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.

关键词： ATF3   ChIP-seq   Enhancer   p300   H3K27ac   p53  

摘要： Background: Dysregulation of the common stress responsive transcription factor ATF3 has been causally linked to many important human diseases such as cancer, atherosclerosis, infections, and hypospadias. Although it is believed that the ATF3 transcription activity is central to its cellular functions, how ATF3 regulates gene expression remains largely unknown. Here, we employed ATF3 wild-type and knockout isogenic cell lines to carry out the first comprehensive analysis of global ATF3-binding profiles in the human genome under basal and stressed (DNA damage) conditions. Results: Although expressed at a low basal level, ATF3 was found to bind a large number of genomic sites that are often associated with genes involved in cellular stress responses. Interestingly, ATF3 appears to bind a large portion of genomic sites distal to transcription start sites and enriched with p300 and H3K27ac. Global gene expression profiling analysis indicates that genes proximal to these genomic sites were often regulated by ATF3. While DNA damage elicited by camptothecin dramatically altered the ATF3 binding profile, most of the genes regulated by ATF3 upon DNA damage were pre-bound by ATF3 before the stress. Moreover, we demonstrated that ATF3 was co-localized with the major stress responder p53 at genomic sites, thereby collaborating with p53 to regulate p53 target gene expression upon DNA damage. Conclusions: These results suggest that ATF3 likely bookmarks genomic sites and interacts with other transcription regulators to control gene expression.

关键词： 肝细胞癌   转录激活因子3   蛋白质类  

摘要： 目的筛选及验证肝癌细胞中与转录激活因子3（ATF3）相互结合的蛋白质，初步探讨在肝癌发生发展中协助ATF3发挥生物学功能的相关分子机制。方法应用免疫沉淀法沉淀出HepG2细胞中与ATF3相互结合的蛋白，经变性聚丙烯凝胶分析，与空载体组比对，挑选出差异性的电泳条带进行蛋白质谱分析，筛选出候选蛋白；再经免疫共沉淀验证二者是否相互结合；应用免疫组织化学及Westernblot检测并分析ATF3和候选蛋白在肝癌中的表达模式。结果过表达ATF3的HepG2实验组呈现出差异性表达的电泳条带；经质谱检测，Mascot软件分析及NCBI数据库检索，得到候选蛋白肽段信息，结合前期实验结果，PubMed文献报道，从中筛选出与ATF3最可能相关的蛋白gelsolin（GSN）；免疫共沉淀结果验证了ATI^3与GSN相互结合的关系，免疫组织化学及Westernblot检测出肝癌组织中ATF3与GSN的表达模式一致。结论ATF3可能通过与GSN蛋白之间的相互作用，在肝癌形成过程中协同发挥抑癌作用。

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 lethal Streptococcus pneumoniae infection, but the role of ATF3 in other Gram-positive (G⁺) infections remains unclear. Here, we report that infection with other G⁺ bacteria (Staphylococcus aureus and Listeria monocytogenes) and with G^? bacteria (uropathogenic Escherichia 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 in S.?aureus and L. monocytogenes infection, but decreased in uropathogenic E. coli (UPEC) infection. In addition, in S.?aureus and L. monocytogenes infections, ATF3 WT mice cleared bacteria more efficiently and had higher survival rates than ATF3 knockout mice. However, in UPEC infection, no significant difference was found in survival rate. Taken together, these data suggest that ATF3 provides protection from S.?aureus and L. monocytogenes infections; however, the role of ATF3 in UPEC infection is more complicated and should be further elucidated.