关键词： coxsackievirus B3   ATF3   p53   apoptosis   virus titer  

摘要： Activating transcription factor 3 (ATF3) is an early-induced gene involved in diverse cellular functions in response to various stresses including viral infection. Here we observed marked reduction of ATF3 by coxsackievirus B3 (CVB3) infection and investigated the regulation and functional role of ATF3 in HeLa cells for the understanding of biological significance of ATF3 downregulation. CVB3 infection markedly reduced ATF3 expression at mRNA and protein levels in parallel with p53 degradation, and preservation of p53 expression rescued CVB3 infection-induced ATF3 downregulation. ATF3 overexpression stimulated apoptotic cell death following CVB3 infection, accompanying with augmentation of CVB3 infection-induced eIF2 alpha phosphorylation. However, ATF3 overexpression did not affect viral protein production but promoted virus progeny release. Taken together, our results suggest that ATF3 is under control of p53 in part and that the ATF3 downregulation via p53 degradation may contribute to effective viral production as a modulation mechanism of CVB3 infection-induced cell death. (c) 2007 Elsevier B.V. All rights reserved.

关键词： ATF3   congenital abnormality   endocrine disruption   estradiol   hypospadias  

摘要： Hypospadias is a penile developmental abnormality that may partly result from in utero exposure to estrogenic compounds. Expression of activating transcription factor 3 (ATF3) is elevated in human foreskin tissue from hypospadic patients, and in utero exposure to ethinyl estradiol (17-EE) causes ATF3 upregulation in a hypospadias mouse model. We investigated the effects of in vitro exposure to EE on ATF3 expression and promoter activity in human foreskin fibroblasts using immunocytochemistry, quantitative polymerase chain reaction (PCR), western blot, and the luciferase activity assay. Immunocytochemistry showed peak positive staining at 2 hours after 0.5 to 3 hours of EE treatment (0.1 μM). Western blot showed significantly increased ATF3 protein expression (P = 0.006) after EE exposure. ATF3 mRNA, as evaluated using reverse transcriptase PCR and TaqMan real-time PCR, also increased (P = 0.146). In addition, the luciferase activity assay showed that ATF3 promoter activity was significantly enhanced after 1 hour of EE exposure (P < 0.0001). Thus, EE upregulates ATF3 expression in fibroblasts in vitro, consistent with our previous results with human tissue and in vivo mouse models. ATF3 is involved in the TGF-ß epithelialmesenchymal signaling pathway, and its involvement in hypospadias suggests that ATF3 plays a role in development of this anomaly as a result of exposure to estrogenic compounds. Its potential involvement in other manifestations of developmental endocrine disruption is worth investigating. [ABSTRACT FROM AUTHOR]

关键词： ATF3   ECG   EGCG   EGR-1  

摘要： Epicatechin gallate (ECG) is the third major catechin component in green tea, but it shows strong biological activity in some aspects, including apoptosis, cell growth inhibition, and membrane transport system in various cells. We previously reported that ECG induces activating transcription factor 3 (ATF3), which is involved in pro-apoptosis in HCT-116 cells. In this report, we present a molecular mechanism by which ECG induces ATF3 expression at the transcriptional *** found that Sp3 contributed to the basal expression of the ATF3 gene, whereas EGR-1 played an important role in ECG-induced ATF3 expression in HCT-116 cells, as assessed by EMSA and co-transfection experiments. These results suggested that EGR-1, a tumour suppressor protein, could substantiate ECG's role of ATF3 expression in human colorectal cancer cells. We also found that pro-oxidant activity of ECG contributed to ECG-induced ATF3 expression. (c) 2007 Elsevier Ltd. All rights reserved.

关键词： ATF3   congenital abnon-nality   endocrine   disruption   estradiol   hypospadias  

摘要： Hypospadias is a penile developmental abnormality that may partly result from in utero exposure to estrogenic compounds. Expression of activating transcription factor 3 (ATF3) is elevated in human foreskin tissue from hYpospadic patients, and in utero exposure to ethinyl estradiol (17-EE) causes ATF3 upregulation in a hypospadias mouse model. We investigated the effects of in vitro exposure to EE on ATF3 expression and promoter activity in human foreskin fibroblasts using immunocytochemistry, quantitative polymerase chain reaction (PCR). western blot, and the luciferase activity assay. Immunocytochemistry showed peak positive staining at 2 hours after 0.5 to 3 hours of EE treatment (0.1 mu M). Western blot showed significantly increased ATF3 protein expression (P 0.006) after EE exposure. ATF3 mRNA, as evaluated using reverse transcriptase PCR and TaqMan real-time PCR. also increased (P = 0.146). In addition, the luciferase activity assay showed that ATF3 promoter activity was significantly enhanced after 1 hour of EE exposure (P < 0.0001). Thus, EE upregulates ATF3 expression in fibroblasts in vitro, consistent with our previous results with human tissue and in vivo mouse models. ATF3 is involved in the TGF-beta epithelialmesenchymal signaling pathway, and its involvement in hypospadias suggests that ATF3 plays a role in development of this anomaly as a result of exposure to estrogenic compounds. Its potential involvement in other manifestations of developmental endocrine disruption is worth investigating.

关键词： ATF3   DRG   axon   nerve regeneration   myelin inhibition   growth-associated genes  

摘要： Peripheral axons of dorsal root ganglion (DRG) neurons, but not their central axons in the dorsal columns, regenerate after injury. However, if the neurons are conditioned by a peripheral nerve injury into an actively growing state, the rate of peripheral axonal growth is accelerated and the injured central axons begin to regenerate. The growth-promoting effects of conditioning injuries have two components, increased axonal growth and a reduced response to inhibitory myelin cues. We have examined which transcription factors activated by peripheral axonal injury may mediate the conditioning effect by regulating expression of effectors that increase the intrinsic growth state of the neurons. Activating transcription factor 3 (ATF3) is a prime candidate because it is induced in all injured DRG neurons after peripheral, but not central, axonal damage. To investigate if ATF3 promotes regeneration, we generated transgenic mice that constitutively express this transcription factor in non-injured adult DRG neurons. The rate of peripheral nerve regeneration was enhanced in the transgenic mice to an extent comparable to that produced by a preconditioning nerve injury. The expression of some growth-associated genes, such as SPRR1A, but not others like GAP-43, was increased in the non-injured neurons. ATF3 increased DRG neurite elongation when cultured on permissive substrates but did not overcome the inhibitory effects of myelin or promote central axonal regeneration in the spinal cord in vivo. We conclude that ATF3 contributes to nerve regeneration by increasing the intrinsic growth state of injured neurons.

关键词： transcription factors   hair follicle   p53   cytokeratin   ATF3  

摘要： ATF3 is a highly conserved eukaryotic transcription factor that is ubiquitously upregulated transcriptionally during cellular responses to a variety of stresses, in particular DNA damage. However, the role of ATF3 in the DNA damage response is unclear. Transgenic mice that overexpress human ATF3 in basal epithelial cells under the control of the bovine keratin 5 (K5) promoter were constructed and characterized for epidermal alterations. Strong, nuclear expression of the exogenous ATF3 protein was seen in basal cells of the epidermis, hair follicles, and oral mucosa. Hyperplastic changes in the K5-expressing, outer root sheath (ORS) cells of the hair follicle were observed in young mice, resulting in multiple layers of ORS cells in the mature follicle and large aberrantly shaped follicles. Mild hyperplasia of the interfollicular epidermis was also noted, increasing with age. However, no epidermal tumors were identified in BK5. ATF3 mice observed for 16 mo. At 16 mo of age, most transgenic mice exhibited multi-focal areas of hyperplasia and dysplasia in the oral mucosa, with cellular atypia and underlying acute inflammatory changes. Neoplastic lesions were also seen in the oral cavity of BK5. ATF3 mice, including oral squamous cell carcinoma (60% incidence) and basal cell tumors with follicular differentiation (70% incidence), but not in non-transgenic FVB/N littermates. Heterogeneous nuclear expression (or stabilization) of p53 protein was seen in some oral dysplasias, with a patchy distribution primarily in the least differentiated layers of the lesions. This represents the first indication that ATF3 may have oncogenic properties in epithelial cells. (C) 2007 Wiley-Liss, Inc.

关键词： cardiac hypertrophy   apoptosis   cardiomyocytes  

关键词： ATF3   congenital anomaly   endocrine disruptor   hypospadias   steroid  

摘要： The molecular events that lead to isolated hypospadias remain largely unknown, and the etiology of this common congenital anomaly seems to be multifactorial. We have explored the response of several candidate genes to environmental agents that cause hypospadias in a mouse model. Here, we provide an overview of current findings in relation to candidate genes and their response to environmental agents, including the results of genomic analyses of both mouse and human tissues. In addition to steroid-hormone receptors, one gene of specific interest is activating transcription factor 3 (ATF3). We hypothesize a potential mechanism of action for ATF3 and other identified genes, including TGF-B.

关键词： 转录激活因子3   转录调控   细胞凋亡  

摘要： 转录激活因子3(activating transcription factor3,ATF3)属含亮氨酸拉链结构的转录因子ATF/CREB家族成员,分子量21ku,在大部分正常细胞中呈低浓度稳态表达。ATF3是个应激早期快反应基因,体内外可被一系列损伤性应激信号快速诱导表达。ATF3不仅在应激反应中是个关键性的调控因子,还广泛参与了机体稳态维持、创伤愈合、细胞黏附、肿瘤形成、凋亡以及信号传导等生理和病理过程。ATF3与细胞生存和凋亡有关,但在不同的细胞状态下发挥不同甚至相反的作用。

关键词： lipopolysaccharide   chemokine   gene expression   MIP-1 beta   inflammation  

摘要： Acute expression of macrophage inflammatory protein-1 beta (also known as CCL4) promotes beneficial leukocyte recruitment to infected tissues, but chronic expression of this chemokine contributes to inflammatory disease. CCL4 expression is controlled largely at the transcriptional level and an ATF/CRE sequence located in the promoter (-104 to -97 bp, relative to the transcriptional start site) has been identified as a critical cis-acting element. The trans-acting binding proteins that influence CCL4 transcription via this site are largely unknown. We investigated whether activating transcription factor 3 (ATF3), a member of the ATF/CREB family of transcription factors, binds to the CCL4 ATF/CRE site in macrophages. Using the electrophoretic mobility shift assay and the chromatin immunoprecipitation assay, we found that ATF3 binds to the ATF/CRE site within the CCL4 promoter in untreated and lipopolysaccharide (LPS)-stimulated macrophages. Quantitative RT-PCR analysis showed that CCL4 mRNA levels in elicited peritoneal macrophages from ATF3(-/-) mice are significantly higher than in congenic ATF3(+/+) macrophages under both unstimulated and LPS-stimulated conditions, suggesting that ATF3 represses transcription of the CCL4 gene. Consistent with the higher gene expression, ATF3-deficient macrophages secreted more CCL4 protein than ATF(+/+) macrophages. Similar results were obtained in bone-marrow-derived macrophages treated with Toll-like receptor 2, 3, 4 and 5 agonists. Thus, we conclude that ATF3 constitutively binds to the ATF/CRE site in the CCL4 promoter where it represses basal and pathogen-associated molecular pattern (PAMP)-stimulated transcription. Consequently, ATF3 appears to be part of a control mechanism that limits the amount of CCL4 released by macrophages, preventing excessive inflammation. (c) 2006 Elsevier Ltd. All rights reserved.