关键词： ATF3   microRNA   ossification   osteogenic differentiation   osteoporosis   POSTERIOR LONGITUDINAL LIGAMENT   OSSIFICATION   EXPRESSION   OSTEOBLAST   MICRORNAS   BONE   PROLIFERATION   GENE   TRANSCRIPTION   ASSOCIATION  

摘要： Through their multiple targets, microRNAs (miRNAs) are involved in numerous physiological and pathological processes. In this study, miR-342-3p was found to be deregulated with ossification of ligament or osteoporosis. We demonstrate that silencing miR-342-3p impairs osteoblast activity and matrix mineralization, while over expression of miR-342-3p promotes osteoblast differentiation significantly. Moreover, miR-342-3p directly targets activating transcription factor 3 (ATF3), which inhibits transcription of pro-osteogenic differentiation-associated genes. In addition, there exists a higher frequency of methylation at the CpG island of the Enah/Vasp-Like (EVL) locus in undifferentiated pre-osteoblasts; however, demethylation of the EVL CpG island induces over expression of miR-342-3p during osteogenic differentiation. This study suggests that miR-342-3p may serves as a potential marker for diagnosis and treatment of ossification of ligament and osteoporosis.

关键词： ATF3   Breast cancer   Runx2   ENDOPLASMIC-RETICULUM STRESS   ADAPTIVE-RESPONSE GENE   BREAST-CANCER   TGF-BETA   ER STRESS   ATF3 EXPRESSION   C-JUN   INDUCED APOPTOSIS   UP-REGULATION   TNF-ALPHA  

摘要： Activating transcription factor 3 (ATF3) is a stress-responsive factor that belongs to the activator protein 1 (AP-1) family of transcription factors. ATF3 expression is stimulated by various factors such as hypoxia, cytokines, and chemotherapeutic and DNA damaging agents. Upon stimulation, ATF3 can form homodimers or heterodimers with other members of the AP-1 family to repress or activate transcription. Under physiological conditions, ATF3 expression is transient and plays a pivotal role in controlling the expression of cell-cycle regulators and tumor suppressor, DNA repair, and apoptosis genes. However, under pathological conditions such as those during breast cancer, a sustained and prolonged expression of ATF3 has been observed. In this review, the structure and function of ATF3, its posttranslational modifications (PTM), and its interacting proteins are discussed with a special emphasis on breast cancer metastasis. (C) 2018 Elsevier B.V. All rights reserved.

关键词： carnosol   IL-6   ATF3   lung ischemia-reperfusion injury   NF-KAPPA-B   ATF3   TRANSCRIPTION   EXPRESSION   STRESS   APOPTOSIS   RESPONSES   PROTECTS   ALPHA   IL-6  

摘要： Carnosol is a naturally occurring herbal compound, known for its antioxidative properties. We previously found that carnosol protected mouse lungs from ischemia-reperfusion injury in ex vivo cultures. To elucidate the molecular mechanisms underpinning carnosol-mediated lung protection, we analyzed modes of interleukin-6 (IL-6) gene expression, which is associated with lung ischemia-reperfusion injury. Microarray analysis of mouse lungs suggested that IL-6 mRNA levels were elevated in the mouse lungs subjected to clamp-reperfusion, which was associated with elevated levels of other inflammatory modulators, such as activating transcription factor 3 (ATF3). Carnosol pretreatment lowered the IL-6 protein levels in mouse lung homogenates prepared after the clamp-reperfusion. On the other hand, the ATF3 gene expression was negatively correlated with that of IL-6 in RAW264.7 cells. IL-6 mRNA levels and gene promoter activities were suppressed by carnosol in RAW264.7 cells, but rescued by ATF3 knockdown. When RAW264.7 cells were subjected to hypoxia-reoxygenation, carnosol treatment lowered oxygen consumption after reoxygenation, which was coupled with a correlation with a transient production of mitochondrial reactive oxygen species and following ATF3 gene expression. These results suggest that carnosol treatment could be a new strategy for protecting lungs from ischemia-reperfusion injury by modulating the ATF3-IL-6 axis.

关键词： Cervical squamous epithelial cancer   Activating transcription factor   Tumor protein 53 (P53)   Tumor suppressor   Dichloroacetic acid   ATF3   STABILITY   OUTCOMES   COMPLEX  

摘要： Purpose: To investigate the effect of activating transcription factor 3 (ATF) on dichloroacetic acid (DCA) for the treatment of cervical cancer. Methods: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry assays were first used to determine the effect of DCA treatment on SW756 cells. Next, western blotting was performed to test apoptotic markers and activating transcription factor 3 (ATF3) expression. MTT and flow cytometry assays were conducted to test the effect of ATF3 on the viability and apoptosis of cervical cancer cells. Finally, western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and flow cytometry assays were used to examine the causality between ATF3 and P53. Results: The expression of ATF3 was significantly upregulated (p < 0.001) in cervical cancer cells treated with DCA. ATF3 overexpression consolidated the suppressive effect of DCA on cell proliferation and induced apoptosis (p < 0.001), suggesting that tumor protein 53 (P53), a tumor suppressor, was responsible for ATF3-mediated anti-tumorigenesis in DCA-treated cervical cancer. Conclusion: These results indicate that ATF3/P53 signaling is critical to treating cervical cancer with DCA and provides new insights into cervical cancer diagnosis, treatment and prognosis.

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： ATF3   Sirolimus   Cutanous squamous cell carcinoma   NONMELANOMA SKIN-CANCER   RENAL-TRANSPLANT RECIPIENTS   SQUAMOUS-CELL CARCINOMA   RAPAMYCIN INHIBITORS   IMMUNOSUPPRESSION   CALCINEURIN   KIDNEY   SWITCH   TARGET   RISK  

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： miR-590   Breast cancer   Runx2   ATF3   Proliferation   Apoptosis   EPITHELIAL-MESENCHYMAL TRANSITION   BETA SIGNALING PATHWAY   OSTEOBLAST DIFFERENTIATION   ADAPTIVE-RESPONSE   DOWN-REGULATION   STEM-CELLS   KAPPA-B   RUNX2   BONE   MICRORNA  

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   TUMOR-ASSOCIATED MACROPHAGES   PACLITAXEL CHEMOTHERAPY   CELLS   ATF3   MICROENVIRONMENT   THERAPY   REVEALS   INFLAMMATION   PATHOGENESIS   RESISTANCE  

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   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. [ABSTRACT FROM AUTHOR]