摘要： ATF3 (Activating transcription factor 3), a member of the CREB/ATF family, can be induced by stress and growth factors in mammalian cells, and is thought to play an important role in the cardiovascular system. However, little is currently known about how the induction of ATF3 is regulated, except that the JNK pathway is involved. Here, we investigated the differential roles of the MAPK pathways involved in TNFalpha (tumour necrosis factor alpha)-induced ATF3 expression in vascular endothelial cells. In human umbilical vein endothelial cells, the expression of constitutively active MKK7 (MAPK kinase 7) increased the number of ATF3-positive cells, and dominant negative MKK7 suppressed the TNFalpha-induced expression of ATF3, indicating a requirement for the JNK pathway. In contrast, the expression of constitutively active or dominant negative MEK1/2 (MAPK/ERK kinase 1/2) suppressed or enhanced TNFalpha-mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNFalpha. Furthermore, the ERK pathway inhibits the TNFalpha-mediated induction of ATF3 mRNA, but not its stability, suggesting the involvement of ERK activity in the transcriptional regulation of the ATF3 gene. Our results suggest that TNFalpha-induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells.

关键词： c-jun   ATF3   axonal regeneration   neurite   PC12   neuro-2a  

摘要： The AP-1 transcription factor c-Jun is induced in axotomized neurons of the peripheral and central nervous systems, and in both cases upregulation of c-Jun expression has been correlated with axonal regeneration. More recently there has been interest in the c-Jun-related bZIP transcription factor, ATF3, and its function in neurons. ATF3 is also induced in nerve cells in response to axotomy and there is a correlation between increased ATF3 expression and upregulation of c-Jun in surviving neurons. Moreover, c-Jun is able to induce expression of ATF3. We investigated the effect of co-expressing c-Jun and ATF3 in two neuronal-like cell lines to model transcriptional events occurring in axotomized neurons undergoing regeneration. We show that expression of ATF3 with c-Jun significantly enhances c-Jun-mediated neurite sprouting, and that this phenotype is most likely mediated by a physical association of these two transcription factors. Our results suggest that a program of axonal regeneration is initiated when both c-Jun and ATF3 are upregulated in neurons in response to axotomy. (C) 2003 Elsevier B.V. All rights reserved.

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

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.

关键词： ATF3   UVA   c-fos   immediate-early gene   DNA microarray  

摘要： Long-wavelength UV light (UVA) is known to induce transcription of various genes in the cell and to cause a variety of pathological or protective responses in the skin. To find additional UVA-responsive genes, human skin-derived fibroblasts were exposed to UVA under non- or partially lethal conditions, and the effects of UVA on the transcriptional profile were examined by using DNA microarray and RT-PCR. Transcription of several genes including those already known to be UVA-responsive was induced to a significant extent under 50% lethal conditions of exposure. Among those, ATF3 was the most sensitive and its transcription was increased 10-fold within 1 h. Even at a non-lethal dose of UVA (8 J/cm(2)), it was increased 8-fold, if cells were cultured for 3 h post-exposure. Typical immediate-early genes such as c-fos and c-jun were not affected at this dose. We thus suggest that ATF3 could be a key regulator for a variety of cellular responses in the skin, particularly to low doses of UVA. (C) 2003 Elsevier Inc. All rights reserved.