关键词： 转录激活因子3   乳腺肿瘤   生物信息学  

摘要： 目的 分析活化转录因子3(ATF3)在乳腺癌中的表达情况及作用.方法 查询癌症和肿瘤基因表达图谱\基因表达汇编(TCGA\GEO)数据库信息,应用生物信息学方法分析ATF3在乳腺癌中的表达水平,绘制生存曲线,构建ATF3基因互作网络并行功能和通路富集分析.结果 乳腺癌中ATF3mRNA水平明显低于正常乳腺组织,经过化疗后其ATF3表达水平显著升高.生存分析发现经过系统治疗后,ATF3高表达组的乳腺癌患者,其生存期明显延长,差异有统计学意义(P<0.05).富集分析发现与乳腺癌相关的通路富集在Estrogen信号通路、丝裂原活化蛋白激酶(MAPK)信号通路、磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-Akt)信号通路、Wnt信号通路、Breast cancer信号通路、cell cycle信号通路.结论 ATF3参与调控乳腺癌细胞的增殖,系统治疗后,ATF3的高表达预示着更好的预后.

关键词： activating transcription factor 3   Crohn's disease   ulcerative colitis   inflammatory bowel disease  

摘要： Introduction: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. Known types are Crohn's disease (CD) and ulcerative colitis (UC), but their cause remains unclear and there is no convenient biomarker for IBD. The present study aimed to demonstrate an association between the onset of CD and activating transcription factor 3 (ATF3);as a new biomarker, measurement of blood ATF3 mRNA would be useful for distinguishing between CD and UC. Methods: First, in a mouse model of IBD in which damage to the intestinal mucosa was chemically induced with dextran sulfate sodium (DSS), intestinal ATF3 mRNA was evaluated. Next, in human subjects, CD and UC patients, blood ATF3 mRNA and intestinal ATF3 protein production were evaluated. Results: In the mouse model of IBD, intestinal ATF3 mRNA was elevated compared with the control (P < 0.0001). In CD patients, blood ATF3 mRNA was elevated as compared with normal controls (NCs) and UC patients (P < 0.05). In addition, we observed an increase in ATF3 production in the intestinal tract specific to CD. Conclusion: ATF3 is involved in the onset of CD, and blood ATF3 mRNA measurements would be useful for distinguishing it from UC.

关键词： ATF3   bta-miR-1271   preadipocyte differentiation   Yanbian yellow cattle  

摘要： Yanbian yellow cattle are one of the top five largest breeds of cattle in China. We had previously found that bta-miR-1271 is differentially expressed in the longissimus dorsi muscles of Yanbian yellow bulls and steers. However, whether bta-miR-1271 affects bovine fat formation is unclear. In this study, we used target gene prediction, dual-luciferase reporter assay, and transfection-mediated overexpression and inhibition of bta-miR-1271 in a culture of Yanbian yellow cattle preadipocytes to investigate the role of bta-miR-1271 in adipogenesis. We showed that bta-miR-1271 directly targets the 3 '-untranslated region (3 '-UTR) of the activating transcription factor 3 (ATF3) mRNA and downregulates its expression. Overexpression of bta-miR-1271 enforced by the miRNA mimics promoted triglyceride accumulation and significantly upregulated expression of the adipogenic peroxisome proliferator-activated receptor gamma (PPAR gamma) and CCAAT enhancer-binding protein alpha (C/EBP alpha) genes at both the protein and mRNA levels, as demonstrated by RT-qPCR and Western blot analyses. Conversely, inhibition of bta-miR-1271 expression produced the opposite effect. Our results show that bta-miR-1271 regulates differentiation of Yanbian yellow cattle preadipocytes by inhibitingATF3expression, which highlights the importance of microRNA-mediated regulation of adipogenesis. miR-1271 and its target gene(s) may provide a new research direction for investigating biological agents affecting intramuscular fat deposition in cattle.

关键词： Kupffer cell   nonalcoholic steatohepatitis   genomics   epigenetics   scRNA-seq   ChIP-seq   tissue macrophage   TREM2   ATF3   LXR  

摘要： Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death, Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.

关键词： 乳腺癌   ATF3   侵袭转移   化疗敏感性   放疗敏感性   信号通路调节  

摘要： 转录激活因子3(activating transcription factor 3,ATF3)作为转录激活因子,可通过调控细胞增殖及凋亡机制的平衡在乳腺癌的形成、转移和治疗中发挥着重要作用,而乳腺癌作为女性最常见的恶性肿瘤一直是医学界广泛关注的热点。该文就ATF3在乳腺癌中调节增殖、侵袭和转移机制,化、放疗敏感性以及相关信号通路调节方面的研究进展进行介绍,阐述ATF3与乳腺癌之间的关系,为乳腺癌的临床治疗提供参考靶点和理论依据。

关键词： 肝细胞肝癌   LC3-Ⅱ   激活转录因子3   免疫组织化学   Western blot  

摘要： 目的分析微管相关蛋白1轻链3-Ⅱ(LC3-Ⅱ)和激活转录因子3(ATF3)在肝细胞癌中的表达情况,探讨其蛋白表达与HCC患者预后的关系,并分析在HCC组织中,两者的表达是否具有相关性。方法应用免疫组织化学法检测HCC组织及相应癌旁组织蜡块标本中LC3-Ⅱ与ATF3蛋白的表达情况,并分析其与患者临床病理特征和生存期之间的关系。使用免疫蛋白印迹(Western blot)法检测新鲜HCC组织及相应癌旁组织中LC3-Ⅱ与ATF3蛋白的表达,分析两种蛋白表达的相关性。结果LC3-Ⅱ和ATF3蛋白在癌旁组织中的表达明显高于HCC组织,两者的表达水平与HCC组织病理分级和静脉癌栓情况相关(均P<0.05),但与年龄、性别、血清甲胎蛋白、肿瘤直径、HBsAg等的相关性无统计学意义(均P>0.05)。LC3-Ⅱ和ATF3的低表达与HCC患者的不良预后显著相关(均P<0.05)。结论LC3-Ⅱ和ATF3蛋白表达均与HCC的发生发展有关,两者的联合检测有助于HCC的恶性程度的评估,有望成为判断患者预后的重要指标。

关键词： ATF3   ChIP-seq   epigenetics   genomics   Kupffer cell   LXR   nonalcoholic steatohepatitis   scRNA-seq   tissue macrophage   TREM2  

摘要： Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions. • Myeloid cell diversity in NASH is associated with distinct microanatomical niches • Reprogramming of LXR activity leads to impaired Kupffer cell identify and survival • ATF3 collaborates with LXRs to promote a scar-associated macrophage phenotype • Altered enhancer landscapes enable inference of disease mechanisms Kupffer cells and recruited myeloid cells contribute to the pathology of nonalcoholic steatohepatitis (NASH), but molecular mechanisms specifying their distinct identities and functions are not known. Seidman and colleagues address this problem by defining cell- and disease-specific enhancer landscapes that enable inference of key transcription factors that drive myeloid cell diversity in NASH. [ABSTRACT FROM AUTHOR]

关键词： Neddylation   MLN4924   NF-kappa B   catalase   ATF3   Autophagy   Apoptosis   Esophageal Cancer  

摘要： Background Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3. Methods The expression of relevant proteins of NF-kappa B/Catalase/ATF3 pathway after neddylation inhibition was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. ROS generation upon MLN4924 treatment was determined by H2-DCFDA staining. The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining. Results For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer. Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate I kappa B alpha to block NF-kappa B activation and Catalase expression. As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing. Conclusions In our study, we elucidates a novel mechanism of NF-kappa B/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g. MLN4924).

关键词： Heat shock factor protein 1 (HSF1)   gene regulation   obesity   lipid metabolism   uncoupling protein   uncoupling protein 1 (UCP1)   activating transcription factor 3 (ATF3)   beta-adrenergic stimuli   brown fat   beige fat   thermogenesis  

摘要： Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues;however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of ?-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at ?258 to ?250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the ?-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

关键词： digital gene expression   hepatic steatosis   high-fat diet   nonalcoholic fatty liver disease   transcription repressor  

摘要： Background and Aims Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor-2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down-regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Approach and Results Herein, using gain-of-function and loss-of-function approaches in mice, we demonstrated that while hepatocyte-specific Irf2bp2 knockout exacerbated high-fat diet-induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout-exaggerated hepatosteatosis in vitro. Conclusion IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.