关键词： preprotachykinin   activating transcription factor 3   uninjured primary afferent neurons   infraorbital nerve transection   mechanical allodynia   NEUROPATHIC PAIN   SUBSTANCE-P   DORSAL HORN   INJURY   MODEL   RECEPTOR   NEUROPEPTIDES   DISORDERS   INDUCTION   ATF3  

摘要： An increasing number of studies are suggesting that the adjacent uninjured primary afferents contribute to the mechanisms of neuropathic pain following peripheral nerve injury. In this study, we report that transection of the infraorbital nerve, a major branch of the maxillary nerve, causes exaggerated face grooming to normally innocuous mechanical stimuli in the skin territory of the uninjured mandibular nerve, and increases the expression of preprotachykinin mRNA in the primary afferent neurons in the mandibular zone in the trigeminal ganglia. Considering the various functions of substance P in the sensory transmission process, the increase in preprotachykinin mRNA in the uninjured primary afferent neurons may be one of the mechanisms of pain-related behavior in this neuropathic pain model. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

关键词： ionizing radiation   ATM   NBS   ATF3   ATF-2   NIJMEGEN BREAKAGE SYNDROME   CELL-CYCLE CHECKPOINT   MAMMALIAN UV RESPONSE   DNA-DAMAGE RESPONSE   S-PHASE CHECKPOINT   C-JUN INDUCTION   NF-KAPPA-B   ATAXIA-TELANGIECTASIA   GENOTOXIC STRESS   GROWTH-FACTOR  

摘要： Exposure of human cells to genotoxic agents induces various signaling pathways involved in the execution of stress- and DNA-damage responses. Inappropriate functioning of the DNA-damage response to ionizing radiation (IR) is associated with the human diseases ataxia-telangiectasia (A-T) and Nijmegen Breakage syndrome (NBS). Here, we show that IR efficiently induces Jun/ATF transcription factor activity in normal human diploid fibroblasts, but not in fibroblasts derived from A-T and NBS patients. IR was found to enhance the expression of c-Jun and, in particular, ATF3, but, in contrast to various other stress stimuli, did not induce the expression of c-Fos. Using specific inhibitors, we found that the ATM- and Nibrin1-dependent activation of ATF3 does neither require p53 nor reactive oxygen species, but is dependent on the p38 and JNK MAPkinases. Via these kinases, IR activates ATF-2, one of the transcription factors acting on the atf3 promoter. The activation of ATF-2 by IR resembles ATF-2 activation by certain growth factors, since IR mainly induced the second step of ATF-2 phosphorylation via the stress-inducible MAPkinases, phosphorylation of Thr69. As IR does not enhance ATF-2 phosphorylation in ATM and Nibrin1-deficient cells, both ATF-2 and ATF3 seem to play an important role in the protective response of human cells to IR.

关键词： nerve regeneration   neurite elongation   cell death   ATF   c-Jun   motor neuron   HEAT-SHOCK-PROTEIN   NERVE-INJURY   SYMPATHETIC NEURONS   CELL-DEATH   RECOMBINANT ADENOVIRUS   REPRESSOR ATF3/LRF1   CRE RECOMBINASE   UP-REGULATION   SURVIVAL   ATF3  

摘要： Activating transcription factor 3 (ATF3) is induced and functions both as a cellular response to stress and to stimulate proliferation in multiple tissues. However, in the nervous system ATF3 is expressed only in injured neurons. Here we reveal a function of ATF3 in neurons under death stress. Overexpression of ATF3 by adenovirus inhibits the mitogen-activated kinase kinase kinase 1 (MEKK1)-c-jun N-Terminal Kinase (JNK)-induced apoptosis and induces neurite elongation via Akt activation in PC 12 cells and superior nerve ganglion neurons. A DNA microarray study reveals that ATF3 expression and JNK activation induce expression of the heat shock protein 27 (Hsp27). Immunoprecipitation analysis and promoter assay for Hsp27 expression suggest that both ATF3 and c-Jun are necessary for transcriptional activation of Hsp27. Hsp27 expression significantly inhibits JNK-induced apoptosis as well as Akt activation in PC 12 cells and superior cervical ganglion neurons. We conclude that the combination of ATF3 and c-Jun induces the anti-apoptotic factor Hsp27, which directly or indirectly activates Akt, and thereby possibly inhibits apoptosis and induces nerve elongation. Our results suggest that ATF3- and c-jun-induced Hsp27 expression is a novel survival response in neurons under death stress such as nerve injury.

关键词： BREAST-CANCER CELLS   MICE LACKING SMAD3   RNA EXPORT FACTOR   GROWTH-FACTOR   DNA-BINDING   C-JUN   PROTEINS   GENE   MYC   DISTINCT  

摘要： Genome-wide transcriptional profiling of human epithelial cells revealed that repression of Id inhibitors of differentiation (Id1, Id2, and Id3) is a general feature of the TGFbeta cytostatic program. Opposite responses of Id1 to TGFbeta and the related factor BMP are dictated by the specific ability of the TGFbeta mediator, Smad3, to activate expression of stress response factor ATF3 and then recruit this factor to the Id1 promoter. Thus, a Smad3-mediated primary gene response, ATF3 induction, enables Smad3 to participate in an ATF3-mediated, secondary gene response. As a common target of TGFbeta/Smad signals and stress signals via p38 kinase, ATF3 additionally serves to channel synergy between these pathways in the response of epithelial cells to stress and injury.

关键词： neurotrophic factor   apoptosis   caspase 3   ATF3   ALS   GROWTH-FACTOR RECEPTOR   PROGRAMMED CELL-DEATH   MOTOR-NEURON DEATH   MESSENGER-RNA   PERIPHERAL-NERVES   DISEASE ONSET   SCHWANN-CELLS   C-JUN   MICE   CORD  

摘要： Amyotrophic lateral sclerosis is a lethal neurodegenerative disorder involving motoneuron loss in the cortex, brainstem and spinal cord, resulting in progressive paralysis. Aberrant neurotrophin signalling via the low affinity neurotrophin receptor p75 has been suggested to be involved in the motoneuron death by the activation of apoptotic pathways. In order to investigate the involvement of neurotrophin receptor p75 in the amyotrophic lateral sclerosis related motoneuron degeneration process, we have studied the expression of this receptor in the spinal cord of transgenic mice carrying a mutated human Cu, Zn superoxide dismutase gene. Mutations in the superoxide dismutase gene are one of the genetic causes for familiar amyotrophic lateras sclerosis and human superoxide dismutase-1 transgenic mice develop symptoms and pathology similar to those in human amyotrophic lateras sclerosis. Our study shows that in these mice, spinal motoneurons, which normally do not contain the neurotrophin receptor p75 receptor, express this receptor during the progress of the disease. Expression of the neurotrophin receptor p75 receptor coincides with the expression of activating transcription factor 3, a member of the activating transcription factor/cyclic AMP family of stress transcription factors. Only a minority of these spinal motoneurons actually showed co-expression of neurotrophin receptor p75 with caspase-3 activity, suggesting that expression of the neurotrophin receptor p75 receptor is not directly related to the execution phase of the apoptosis process. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.

关键词： Ataxia telangiectasia (A-T)   ATF-2   ATF3   Nijmegen breakage syndrome (NBS)   X-ray  

摘要： Exposure of human cells to genotoxic agents activates various signaling pathways involved in the execution of stress- and DNA-damage responses. Inappropriate functioning of the DNA-damage response to ionizing radiation is responsible for the human diseases ataxia telangiectasia (A-T) and Nijmegen breakage syndrome (NBS). Here, we show that ionizing radiation efficiently induces Jun/ATF transcription factor activity in normal human diploid fibroblasts, but not in fibroblasts derived from A-T and NBS patients. In normal cells, ionizing radiation was found to enhance the expression of c-Jun and, in particular ATF3, but in contrast to various other stress stimuli, ionizing radiation did not induce the expression of c-Fos and Fra1. Using specific inhibitors, we found that the ATM- and NBS-dependent activation of ATF3 does not require either p53 or reactive oxygen species, but is dependent on the p38 and JNK MAP kinases. Via these kinases, ionizing radiation activates ATF-2, one of the transcription factors acting on the atf3 promoter. As ionizing radiation does not activate ATF-2 phosphorylation in ATM- and NBS-deficient cells, both ATF-2 and ATF3 may play an important role in the protective response of human cells to ionizing radiation. © 2003, Elsevier B.V.

关键词： ATF3   p53   DNA damage   gene regulation   TRANSCRIPTION FACTOR   MOLECULAR-BIOLOGY   C-FOS   P53   GADD45   GENE   CYCLE   ACTIVATION   INHIBITOR   STRESS  

摘要： Mammalian cells have a remarkable diverse repertoire of response to genotoxic stress that damage DNA. Cellular responses to DNA damaging agents will initially exhibit gene induction, which is regulated by complex mechanism(s) and probably involves multiple signaling pathways. In this paper, we demonstrate that induction of ATF3 protein, a member of the ATF/CREB family of transcription factors, by ionizing radiation (IR) requires normal cellular p53 function. In contrast, induction of ATF3 after UV radiation (UV) or Methyl methanesulphonate (MMS) is independent of p53 status. Induction of ATF3 by DNA damage is rapid, transient, and through a transcriptional mechanism. The ATF3 promoter is induced by UV and MMS, but not by IR. In addition, ATF3 promoter can be activated by MEKK1, an upstream activator of the ERK and JNK kinase pathway, but not induced following p53 expression. Those results indicate that regulation of ATF3 induction after DNA damage utilizes both the p53-dependent and independent pathways, and may also involve MAP kinase signaling pathways. Using the tetracycline-inducible system (tet-off), we have found that overexpression of ATF3 protein moderately suppresses cell growth. Interestingly, over-expression of ATF3 protein is able to slow down progression of cells from G1 to S phase, indicating that ATF3 protein might play a negative role in the control of cell cycle progression.

关键词： ATF3   transcriptional repressor   stress response   p53   target gene   promoter element   DNA binding   WILD-TYPE   BINDING PROTEIN   CELL-CYCLE   EXPRESSION   IDENTIFICATION   SEQUENCE   GROWTH   SUPPRESSION   FIBROBLASTS   RESPONSES  

摘要： . Activating transcription, factor 3 (ATF3) is an immediate early response gene that is induced in cells exposed to a variety of stress stimuli. In this report, upon exposure of cells to ultraviolet (UV) or proteasome inhibitor NIG132, ATF3 protein was induced more efficiently in cells with intact p53 allele than in those with null mutant p53 allele. In Saos-2 cells harboring the temperature-sensitive mutant p53(Val-138), the expression of ATF3 gene was more significant at permissive temperature of 32.5degreesC than at non-permissive 37.5degreesC. Reporter assay of the human ATF3 gene promoter identified two p53-responsive elements at -379 to -370 and -351 to -342 from the transcriptional start site. These elements were capable of conferring p53 responsiveness to a heterologous promoter and specifically bound p53 protein in electrophoretic mobility shift assay. Furthermore, ATF3 gene promoter was more significantly activated by UV in cells with wild p53 allele. These results clearly show that the human ATF3 gene is one of the target genes directly activated by p53 and may suggest a functional link between stress-inducible transcriptional repressor ATF3 and p53. (C) 2002 Elsevier Science (USA). All rights reserved.

关键词： NF-KAPPA-B   C-JUN   AP-1 REPRESSOR   IN-VIVO   EXPRESSION   ATF3   PROMOTER   BINDING   DEATH   INDUCTION  

摘要： Activating transcription factor 3 (ATF3) is a transcriptional repressor that is rapidly induced in cells exposed to a wide range of stress stimuli. To clarify the role of ATF3 in determining cell fate, we overexpressed it in human umbilical vein endothelial cells (HUVECs) by adenovirus-mediated gene transfer. ATF3 protected these cells from tumor necrosis factor (TNF)-alpha-induced apoptosis, as measured by flow cytometric analysis, trypan blue exclusion assay, and cleavage of procaspase 3 and poly(ADP-ribose) polymerase. Northern blot and nuclear run on assay showed that the transcription of tumor suppressor gene p53 was down-regulated in the ATF3-overexpressing cells. In the transient expression assay, ATF3 suppressed the p53 gene promoter activity through its specific binding to an atypical AP-1 element, PF-1 site, in the p53 gene promoter. Furthermore, the cell-protecting effect of ATF3 was remarkably reduced in p53-deficient cells. These results demonstrate that overexpression of ATF3 suppresses TNF-alpha-induced cell death of HUVECs, at least in part, through down-regulating the transcription of p53 gene. ATF3 may function as a cell survival factor of endothelial cells during vascular inflammation and atherogenesis.

关键词： apoptosis   doxorubicin   cardiac myocytes   MAPK   ATF3   p53   ACTIVATED PROTEIN-KINASES   TRANSCRIPTIONAL REPRESSOR ATF3   HYPOXIA-INDUCED APOPTOSIS   STRESS-INDUCIBLE GENE   C-JUN   MEDIATED APOPTOSIS   CARDIOVASCULAR-DISEASE   REPERFUSION INJURY   CELLS   P53  

摘要： Activating transcription factor (ATF) 3, a member of the ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors, is induced by a wide range of stress stimuli. Although the ATF3 homodimer is known to repress transcription of several genes, its precise biological roles are still unclear. In this study. we investigated the functional role of ATF3 in doxorubicin (DOX = adriamycin)-treated neonatal rat cardiac myocytes. DOX rapidly activated JNK and c-Jun and induced ATF3 at both mRNA and protein level. Adenovirus-mediated expression of ATF3 protected cardiomyocytes from DOX-induced apoptosis, as determined by flow cytometry, cell viability, and TUNEL assay. It was further shown that p53, one of the apoptosis-inducing transcription factors, was down-regulated in the ATF3-overexpressing cardiomyocytes. These results strongly suggest that ATF3 may function as a cytoprotective transcription factor in DOX-treated cardiac myocytes, at least in part, owing to downregulation of p53. ATF3 may be a novel therapeutic target that protects cardiac myocytes from DOX-induced apoptosis. (C) 2002 Published by Elsevier Science Ltd.