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   DRG   axon   nerve regeneration   myelin inhibition   growth-associated genes   DORSAL-ROOT GANGLION   MYELIN-ASSOCIATED GLYCOPROTEIN   CHONDROITIN SULFATE PROTEOGLYCANS   PROMOTES NEURITE OUTGROWTH   PRIMARY SENSORY NEURONS   RECEPTOR FAMILY-MEMBER   AXONAL REGENERATION   C-JUN   TRANSCRIPTION FACTOR   CONDITIONING LESION  

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： axotomy   middle and inferior cervical ganglia   nerve injury   superior cervical ganglion   sympathetic ganglia   EXPRESSION   ATF3   INJURY   GENES   JUN  

摘要： Activating transcription factor 3 (ATF3) has been proposed as a marker for injured neurons. Thus, while undetectable normally in sensory, motor, or sympathetic neurons, ATF3-like immunoreactivity (ATF3-IR) is readily detectable in such cells after axotomy. Here we examined ATF3-IR in the superior cervical ganglion (SCG) and the middle and inferior cervical ganglia (MICG) after transection of the predominantly preganglionic cervical sympathetic trunk (CST). The purpose of the study was to determine whether neurons in the SCG would exhibit ATF3-IR after decentralization and, if they did not, whether the induction of ATF3-IR was sensitive enough to identify the small numbers of neurons in the SCG and MICG that project their axons into the CST. Following transection of the CST, the majority of deafferented neurons in the SCG showed no ATF3-IR; however, a small group of neurons in both the SCG and MICG were labeled, and the location of the labeled neurons within these ganglia corresponded to that of neurons axotomized by this procedure. Furthermore, the ATF3-positive neurons in the MICG could be retrogradely labeled from the transected CST. In addition, a large number of smaller cells were labeled in the SCG, though not in the MICG, and some of these cells were double labeled with an antiserum to the glial protein S-100. These data indicate that, after transection of the CST, neuronal labeling in the SCG and MICG is restricted to axotomized neurons but that in addition there is extensive labeling of glial cells associated with anterograde degeneration within the SCG. (C) 2007 Elsevier B.V. All rights reserved.

关键词： transcription factors   hair follicle   p53   cytokeratin   ATF3   TGF-BETA   HAIR-FOLLICLES   STEM-CELLS   SKIN   GENE   P53   EXPRESSION   TRANSACTIVATION   DIFFERENTIATION   CARCINOGENESIS  

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   ACTIVATING TRANSCRIPTION FACTOR-3   EXTERNAL GENITALIA   ATF3 INDUCTION   EXPRESSION   ESTROGEN   CYR61   RECEPTOR   CELLS   DISRUPTION   EPITHELIUM  

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   NF-KAPPA-B   INFLAMMATORY PROTEIN-1-BETA   GENE-EXPRESSION   INDUCTION   CELLS   LIPOPOLYSACCHARIDE   MIP-1-BETA   FAMILY   PROGENITOR   CYTOKINES  

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.

关键词： activating transcription factor 3 (ATF3)   mitogen activated protein kinase (MAPK)   MAPK kinase (MKK)   p38   stress kinase   stress response   VASCULAR ENDOTHELIAL-CELLS   JUN NH2-TERMINAL KINASE   C-JUN   TRANSCRIPTION FACTOR-3   MAP KINASE   STRESS   INHIBITOR   APOPTOSIS   PHOSPHORYLATION   INDUCTION  

摘要： ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an 'adaptive response' gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1 beta (interleukin 1 beta), TNF alpha (tumour necrosis factor alpha) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.

关键词： amino acid response element (AARE)   amino acid-sensing   activating transcription factor 3 (ATF3)   CCAAT/enhancer-binding protein (C/EBP)   histone acetylation   transcription regulation   ASPARAGINE SYNTHETASE GENE   UNFOLDED PROTEIN RESPONSE   STRESS-RESPONSE   MAMMALIAN-CELLS   NUTRITIONAL CONTROL   EXPRESSION   RNA   BINDING   DEPRIVATION   PROMOTER  

摘要： Expression of ATF3 (activating transcription factor 3) is induced by a variety of environmental stress conditions, including nutrient limitation. In the present study, we demonstrate that the increase in ATF3 mRNA content following amino acid limitation of human HepG2 hepatoma cells is dependent on transcriptional activation of the ATF3 gene, through a highly coordinated amino acid-responsive programme of transcription factor synthesis and action. Studies using transient overexpression and knockout fibroblasts showed that several ATF and C/EBP (CCAAT/enhancer-binding protein) family members contribute to ATF3 regulation. Promoter analysis showed that a C/EBP-ATF composite site at -23 to -15 bp relative to the transcription start site of the ATF3 gene functions as an AARE (amino acid response element). Chromatin immunoprecipitation demonstrated that amino acid limitation increased ATF4, ATF3, and C/EBP beta binding to the ATF3 promoter, but the kinetics of each was markedly different. Immediately following histidine removal, there was a rapid increase in histone H3 acetylation prior to an enhancement in ATF4 binding and in histone H4 acetylation. These latter changes closely paralleled the initial increase in RNA pol II (RNA polymerase II) binding to the promoter and in the transcription rate from the ATF3 gene. The increase in ATF3 and C/EBP beta binding was considerably slower and more closely correlated with a decline in transcription rate. A comparison of the recruitment patterns between ATF and C/EBP transcription factors and RNA polymerase II at the AARE of several amino acid-responsive genes revealed that a highly co-ordinated response programme controls the transcriptional activation of these genes following amino acid limitation.