关键词： DDIT3 gene   Erbium   Transcription Factors   ATF4 gene   Activating Transcription Factor 4   Death Domain Receptors   PC12 Cells  

摘要： Tetrachlorobenzoquinone (TCBQ) is a downstream metabolite of pentachlorophenol (PCP). Previously, we demonstrated that TCBQ caused cytotoxicity due to mitochondrial-related apoptosis. Here, we confirmed the upregulation of death receptor 5 (DR5) followed by the construction of the death-inducing signaling complex (DISC). We also detected the activation of the caspase cascade, which was correlated with TCBQ-induced apoptotic cell death in PC12 cells. The upregulation of DR5 included transcriptional activation and de novo protein synthesis in response to TCBQ, We also identified the endoplasmic reticulum (ER) as a new target for the TCBQ challenge in PC12 cells. The protein kinase R-like ER kinase/eukaryotic translation initiation factor 2 alpha (PERK/eIF2 alpha)-mediated activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) signaling pathway contributed to the process of TCBQ-induced ER stress. Blocking ATF4, ATF3, or CHOP signaling by gene silencing technology resulted in decreased cell apoptosis after exposure to TCBQ Finally, NAC ameliorated TCBQ-induced apoptosis and ER stress, which illustrated that TCBQ-induced apoptosis is somehow ROS-dependent. In summary, this study provided important mechanistic insight into how TCBQ utilizes ER stress-related signaling to exhibit pro-apoptotic activity in PC12 cells.

关键词： esophageal squamous cell carcinoma   activating transcription factor 3   inhibitor of DNA binding 1   proliferation   metastasis  

摘要： Esophageal cancer is one of the most prevalent forms of cancer and has a particularly high mortality rate due to early metastasis;however, the underlying mechanisms of its formation and progression remain unclear. The present study performed immunohistochemical analysis and observed that the expression of activating transcription factor 3 (ATF3) was reduced in esophageal squamous cell carcinoma (ESCC) in comparison with non-tumor adjacent tissues. By contrast, inhibitor of DNA binding 1 (ID1) was overexpressed in ESCC tissues, demonstrating an inverse correlation with ATF3 (P<0.01). In ESCC EC109 and KYSE450 cells lines, transfection with an ATF3-overexpression plasmid resulted in the inhibition of cell proliferation, motility and migration, which was associated with the induction of E-cadherin expression and inhibition of cyclin D1 and Twist. Notably, ATF3 exerted an inverse regulatory interaction with ID1. The results of the present study provide additional evidence of the tumor suppressive features of ATF3 and demonstrate a novel mechanism of ATF3-mediated inhibition of cancer metastasis in esophageal cancer.

关键词： Ras   scribble   Hippo pathway   Drosophila   tumor   invasion   AP-1   Fos   Kayak   Atf3   Pdp-1   CG6272   CEBPG   Myc   Taiman   Ftz-f1   Mef-2   Cropped   STAT   JNK signaling  

摘要： Cancer cells have abnormal gene expression profiles;however, to what degree these are chaotic or driven by structured gene regulatory networks is often not known. Here we studied a model of Ras-driven invasive tumorigenesis in Drosophila epithelial tissues and combined in vivo genetics with next-generation sequencing and computational modeling to decipher the regulatory logic of tumor cells. Surprisingly, we discovered that the bulk of the tumor-specific gene expression is controlled by an ectopic network of a few transcription factors that are overexpressed and/or hyperactivated in tumor cells. These factors are Stat, AP-1, the bHLH proteins Myc and AP-4, the nuclear hormone receptor Ftz-f1, the nuclear receptor coactivator Taiman/SRC3, and Mef2. Notably, many of these transcription factors also are hyperactivated in human tumors. Bioinformatic analysis predicted that these factors directly regulate the majority of the tumor-specific gene expression, that they are interconnected by extensive cross-regulation, and that they show a high degree of co-regulation of target genes. Indeed, the factors of this network were required in multiple epithelia for tumor growth and invasiveness, and knockdown of several factors caused a reversion of the tumor-specific expression profile but had no observable effect on normal tissues. We further found that the Hippo pathway effector Yorkie was strongly activated in tumor cells and initiated cellular reprogramming by activating several transcription factors of this network. Thus, modeling regulatory networks identified an ectopic and ordered network of master regulators that control a large part of tumor cell-specific gene expression.

摘要： Bone homeostasis is maintained by the sophisticated coupled actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here we identify activating transcription factor 3 (ATF3) as a pivotal transcription factor for the regulation of bone resorption and bone remodeling under a pathological condition through modulating the proliferation of osteoclast precursors. The osteoclast precursor-specific deletion of ATF3 in mice led to the prevention of receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL)-induced bone resorption and bone loss, although neither bone volume nor osteoclastic parameter were markedly altered in these knockout mice under the physiological condition. RANKL-dependent osteoclastogenesis was impaired in vitro in ATF3-deleted bone marrow macrophages (BMM). Mechanistically, the deficiency of ATF3 impaired the RANKL-induced transient increase in cell proliferation of osteoclast precursors in bone marrow in vivo as well as of BMM in vitro. Moreover, ATF3 regulated cyclin D1 mRNA expression though modulating activator protein-1-dependent transcription in the osteoclast precursor, and the introduction of cyclin D1 significantly rescued the impairment of osteoclastogenesis in ATF3-deleted BMM. Therefore, these findings suggest that ATF3 could have a pivotal role in osteoclastogenesis and bone homeostasis though modulating cell proliferation under pathological conditions, thereby providing a target for bone diseases.

关键词： 转录激活因子3/代谢   肿瘤/代谢   综述  

摘要： 激活转录因子3（ATF3）是细胞在缺血-再灌注损伤、神经元或肝损伤、皮肤损伤、病毒癌基因表达或DNA损伤刺激下产生的一种蛋白质.近年来研究发现ATF3在人类多种恶性肿瘤发生、发展过程中发挥重要作用.

关键词： chondrocyte   ATF3   NF-kB   osteoarthritis   inflammatory cytokines   endochondral ossification  

摘要： Activating transcription factor 3 (Atf3) has been implicated in the pathogenesis of various diseases, including cancer and inflammation, as well as in the regulation of cell proliferation and differentiation. However, the involvement of Atf3 in developmental skeletogenesis and joint disease has not been well studied to date. Here, we show that Atf3 is a critical mediator of osteoarthritis (OA) development through its expression in chondrocytes. ATF3 expression was markedly up-regulated in the OA cartilage of both mice and humans. Conditional deletion of Atf3 in chondrocytes did not result in skeletal abnormalities or affect the chondrogenesis, but alleviated the development of OA generated by surgically inducing knee joint instability in mice. Inflammatory cytokines significantly up-regulated Atf3 expression through the nuclear factor-kB (NF-kB) pathway, while cytokine-induced interleukin-6 (Il6) expression was repressed, in ATF3-deleted murine and human chondrocytes. Mechanistically, Atf3 deficiency decreased cytokine-induced Il6 transcription in chondrocytes through repressing NF-kB signalling by the attenuation of the phosphorylation status of IkB and p65. These findings suggest that Atf3 is implicated in the pathogenesis of OA through modulation of inflammatory cytokine expression in chondrocytes, and the feed-forward loop of inflammatory cytokines/NF-kB/Atf3 in chondrocytes may be a novel therapeutic target for the treatment for OA. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

摘要： Steroid sex hormones can induce prostate carcinogenesis, and are thought to contribute to the development of prostate cancer during aging. However, the mechanism for hormone-induced prostate carcinogenesis remains elusive. Here, we report that activating transcription factor 3 (ATF3)-a broad stress sensor-suppressed hormone-induced prostate carcinogenesis in mice. Although implantation of testosterone and estradiol (T+E-2) pellets for 2 months in wild-type mice rarely induced prostatic intraepithelial neoplasia (PIN) in dorsal prostates (one out of eight mice), the loss of ATF3 led to the appearance of not only PIN but also invasive lesions in almost all examined animals. The enhanced carcinogenic effects of hormones on ATF3-deficient prostates did not appear to be caused by a change in estrogen signaling, but were more likely a consequence of elevated androgen signaling that stimulated differentiation of prostatic basal cells into transformation-preferable luminal cells. Indeed, we found that hormone-induced lesions in ATF3-knockout mice often contained cells with both basal and luminal characteristics, such as p63(+) cells (a basal-cell marker) showing luminal-like morphology, or cells double-stained with basal (CK5(+)) and luminal (CK8(+)) markers. Consistent with these findings, low ATF3 expression was found to be a poor prognostic marker for prostate cancer in a cohort of 245 patients. Our results thus support that ATF3 is a tumor suppressor in prostate cancer.

关键词： 非小细胞肺癌   ATF3   免疫组化   RT-PCR  

摘要： 目的：初步探讨非小细胞肺癌中ATF3表达与临床特征及预后的关系。方法：回顾分析我院选取98例术后病理诊断为非小细胞肺癌的患者,于2007年1月-2009年5月在我院行肺癌根治术,选取同一患者距离肺癌组织≥5 cm切缘的正常肺组织作为对照组,同时分别选取正常肺组织30例及炎性肺组织30例分别进行检测。采用免疫组化法及RT-PCR检测肺组织中ATF3表达水平,并结合肺癌患者随访数据运用Kaplan-Meier方法进行生存期分析。结果：ATF3在非小细胞肺癌中呈高表达率,ATF3表达与淋巴结转移及TNM分期有显著差异性（P〈0.05）。生存分析提示ATF3的阳性组的生存期较ATF3阴性组的低（P〈0.001）。结论：ATF3蛋白在非小细胞肺癌表达水平与癌旁组、正常肺组织组及炎性肺组织的表达水平有显著差异性;且ATF3蛋白表达在淋巴结转移情况和TNM分期中有相关性;ATF3表达水平可作为肺癌患者术后预后判断的指标之一。

关键词： glomerular mesangial cells   sublytic C5b-9   Thy-1 nephritis   transcription factor   acetylation   apoptosis  

摘要： The apoptosis of glomerular mesangial cells(GMCs)is considered to be an important contributor to the initiation and development of rat Thy-1 nephritis(Thy-1N)and is accompanied by sublytic C5b-9 ***,the mechanism by which sublytic C5b-9 triggers GMC apoptosis has not been *** this study,functional and histological examinations were performed on GMCs treated with sublytic C5b-9(in vitro)and renal tissues of Thy-1N rats(in vivo).The in vitro studies found that sublytic C5b-9 could trigger GMC apoptosis through upregulating Egr-1,ATF3,and Gadd45 ***-1-mediated post-transcriptional modulation of ATF3,Egr-1/ATF3-enhanced Gadd45 promoter activity,and p300-mediated ATF3 acetylation were all involved in GMC *** importantly,the effective binding elements for Egr-1 and ATF3 to Gadd45β/γpromoters and the ATF3 acetylation site were *** vivo,silencing renal p300,Egr-1,ATF3,and Gadd45β/γsignificantly decreased GMC apoptosis,secondary GMC proliferation,and urinary protein secretion in Thy-1N ***,these findings implicate that sublytic C5b-9-induced activation of Egr-1/p300–ATF3/Gadd45 axis plays a critical role in GMC apoptosis in Thy-1N rats.

关键词： apoptosis   DNA damage   DNA repair   p53   stress response   ATF3   UV   histone modifications  

摘要： The response to UV irradiation is important for a cell to maintain its genetic integrity when challenged by environmental genotoxins. An immediate early response to UV irradiation is the rapid induction of activating transcription factor 3 (ATF3) expression. Although emerging evidence has linked ATF3 to stress pathways regulated by the tumor suppressor p53 and the histone acetyltransferase Tip60, the role of ATF3 in the UV response remains largely unclear. Here, we report that ATF3 mediated dichotomous UV responses. Although UV irradiation enhanced the binding of ATF3 to Tip60, knockdown of ATF3 expression decreased Tip60 stability, thereby impairing Tip60 induction by UV irradiation. In line with the role of Tip60 in mediating UV-induced apoptosis, ATF3 promoted the death of p53-defective cells in response to UV irradiation. However, ATF3 could also activate p53 and promote p53-mediated DNA repair, mainly through altering histone modifications that could facilitate recruitment of DNA repair proteins (such as DDB2) to damaged DNA sites. As a result, ATF3 rather protected the p53 wild-type cells from UV-induced apoptosis. Our results thus indicate that ATF3 regulates cell fates upon UV irradiation in a p53-dependent manner.