transcriptional regulators, including activating transcription factor 3 (ATF3). ATF3 is a member of the ATF/CREB subfamily of the basic-region leucine zipper (bZIP) family. Recent research has shed new light on the protective role of the ATF3 signaling pathway in attenuating inflammation and I/R-induced tubular cell death and nephrotoxicity. A recent clinical study also reported that ATF3 can serve as an indicator of acute kidney injury (AKI). AKI is associated with a robust inflammatory effect with increased levels of cytokines, including IL-6, IL-12, and IFN gamma. By inhibiting these cytokines, the ATF3 molecule may hold the potential to provide future epigenetic therapy against inflammation-induced renal injury.

关键词： ACTIVATING TRANSCRIPTION FACTOR-3   SIGNALING PATHWAYS   INDUCED APOPTOSIS   IFN-GAMMA   EXPRESSION   PROTECTS   SUPPRESSES   INDUCTION   BINDING   CELLS  

摘要： It is hypothesis that ATF3 is a downstream component of BMP10. The possible function of ATF3 on immune response is partially regulated by BMP10 via Smad dependent pathway. BMP10 is highly expressed in blood cells during embryonic development based on our in situ hybridization. The expression of ATF3 is enhanced by BMP10 in overexpression transgenic mice. Both BMP10 and ATF3 can response to stress stimulate, and ATF3 is well understood as a stress inducible gene which possible contributes to immune response. The Smad dependent pathway is well established for BMP10 in regulation expression of downstream targets. It would be interesting for us to determine the relationship between BMP10 and ATF3, especially to understand the mechanism of BMP10 and ATF3 effecting on heart development, as well as immune response exposed to stress stimulates. (C) 2011 Elsevier Ltd. All rights reserved.

关键词： 慢性阻塞性肺疾病   活化转录因子3   活化转录因子4  

摘要： 目的研究活化转录因子3(ATF3)和活化转录因子4(ATF4)在慢性阻塞性肺疾病(COPD)大鼠肺组织中的定位和表达,探讨其在COPD发病中的可能作用及意义。方法采用气管内注入脂多糖和熏香烟的方法复制大鼠COPD模型。观察COPD大鼠和正常对照组大鼠肺组织病理学改变,检测肺功能;应用原位杂交、逆转录-聚合酶链反应(RT-PCR)、免疫组化、Western blot检测大鼠肺组织中ATF3、ATF4 mRNA及蛋白的表达情况。结果 COPD组的肺功能指标(FEV0.3、FEV0.3/FVC、PEF)明显降低,光镜下肺组织病理改变符合COPD的特征性改变。免疫组化及Westernblot显示COPD组ATF3、ATF4蛋白水平较对照组升高(P<0.05);原位杂交及RT-PCR结果显示ATF3、ATF4 mRNA表达水平在COPD组显著高于对照组(P<0.05)。结论 COPD大鼠肺组织ATF3、ATF4表达明显上调,ATF3、ATF4可能参与调控COPD的氧化/抗氧化失衡。

关键词： 结直肠癌   活化转录因子   免疫组化检测   临床病理  

摘要： 目的:观察结直肠癌组织中活化转录因子2(ATF2)和活化转录因子3(ATF3)的表达并分析其表达的临床病理意义。方法:收集结直肠癌病例,明确其病理诊断并收集临床资料,应用免疫组织化学SP法检测活化转录因子2和活化转录因子3蛋白的表达。结果:ATF2在癌旁肠组织、腺瘤、腺癌组的阳性表达率分别为38%,32%,64%,差异有统计学意义,其中癌旁肠组织、腺瘤分别与腺癌有显著性差异。ATF3在癌旁肠组织、腺瘤、腺癌组的阳性表达率分别为56%,44%,52%,差异无统计学意义。ATF2表达与浸润肠壁深度,淋巴结转移有关,而与肿块大小、部位、分化程度无关。ATF3表达与肿块直径、浸润肠壁深度,而与淋巴结转移、部位、分化程度无关。结论:ATF2与结直肠癌反生和发展有关,而ATF3与结直肠癌的恶性演进有关。

关键词： endoplasmic reticulum (ER) stress response   mitochondrial dysfunction   sterol-independent regulation   ENDOPLASMIC-RETICULUM STRESS   MITOCHONDRIAL DYSFUNCTION   GENE-EXPRESSION   INSULIN   ATF3   DISEASE   ADIPOCYTES   PROMOTER   OBESITY   ER  

摘要： The low-density lipoprotein receptor (LDLR) plays a central role in cholesterol homeostasis. Here, we provide evidence that an increase in endoplasmic reticulum (ER) stress response or a disturbance of mitochondrial function inhibits LDLR expression in human liver Sk-Hep1 cells. Both organelle stresses triggered activation of activating transcription factor-3 (ATF3), which subsequently reduced LDLR expression. Serial deletion studies revealed that the LDLR promoter region within -234 bp was involved in the repression of LDLR by ATF3. In addition, we identified the region between -8 and -3 of LDLR promoter region as a putative binding site for ATF3 by using deletion construct lacking 6 bp nucleotide corresponding to this region. Transfection of ATF3-specific siRNA rescued LDLR expression under organelle stress, indicating that ATF3 was mainly responsible for the repression of LDLR by these stressors. Additionally, chromatin immunoprecipitation revealed that ATF3 directly binds to the LDLR promoter in a stress-dependent manner. The unique sterol-independent LDLR repression by organelle stress via ATF3 demonstrated here could be involved in obesity-related hypercholesterolemia, which can lead to insulin resistance and type 2 diabetes.

关键词： Pregnancy   Pancreatic islet beta-cell   Proliferation   Gene chips   EXPRESSION   REPLICATION   CATENIN   ACINAR   GROWTH   MODEL   ATF3  

摘要： There is a widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet beta-cells. Pregnancy is a special periods when the pancreatic islet display a highly reproducible physiological proliferation. However, the molecular mechanism of beta-cell proliferation during pregnancy is unclear. Here, we used cDNA expression array to explore gene expression profiles of islet at various stages of pregnancy in rats. Differentially expressed genes related to islet proliferation were screened by bioinformatics methods, and further verified by real-time PCR, RT-PCR, and Western blotting. Compared with control group, expressions of hundreds of genes were changed during pregnancy. The differentially expressed genes related to islet proliferation were mainly distributed in three groups: genes involved in transcription regulator activity, genes involved in apoptosis or tumor, and genes for Wnt signaling pathway. Among these genes, expressions of Nupr1, Atf3, Btg2, beta-catenin, and c-Myc mRNA were up-regulated during pregnancy. A prominent expression of Nupr1 and Atf3 protein was observed in islets on day 10.5 of pregnancy, i.e., with earlier time phases than proliferation peak. Moreover, we found that prolactin (PRL) can increase the proliferation of beta-cell in vitro, which is accompanied by up-regulation of Atf3 and Nupr1, indicating that they may play a crucial role in PRL-induced pancreatic beta-cell growth. In conclusion, our results suggest that the transcription factor Nupr1, Atf3, and Wnt pathway may play an important role in adaptive proliferation of pancreatic islets during pregnancy in rats.