关键词： Activating transcription factor 3 (ATF3)   Staphylococcus aureus   Listeria monocytogenes   bacterial infection   cytokine  

摘要： Activating transcription factor 3 (ATF3) is a stress-induced transcriptional regulator in eukaryote. The role of ATF3 in cancer has been well defined, but how ATF3 functions in bacterial infection is not well understood. Pneumococcal infection has been shown to induce ATF3 expression, which subsequently enhances cytokine production and provides protection from lethalStreptococcus pneumoniaeinfection, but the role of ATF3 in other Gram-positive (G+) infections remains unclear. Here, we report that infection with other G+bacteria (Staphylococcus aureusandListeria monocytogenes) and with G−bacteria (uropathogenicEscherichia coli) also significantly induced ATF3 expression. Moreover, the production of cytokines (tumor necrosis factor alpha [TNF]-α, interleukin [IL]-1β, IL-6 and interferon [IFN]-γ) was enhanced by ATF3 inS. aureusandL. monocytogenesinfection, but decreased in uropathogenicE. coli(UPEC) infection. In addition, inS. aureusandL. monocytogenesinfections,ATF3WT mice cleared bacteria more efficiently and had higher survival rates thanATF3knockout mice. However, in UPEC infection, no significant difference was found in survival rate. Taken together, these data suggest that ATF3 provides protection fromS. aureusandL. monocytogenesinfections; however, the role of ATF3 in UPEC infection is more complicated and should be further elucidated.

关键词： LYMPHOMA   EXPRESSION   JUN  

摘要： In this issue of Blood, Juilland and colleagues reveal the expression pattern and the role of different members of the activating transcription factor (ATF) family in survival of diffuse large B-cell lymphoma (DLBCL) cells.

关键词： Echinacoside   Parkinson's disease   1-Methyl-4-phenylpyridinium ion. Reactive oxygen species   ATF3   CHOP  

摘要： Echinacoside （ECH） is protective in a mouse model of Parkinson＇ s disease （PD） induced by 1-methyl-4- phenylpyridinium ion （MPP＋）. To investigate the mechanisms involved, SH-SYSY neuroblastoma ceils were treated with MPP＋ or a combination of MPP＋ and ECH, and the expression of ATF3 （activating transcription factor 3）, CHOP （C/EBP-homologous protein）, SCNA （synuclein alpha）, and GDNF （glial cell line-derived neurotrophic factor） was assessed. The results showed that ECH significantly improved cell survival by inhibiting the generation of MPP＋-induced reactive oxygen species （ROS）. In addition, ECH suppressed the ROS and MPP＋- induced expression of apoptotic genes （ATF3, CHOP, and SCNA）. ECH markedly decreased the MPP＋-induced cas- pase-3 activity in a dose-dependent manner. ATF3- knockdown also decreased the CHOP and cleaved caspase- 3 levels and inhibited the apoptosis induced by MPP＋. Interestingly, ECH partially restored the GDNF expression that was down-regulated by MPP＋. ECH also improved dopaminergic neuron survival during MPP＋ treatment and protected these neurons against the apoptosis induced by MPTP. Taken together, these data suggest that the ROS/ ATF3/CHOP pathway plays a critical role in mechanisms by which ECH protects against MPP＋-induced apoptosis in PD.

关键词： Sclerostin   SOST   Human fibroblasts   Hypoxia   Parathyroid hormone   Prostaglandin E2   BONE-FORMATION   EXPRESSION   SOST   GENE   PTH   IDENTIFICATION   SUPPRESSION   TARGET   ATF3   BMPS  

摘要： Sclerostin, coded by SOST, is a secretory protein that is specifically expressed in osteocytes and suppresses osteogenesis by inhibiting WNT signaling. The regulatory mechanism underlying SOST expression remains unclear mainly due to the absence of an adequate human cell model. Thus, we herein attempted to establish a cell model of human dermal fibroblasts in order to investigate the functions of sclerostin. We selected 20 candidate transcription factors (TFs) that induce SOST expression by analyzing gene expression patterns in the human sarcoma cell line, SaOS-2, between differentiation and maintenance cultures using microarrays. An effective set of TFs to induce SOST expression was sought by their viral transduction into fibroblasts, and a combination of four TFs: ATF3, KLF4, PAX4, and SP7, was identified as the most effective inducer of SOST expression. Quantitative PCR demonstrated that the expression levels of SOST in fibroblasts treated with the 4 TFs were 199- and 1439-fold higher than those of the control after 1-week and 4-week cultures, respectively. The level of sclerostin in the conditioned medium, as determined by ELISA, was 21.2 pmol/l 4 weeks after the transduction of the 4 TFs. Interestingly, the production of Dickkopfl (DKK1), another secreted inhibitor of WNT signaling, was also increased by transduction of these 4 TFs. Parathyroid hormone (PTH) significantly suppressed the induced SOST by 38% and sclerostin by 82% that of the vehicle. Hypoxia increased the induced SOST by 62% that of normoxia. Furthermore, prostaglandin E2 (PGE2) increased SOST expression levels to 16-fold those of the vehicle. In conclusion, the efficient induction of SOST expression and sclerostin production was achieved in human dermal fibroblasts by the transduction of ATF3, KLF4, PAX4, and SP7, and the induced SOST and sclerostin were regulated by PTH, hypoxia, and PGE2. This model may contribute to elucidating the regulatory mechanisms underlying SOST expression and advancin

关键词： Activating transcription factor 3   Cardiac remodeling   Hypertrophy   Autophagy   Macrophages   ACTIVATING TRANSCRIPTION FACTOR-3   HEART-FAILURE   CARDIOMYOCYTES   MICE  

关键词： Activating transcription factor 3   SUMOylation   Endothelial cell   PROSTATE-CANCER CELLS   PROTEIN SUMOYLATION   SIGNALING PATHWAYS   DISTURBED FLOW   ATF3   GENE   UBIQUITINATION   REPRESSION   REGULATOR   ROLES  

摘要： Activating transcription factor 3 (ATF3) is an adaptive-response protein induced by various environmental stresses and is implicated in the pathogenesis of many disease states. However, the role of ATF3 SUMOylation in hypertension-induced vascular injury remains poorly understood. Here we investigated the function of ATF3 SUMOylation in vascular endothelial cells (ECs). The expression of ATF3 and small ubiquitin-like modifier 1 (SUMO1) was increased in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs). Microscopic analyses further revealed that the expression of ATF3 and SUMO1 is upregulated and colocalized in the endothelium of thoracic aortas from Ang II-induced hypertensive mice. However, Ang II-induced upregulation of ATF3 and SUMO1 in vitro and in vivo was blocked by Ang II type I receptor antagonist olmesartan. Moreover, Ang II induced ATF3 SUMOylation at lysine 42, which is SUMO1 dependent. ATF3 SUMOylation attenuated ATF3 ubiquitination and in turn promoted ATF3 protein stability. ATF3 or SUMO1 knockdown inhibited Ang II induced expression of inflammatory molecules such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8. Wild type ATF3 but not ATF3-K42R (SUMOylation defective mutant) reduced the production of nitric oxide (NO), a key indicator of EC function. Consistently, ginkgolic acid, an inhibitor of SUMOylation, increased NO production in HUVECs and significantly improved vasodilatation of aorta from Ang II-induced hypertensive mice. Our findings demonstrated that ATF3 SUMOylation is involved in Ang II-induced EC inflammation and dysfunction in vitro and in vivo through inhibiting ATF3 ubiquitination and increasing ATF3 protein stability. (C) 2016 Elsevier Ltd. All rights reserved.

关键词： Bortezomib   CCL2   Allodynia   c-Jun   ATF3   ACTIVATING TRANSCRIPTION FACTOR-3   DORSAL-ROOT GANGLIA   PRIMARY SENSORY NEURONS   C-JUN   MULTIPLE-MYELOMA   ENDOTHELIAL-CELLS   JNK ACTIVATION   KAPPA-B   PAIN   PROTEIN-1  

摘要： Bortezomib (BTZ) is a frequently used chemotherapeutic drug for the treatment of refractory multiple myeloma and hematological neoplasms. The mechanism by which the administration of BTZ leads to painful peripheral neuropathy remains unclear. In present study, we found that application of BTZ at 0.4 mg/kg for consecutive 5 days significantly increased the expression of CCL2 in DRG, and intrathecal administration of neutralizing antibody against CCL2 inhibited the mechanical allodynia induced by BTZ. We also found an increased expression of c-Jun in DRG, and that inhibition of c-Jun signaling prevented the CCL2 upregulation and mechanical allodynia in the rats treated with BTZ. Furthermore, the results with luciferase assay in vitro and ChIP assay in vivo showed that c-Jun might be essential for BTZ-induced CCL2 upregulation via binding directly to the specific position of the ccl2 promoter. In addition, the present results showed that an upregulated expression of ATF3 was co-expressed with c-Jun in the DRG neurons, and the enhanced interaction between c-Jun and ATF3 was observed in DRG in the rats treated with BTZ. Importantly, pretreatment with ATF3 siRNA significantly inhibited the recruitment of c-Jun to the ccl2 promoter in the rats treated with BTZ. Taken together, these findings suggested that upregulation of CCL2 resulting from the enhanced interaction between c-Jun and ATF3 in DRG contributed to BTZ-induced mechanical allodynia. (C) 2015 Published by Elsevier Inc.

关键词： off-pump coronary artery bypass   pathway analysis   protein-protein interaction network   miRNA regulatory network   MYOCARDIAL ISCHEMIA-REPERFUSION   INFLAMMATORY RESPONSE   ON-PUMP   PROTEIN   INJURY   GENES   ATF3   CELL  

摘要： Off-pump coronary artery bypass (OPCAB) surgery is the most effective treatment for coronary heart disease. The aim of this study was to explore the effects of OPCAB on the basis of the associated molecular mechanisms. GSE12486 expression profiles downloaded from the Gene Expression Omnibus database (GEO) were analyzed to identify the differentially expressed genes (DEGs). Principal component analysis (PCA) was conducted based on the expression profiles of DEGs. Function and pathway enrichment of upregulated DEGs was performed, followed by protein-protein interaction (PPI) network construction. Gene Set Enrichment Analysis (GSEA) was used for miRNA enrichment analysis based on expression profiles and prediction of their association with the disease. Cytoscape was applied to construct miRNA regulatory networks of DEGs. In total 64 DEGs were identified, including 63 upregulated and 1 downregulated gene. The first principal component in the PCA analysis was able to distinguish between pre- and post-OPCAB samples. Upregulated DEGs mainly enriched 20 Gene Ontology terms, such as chemokine activity, and 5 pathways including the chemokine signaling pathway. The constructed PPI network contained 234 edges and 55 nodes, and 10 upregulated hub nodes, including FBJ murine osteosarcoma viral oncogene homolog (FOS), were screened. A total of 36 miRNAs, including MIR-224 and MIR-7, were screened by GSEA enrichment analysis. A miRNA regulatory network including 176 edges and 97 nodes was constructed, showing the regulatory relationships between miRNAs and DEGs. For example, early growth response 2 (EGR2) was regulated by 8 miRNAs including MIR-150, MIR-142-3P, MIR-367 and MIR-224. The identified DEGs might play important roles in patients pre- and post-OPCAB surgery via the regulation of associated genes.

关键词： Activating transcription factor 3   Endoplasmic reticulum stress   Reactive oxygen species   Liver cancer   ENDOPLASMIC-RETICULUM STRESS   TRANSCRIPTION FACTOR-3   CANCER CELLS   LUNG-CANCER   EXPRESSION   RESPONSES   PATHWAY   PROTEIN   KINASE   DEATH  

摘要： Background: Hepatocellular carcinoma (HCC) is one of most common and aggressive human malignancies in the world, especially, in eastern Asia, and its mortality is very high at any phase. We want to investigate mechanism of niclosamide inducing cell apoptosis in HCC. Methods: Two hepatoma cell lines were used to evaluate activity of niclosamide inducing cell apoptosis and study its mechanism. Quantitative real-time PCR and western blotting were used in analysis of genes expression or protein active regulated by niclosamide. Results: Niclosamide remarkably induced cell apoptosis in hepatoma cells. Furthermore, our study revealed that RNA-dependent protein kinase-like kinase (PERK) is activated and its expression is up-regulated in HCC cells which are exposed to niclosamide. niclosamide also significantly increase activating transcription factor 3 (ATF3), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP) expression in HCC cells. It's suggested that the function of niclosamide was abrogated by PERK inhibitor or absent ATF3. Expression of PERK and CHOP is correlated with ATF3 level in the cells. Conclusion: Taken together, our results indicate that ATF3 plays an integral role in ER stress activated and cell apoptosis induced by niclosamide in HCC cells. In this study, the new mechanism of niclosamide as anti-cancer we investigated, too.

关键词： ATF3   cleaved caspase 3   diabetes   nerve reconstruction   Schwann cell   SCHWANN-CELL PROLIFERATION   AXONAL OUTGROWTH   SCIATIC-NERVE   SILICONE TUBES   FOLLOW-UP   CASPASE 3   REPAIR   NEUROPATHY   INJURIES   TUBULIZATION  

摘要： Knowledge about nerve regeneration after nerve injury and reconstruction in appropriate diabetic animal models is incomplete. Short-term nerve regeneration after reconstruction of a 10-mm sciatic nerve defect with either a hollow chitosan conduit or an autologous nerve graft was investigated in healthy Wistar and diabetic Goto-Kakizaki (GK) rats. After 21days, axonal outgrowth, the presence of activated and apoptotic Schwann cells and the thickness of the formed matrix in the conduits were measured. In general, nerve regeneration was superior in autologous nerve grafts. In chitosan conduits, a matrix, which was thicker in diabetic rats, was formed and was positively correlated with length of axonal outgrowth. Axonal outgrowth in conduits and in nerve grafts extended further in diabetic rats than in healthy rats. There was a higher percentage of activating transcription factor3 (ATF3)-immunostained cells in nerve segments from healthy rats than in diabetic rats after autologous nerve graft reconstruction. In chitosan conduits, more cleaved caspase 3-stained Schwann cells were generally observed in the matrix from the diabetic rats than in healthy rats. However, there were fewer apoptotic cells in the distal segment in diabetic rats reconstructed with a chitosan conduit. Preoperative glucose levels were positively correlated with axonal outgrowth after both reconstruction methods. Axonal regeneration was better in autologous nerve grafts than in hollow chitosan conduits and was enhanced in diabetic GK rats compared to healthy rats after reconstruction. This study provides insights into the nerve regeneration process in a clinically relevant diabetic animal model.