摘要： The genomic alterations that drive acute myeloid leukemia (AML) are well established, however, the molecular pathways that are deregulated as a consequence of these mutations and their impact on AML development and progression remain poorly understood. We and others have previously shown that the transcription factor (TF) JUN, though not mutated, is highly expressed in multiple AML sub-types (e.g. normal karyotype (NK-AML), complex karyotype and 11q23 rearrangements) relative to healthy hematopoietic stem and progenitor cells (HSPCs). We also recently reported that JUN supports cell survival in a panel of genetically diverse AML cell lines and patient-derived AML samples ex vivo. Moreover, we showed that JUN inhibition significantly delays disease onset and improves survival in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. Of critical importance, we have now observed that deletion of JUN does not negatively impact steady-state hematopoiesis or the hematopoietic reconstituting potential of HSPCs. While these results position JUN as an attractive therapeutic target in AML, previous efforts to develop JUN inhibitors have been unsuccessful. Therefore, our objective is to elucidate the mechanisms by which JUN supports AML in order to identify putative therapeutic targets in this pathway. JUN regulates many transcriptional programs by forming hetero-dimers with one of many other TFs and our goal was to identify which dimeric partner cooperates with JUN to regulate transcriptional programs that support AML. We previously reported that JUN supports AML, in part, by regulating the transcriptional output of the unfolded protein response (UPR), which is a signal transduction network that helps cells negotiate endoplasmic reticulum (ER) stress. To identify dimerization partners that cooperate with JUN to drive transcriptional output of the UPR, we utilized the UCSC genome browser, which contains the chromatin immunoprecipitation-sequencing (ChIP-seq) dat

关键词： 慢性阻塞性肺疾病   ATF3   ATF4   γ-GCS表达  

摘要： 目的探究慢性阻塞性肺疾病(COPD)患者肺组织中活化转录因子3(ATF3)与活化转录因子4(ATF4)对γ-谷氨酰半胱氨酸合酶(γ-GCS)表达的影响,为预防及诊断COPD提供临床资料。方法 63例COPD确诊患者(COPD组)及同期在体检中心进行健康体检的正常居民(正常组) 63例,比较2组患者治疗前后ATF3 mRNA、ATF4 mRNA、γ-GCS mRNA表达含量、ATF3、ATF4、γ-GCS蛋白表达含量及COPD组患者ATF3、ATF4、γ-GCS信使RNA和蛋白及心肺功能指标的相关性。结果 COPD组治疗前ATF3 mRNA、ATF4 mRNA、γ-GCS mRNA、ATF3蛋白、ATF4蛋白、γ-GCS蛋白与正常组比较,差异有统计学意义(P <0. 05),COPD组治疗后ATF4 mRNAγ-GCS蛋白与正常组比较差异有统计学意义(P <0. 05);同时COPD组患者ATF3、ATF4、γ-GCS信使RNA和蛋白与心肺功能相关指标相关性明显,差异有统计学意义(P <0. 05)。结论 COPD患者肺组织中ATF3与ATF4可影响γ-GCS的表达,并且可直接反应患者的心肺功能,临床上可以通过对患者肺组织中ATF3与ATF4对γ-GCS表达的影响,及时的预防及诊断COPD。

关键词： miR-590   Breast cancer   Runx2   ATF3   Proliferation   Apoptosis  

摘要： We previously reported that ATF3 and Runx2 are involved in breast cancer progression and bone metastasis. The expression of these genes can be controlled by post-transcriptional regulators such as microRNAs (miRNAs). In this study, we identified and validated the functional role of miR-590-3p in human breast cancer cells (MDA-MB231). There was an inverse correlation between the expression of miR-590-3p and its putative target genes, ATF3 and Runx2 in these cells. Overexpression of miR-590-3p decreased the expression of ATF3 and Runx2 at the mRNA and protein levels in MDA-MB231 cells. Luciferase reporter assay identified a direct interaction of 3' UTRs of ATF3 and Runx2 with miR-590-3p in these cells. Overexpression of miR-590-3p also decreased proliferation and increased apoptosis of breast cancer cells. Based on our results, we suggest that miR-590-3p might have potential clinical applications towards controlling breast cancer progression and bone metastasis. (C) 2018 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

关键词： chemotherapy   breast cancer metastasis   stress response   adaptive-response network   ATF3   seed and soil theory   cancer-host interaction   tumor microenvironment   immune modulation   tumor immune environment  

摘要： An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy;that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

关键词： ATF3   Sirolimus   Cutanous squamous cell carcinoma  

摘要： Background: Due to their immunosuppressive therapy, organtransplant recipients (OTR5) exhibit a high incidence for the development of cutaneous squamous cell carcinoma (cSCC). Randomized studies of kidney-transplanted patients indicate a significant lower susceptibility for cSCC among patients receiving the mTOR-inhibitor Sirolimus, compared to patients without mTOR-regimen. The exact mechanism, how mTOR inhibition affects keratinocyte carcinogenesis remains unclear. Objective: Our aim was to investigate the impact of Sirolimus on the expression level of the oncogene ATF3, which is involved in the development and progression of cSCC. Methods: We incubated human keratinocytes, cSSC cell lines and 3D skin equivalents with Sirolimus, exposed the cells to calcineurin inhibitors (CNI) and UVA-radiation and measured the expression level of ATF3 by real-time PCR and western blot. Results: We show that Sirolimus downregulates the expression of ATF3 induced by cyclosporine or cyclosporine plus UV-radiation in keratinocytes. In line with this we demonstrate a decrease in ATF3 expression, by incubating 3D skin equivalents with Sirolimus prior to cyclosporine and UV-light. However, Sirolimus has no significant impact on the ATF3 expression levels of cyclosporine stimulated cSCC cell lines. Conclusion: Taken together, our study demonstrates that Sirolimus downregulates the CNI or UV-induced ATF3 expression in human keratinocytes, which could be a potential molecular mechanism how Sirolimus reduces cSCC in OTRs. The lack of ATF3 suppression by Sirolimus in cSCC cell lines fits to observations from clinical studies which demonstrated a clinical benefit from the switch to a mTOR-regimen in patients with low tumor burden in early stage of disease. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

关键词： ATF3   CYR61   Hepatocellular carcinoma  

摘要： Background: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a high incidence and high mortality in East Asia. Identifying biomarkers and clarifying the regulatory mechanisms of HCC are of great importance. Herein, we report the role and mechanism of activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors in HCC. Methods: ATF3 overexpression vector and shRNAs were transfected into HCC cancer cells to upregulate or downregulate ATF3 expression. In vitro and in vivo assays were performed to investigate the functional role of ATF3 in hepatocellular carcinoma. RNA-Seq was performed to screen the differentially expressed genes downstream of ATF3. The dual-luciferase reporter assay, chromatin immunoprecipitation (Ch-IP) analysis and functional rescue experiments were used to confirm the target gene regulated by ATF3. Tissue microarrays (TMAs) comprising 236 human primary HCC tissues were obtained and immunohistochemical staining were carried out to analyze the clinical significance of ATF3. Results: The results indicate that ATF3 significantly inhibited the proliferation and mobility of HCC cells both in vitro and in vivo. Cysteine-rich angiogenic inducer 61 (CYR61) is a key target for transcriptional regulation by ATF3. Both ATF3 and CYR61 were consistently downregulated in human HCC tissues, and their expression levels were significantly and positively correlated with each other. Conclusions: Our findings indicate that ATF3 functions as a tumor suppressor in HCC through targeting and regulating CYR61.

关键词： Atf3   Obesity   Adipocyte   Metabolic diseases   Sulfuretin  

摘要： Activating transcription factor 3 (Atf3) has been previously demonstrated to impact obesity and metabolism. However, a metabolic role of Atf3 in mice remains debatable. We investigated the role of Atf3 in mice and further investigated Atf3 expression as a therapeutic target for obesity and metabolic diseases. Atf3 knockout (KO) mice fed with a high fat diet (HFD) aggravated weight gain and impaired glucose metabolism compared to littermate control wild type (WT) mice. Atf3 KO aged mice fed with a chow diet (CD) for longer than 10 months also displayed increased body weight and fat mass compared to WT aged mice. We also assessed requirements of Atf3 in a phytochemical mediated anti-obese effect. Effect of sulfuretin, a previously known phytochemical Atf3 inducer, in counteracting weight gain and improving glucose tolerance was almost completely abolished in the absence of Atf3, indicating that Atf3 induction can be a molecular target for preventing obesity and metabolic diseases. We further identified other Atf3 small molecule inducers that exhibit inhibitory effects on lipid accumulation in adipocytes. These data highlight the role of Atf3 in obesity and further suggest the use of chemical Atf3 inducers for prevention of obesity and metabolic diseases. (C) 2018 Elsevier Inc. All rights reserved.

关键词： ATF3   绿脓杆菌   急性肺损伤   负性调控   保护作用  

摘要： 目的探讨绿脓杆菌致急性肺损伤小鼠的ATF3表达规律及意义。方法以荧光标记的绿脓杆菌(PA)(滴度1.5×108CFU/ml) 50μl经鼻滴入C57BL/6野生型小鼠气管构建急性肺损伤模型,通过肺泡灌洗液(BALF)中的蛋白含量、肺组织干湿比测定肺微血管通透性和肺水肿程度变化;采用组织切片和HE染色观察肺组织病理变化; qRT-PCR检测ATF3在野生型急性肺损伤小鼠肺组织中的表达规律。结果经鼻滴入绿脓杆菌后导致肺微血管通透性增加和肺水肿加重,小鼠肺组织呈典型急性肺损伤病理改变,结果支持成功构建了经鼻滴入绿脓杆菌致ALI模型。ATF3表达于正常小鼠肺组织,经鼻滴入绿脓杆菌后小鼠肺组织中ATF3 mRNA的表达于0、3、6、12 h及24 h时相点分别为1.006±0.136,9.954±0.624,4.578±1.463,2.342±0.122,3.249±0.680,其中在3 h时相点达最高峰,随之逐渐下降,于24 h时相点基本能回到正常水平。结论 ATF3作为负性调控因子对绿脓杆菌致急性肺损伤小鼠有一定保护作用。

关键词： ATF3   chemokine   hematoma   RAG   traumatic brain injury  

摘要： Traumatic brain injury (TBI) induces a neuroinflammatory response resulting in astrocyte and microglia activation at the lesion site. This involves upregulation of neuroinflammatory genes, including chemokines and interleukins. However, so far, there is lack of knowledge on transcription factors (TFs) modulating this TBI-associated gene expression response. Herein, we analyzed activating transcription factor 3 (ATF3), a TF encoding a regeneration-associated gene (RAG) predominantly studied in peripheral nervous system (PNS) injury. ATF3 contributes to PNS axon regeneration and was shown before to regulate inflammatory processes in other injury models. In contrast to PNS injury, data on ATF3 in central nervous system (CNS) injury are sparse. We used Atf3 mouse mutants and a closed-head weight-drop-based TBI model in adult mice to target the rostrolateral cortex resulting in moderate injury severity. Post-TBI, ATF3 was upregulated already at early time points (i.e,. 1-4h) post-injury in the brain. Mortality and weight loss upon TBI were slightly elevated in Atf3 mutants. ATF3 deficiency enhanced TBI-induced paresis and hematoma formation, suggesting that ATF3 limits these injury outcomes in wild-type mice. Next, we analyzed TBI-associated RAG and inflammatory gene expression in the cortical impact area. In contrast to the PNS, only some RAGs (Atf3, Timp1, and Sprr1a) were induced by TBI, and, surprisingly, some RAG encoding neuropeptides were downregulated. Notably, we identified ATF3 as TF-regulating proneuroinflammatory gene expression, including CCL and CXCL chemokines (Ccl2, Ccl3, Ccl4, and Cxcl1) and lipocalin. In Atf3 mutant mice, mRNA abundance was further enhanced upon TBI compared to wild-type mice, suggesting immune gene repression by wild-type ATF3. In accord, more immune cells were present in the lesion area of ATF3-deficient mice. Overall, we identified ATF3 as a new TF-mediating TBI-associated CNS inflammatory responses.

关键词： qRT-PCR   quantitative real-time PCR   TRPV1   transient receptor potential vanilloid type 1  

摘要： Melanoma is the most lethal form of skin cancer with increasing incidence over the years. Because of its rapid proliferative and drastic metastatic capacity, the prognosis of melanoma remains dismal, although the targeted therapy and immunotherapy have gained revolutionary progress recently. Therefore, it is of necessity to further clarify the mechanism of melanoma pathogenesis for developing an alternative treatment strategy. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective Ca2+ channel greatly involved in regulating cell apoptosis, proliferation, metabolism, and cancer development, but its role in melanoma remains unknown. Herein, we first found that TRPV1 expression was significantly decreased in melanoma tissues and cell lines, compared with nevus tissues and normal melanocytes, respectively. We then proved that TRPV1 overexpression or its agonist capsaicin treatment inhibited melanoma growth by activating p53 and inducing cell apoptosis. A subsequent mechanistic study revealed that TRPV1 induced Ca2+ influx to regulate p53 activation via calcineurin-ATF3 transcriptional cascade. Finally, the effect of TRPV1 on melanoma growth was proved in vivo. Altogether, our study demonstrates that TRPV1 is a potential tumor suppressor in melanoma.