关键词： chemotherapy   metastasis   stress response   immune modulation   ATF3  

摘要： Chemotherapy is a double-edged sword. It is anticancer because of its cytotoxicity. Paradoxically, by increasing chemoresistance and cancer metastasis, it is also procancer. However, the underlying mechanisms for chemotherapy-induced procancer activities are not well understood. Here we describe the ability of paclitaxel (PTX), a frontline chemotherapeutic agent, to exacerbate metastasis in mouse models of breast cancer. We demonstrate that, despite the apparent benefit of reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung. At the primary tumor, PTX increased the abundance of the tumor microenvironment of metastasis, a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream. At the metastatic lung, PTX improved the tissue microenvironment (the "soil") for cancer cells (the "seeds") to thrive;these changes include increased inflammatory monocytes and reduced cytotoxicity. Importantly, these changes in the primary tumor and the metastatic lung were all dependent on Atf3, a stress-inducible gene, in the noncancer host cells. Together, our data provide mechanistic insights into the procancer effect of chemotherapy, explaining its paradox in the context of the seed-and-soil theory. Analyses of public datasets suggest that our data may have relevance to human cancers. Thus, ATF3 in the host cells links a chemotherapeutic agent-a stressor-to immune modulation and cancer metastasis. Dampening the effect of ATF3 may improve the efficacy of chemotherapy.

关键词： ATF3   Zebrafish   Spinal cord injury   Regeneration   Inflammation  

摘要： Zebrafish is an excellent model to study the mechanisms underlying successful central nervous system (CNS) regeneration. Previous study shows that activating transcription factor 3 (ATF3) promotes neurite outgrowth and is involved in optic nerve regeneration in zebrafish. Here, we used zebrafish model to investigate the role of ATF3 in regeneration following spinal cord injury (SCI). Quantitative polymerase chain reaction (qPCR) and in situ hybridization revealed that ATF3 mRNA levels increased at 12 h and 6 d following SCI. Double labeled immunofluorescence showed that ATF3 expressed in motoneurons. Treatment of anti-sense ATF3 morpholino (MO) inhibited locomotor recovery and decreased axon regeneration of spinal cord injured zebrafish. Further, inhibition of ATF3 up-regulated the expression of inflammatory factors tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). These data suggest that ATF3 could promote locomotor recovery and axon regrowth in zebrafish SCI model possibly by regulating inflammatory response. (C) 2017 Elsevier Inc. All rights reserved.

关键词： activating transcription factor (ATF3)   triglyceride-rich lipoproteins (TGRL)   vascular dementia (VaD)   vascular inflammation  

摘要： Elevation of blood triglycerides, primarily triglyceride-rich lipoproteins (TGRL), is an independent risk factor for atherosclerotic cardiovascular disease and Vascular Dementia (VaD). The accumulating evidence indicates that the development of atherosclerosis and VaD are linked to vascular inflammation. Previous studies suggest a relationship of blood lipids and/or lipoproteins to vascular inflammation leading to dementia. The objective of this study is to characterize human brain microvascular endothelial cells (HBMVEC) responses to postprandial TGRL and determine the pathways that have potential to increase risk for vascular dementia. To address this question, we treated HBMVEC with TGRL lipolysis products and then we used NGS-based RNA-Seq methods for transcriptional profiling experiments. Our data demonstrated up-regulation of activating transcription factor 3 (ATF3)-dependent inflammatory pathways in HBMVEC. Additionally, system biology analysis exhibited putative lipid-related targets and corresponding isoforms of ATF3 that may be implicated in hypertriglyceridemia-induced vascular inflammation in brain. Furthermore, RNA-Seq analysis determined specific isoforms of key transcriptional regulator ATF3 and stress response signaling pathway in lipolysis products-mediated brain vascular inflammation which may lead to vascular dementia. [ABSTRACT FROM AUTHOR]

关键词： triglyceride-rich lipoproteins (TGRL)   activating transcription factor (ATF3)   vascular inflammation   vascular dementia (VaD)  

摘要： P-198

关键词： ATF3   LIF   Embryo adhesion   Recurrent implantation failure  

摘要： Background: A receptive endometrium is essential for maternal-embryonic molecular communication during implantation. However, the specific molecular regulatory mechanisms of the endometrial capacity remain poorly understood. Here, we examined activating transcription factor 3 (ATF3) expression in human endometria and the functional effect of ATF3 on embryo attachment in vitro. Methods: Immunohistochemistry (IHC) was used to assess the ATF3 expression patterns in human endometria. Quantitative real-time PCR (qRT-PCR), western blotting and immunofluorescence (IF) studies were applied to explore ATF3 expression in Ishikawa cells upon estrogen (E-2) and medroxyprogesterone acetate (MPA) treatment. qRT-PCR and western blotting were performed to inspect LIF (leukemia inhibitory factor) expression after enhancement or inhibition of ATF3, and a luciferase reporter assay and ChIP-PCR were used to confirm the regulatory mechanism of ATF3 to LIF. Endometrial epithelial capacity was assessed by an in vitro model of attachment of BeWo spheroids to Ishikawa cells. Western blotting was performed to compare the expression of ATF3 in endometrial samples of recurrent implantation failure (RIF) patients with that in samples from fertile women (FER) who had undergone no less than one successful embryo transplantation. Results: ATF3 was located in human endometrial epithelial cells and stromal cells and was significantly induced by E-2 and MPA in Ishikawa cells. Adenovirus-mediated overexpression of ATF3 in Ishikawa cells activated LIF promoter activity and enhanced its expression. Accordingly, the stimulation of BeWo spheroid adhesion promoted by ATF3 was inhibited by pretreatment with a specific antibody against LIF via the antibody-blocking assay. Moreover, ATF3 was aberrantly decreased in the endometria of RIF patients. Conclusions: Our findings suggest that ATF3 plays a significant role in regulating human endometrial receptivity and embryo attachment in vitro via up-regulation of

关键词： 乳腺肿瘤   免疫组织化学   激活转录因子3   成骨细胞特异性转录因子2  

摘要： 目的探讨激活转录因子3（ATF3）和成骨细胞特异性转录因子2（Runx2）在乳腺癌组织中的表达及临床意义。方法采用免疫组织化学法检测ATF3和Runx2在105例乳腺浸润性导管癌和相应癌旁乳腺组织中的表达情况，分析其与乳腺癌患者临床病理特征的关系。结果乳腺浸润性导管癌组ATF3和Runx2的阳性表达率分别为80.95%（85/105）和69.52%（73/105），显著高于癌旁乳腺组织的11.43%（12/105）和8.57%（9/105），差异均具有统计学意义（χ2=102.097，P=0.000；χ2=11.595，P=0.001）。ATF3和Runx2的表达与乳腺癌的组织学分级（χ2=14.623，P=0.001；χ2=24.891，P=0.000）、淋巴结转移（χ2=7.059，P=0.008；χ2=6.358，P=0.012）及pTNM分期相关（χ2=5.807，P=0.016；χ2=4.902，P=0.027），而与患者年龄（χ2=0.274，P=0.601；χ2=1.554，P=0.213）及肿瘤大小（χ2=2.476，P=0.290；χ2=5.261，P=0.072）无关。ATF3和Runx2在乳腺癌组织中的表达呈正相关（C=0.498，P=0.000）。结论ATF3和Runx2可能协同参与了乳腺癌的发生，而且ATF3和Runx2与乳腺癌的浸润、转移及临床分期有关，提示二者可能成为预测乳腺癌恶性程度和评估患者预后的重要指标。

关键词： Berberine   Hepatocellular carcinoma   KLF6   ATF3   p21   E2F1   PTTG1   ERK1/2  

摘要： Background: Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit proliferation of human HCC cells, although the underlying mechanism(s) are unclear. Methods: Protein expression was detected by Western blots. Cell viability was determined by using the CellTiter Assay kit. Results: We confirm that BBR treatment inhibits HepG2, Hep3B, and SNU-182 cell viability, and suggest that it regulates this proliferation via the modulation of multiple tumorigenesis-related genes protein expression. BBR treatment up-regulated protein expression of tumor suppressor genes, including Kruppel-like factor 6 (KLF6), activating transcription factor 3 (ATF3) and p21, while down-regulating the expression of selected oncogenes, including E2F transcription factor 1 (E2F1) and pituitary tumor transforming gene 1 (PTTG1). The specific extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor, PD98059, partially inhibited BBR effects including reduction of cell viability, and up-regulation of KLF6 and ATF3 expressions;although, PD98059 did not alter the down-regulation of E2F1 and PTTG1 expression by BBR. Conclusions: Our results suggest that BBR inhibits HCC cell viability by modulating multiple tumorigenesis-related genes, and that up-regulation of tumor suppressor genes by BBR is in part the result of ERK1/2 action. The results of this study augment our understanding of the mechanisms underlying the effect of BBR on hepatocellular cancers and provide further evidence as to the biological plausibility of this agent's role in the treatment of these malignancies.

关键词： Editorials   activating transcription factor 3   cardiac remodeling   fibrosis   hypertrophy   p38 mitogen-activated protein kinases  

摘要： An introduction is presented in which the editor discusses various reports within the issue on topics including hypertensive heart disease, myofibroblasts, and myocyte hypertrophy.

关键词： Genetic effects   ATF3   CDKN1A   Milk production traits   Chinese Holstein  

摘要： Background: Our previous RNA-sequencing study revealed that the ATF3 and CDKN1A genes were remarkably differentially expressed between the mammary glands of lactating Holstein cows with extremely high and low milk protein and fat percentage so that both of them were considered as candidates for milk composition. Herein, we further verified whether these genes have genetic effects on milk production traits in a Chinese Holstein cow population. Results: By re-sequencing the entire coding and regulatory regions, we identified four SNPs in 5'promoter region, two in exons, seven in 3' un-translated region (UTR), and six in 3' flanking region of ATF3 gene, and one SNP in exon 5, two in 3' UTR, and two in 3' flanking region of CDKN1A gene. Of these, only the SNP, c.271C > T (rs442346530), in exon 5 of CDKN1A gene was predicted to result in an amino acid replacement from arginine to tryptophan. Subsequent genotype-phenotype association analysis revealed that 19 SNPs in ATF3 and 5 SNPs in CDKN1A were evidently associated with 305-days milk yield, fat yield, protein yield, or protein percentage (P = < 0.0001 similar to 0.0494). Whilst, no significant SNPs in ATF3 gene were associated with fat percentage in both first and second lactations (P > 0.05), and only two SNPs of CDKN1A gene, c.271C > T (P = 0.0377) and c.*654C > T (P = 0.0144), were markedly associated with fat percentage in the first lactation. Further, linkage disequilibrium (LD) analyses were conducted among the identified SNPs in ATF3 and/or CDKN1A genes to further confirm the association results. We also observed that the four SNPs, g.72834301C > A, g.72834229C > A, g. 72833969A > G, and g.72833562G > T altered the specific transcription factor (TF) binding sites in ATF3 promoter, and one SNP, c.271C > T, changed the CDKN1A protein secondary structure, suggesting they might be the promising potential functional mutations. Conclusion: Our findings first profiled the genetic effects of ATF3 and CDKN1A genes for mi

关键词： neuron   hippocampus   aging   proteasome   mahogunin   survival   ATF3   ubiquitin   stress response  

摘要： A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.