关键词： ATF3 gene   HT29 colon cancer cells   cell migration   cell form  

摘要： We formally reported that ATF3 gene regulated HT29 colon cancer cell metastasis through cell adhesion and invasion. We report here our findings that, on wound filling assay, the ATF3 antisense oligonucleotide changed cell form to a rounder shape and suppressed the cell migration ability of HT29, although FACScan analysis showed that it had no effect on the cell cycle. The growing area of HT29 cells treated with the antisense oligonucleotide decreased, compared with that treated with the sense oligonucleotide. These factors were thought to relate to adhesion and invasion of HT29 cells, hence they influenced metastatic potential.

关键词： ATF3 gene   metastasis   gene expression  

摘要： TI-241 (ATF3 homologue gene) is a metastasis-associated gene that is expressed at higher levels in the high-metastatic mouse B16 melanoma subline B16-FIO than in the low-metastatic clone F1. We studied ATF3 expression in established cell lines of human colon and stomach cancer and surgically excised human colon cancer. ATF3 was expressed at higher levels in the cell lines that were established from metastatic sites than in those from original tumor sites. Also ATF3 was expressed at higher levels in tumor specimens than in adjacent normal mucosa, especially in the tumors that had invaded the lymphatic ducts and/or the vessels, while there was not a significant relationship between its expression and the other pathological features. As metastasis is the most important factor in determining prognosis, these results show the potential for ATF3 in making the prognosis.

关键词： ATF3   stress responses   transcription factors   ATF/CREB  

摘要： The purpose of this review is to discuss ATF3, a member of the ATF/CREB family of transcription factors, and its roles in stress responses. In the introduction, we briefly describe the ATF/CREB family, which contains more than 10 proteins with the basic region-leucine zipper (bZip) DNA binding domain. We summarize their DNA binding and heterodimer formation with other bZip proteins, and discuss the nomenclature of these proteins. Over the years, identical or homologous cDNA clones have been isolated by different laboratories and given different names. We group these proteins into subgroups according to their amino acid similarity;we also list the alternative names for each member, and clarify some potential confusion in the nomenclature of this family of proteins. We then focus on ATF3 and its potential roles in stress responses. We review the evidence that the mRNA level of ATF3 greatly increases when the cells are exposed to stress signals. In animal experiments, the signals include ischemia, ischemia coupled with reperfusion, wounding, axotomy, toxicity, and seizure;in cultured cells, the signals include serum factors, cytokines, genotoxic agents, cell death-inducing agents, and the adenoviral protein E1A. Despite the overwhelming evidence for its induction by stress signals, not much else is known about ATF3. Preliminary results suggest that the JNK/SAPK pathway is involved in the induction of ATF3 by stress signals;in addition, IL-6 and p53 have been demonstrated to be required for the induction of ATF3 under certain conditions. The consequences of inducing ATF3 during stress responses are not clear. Transient transfection and in vitro transcription assays indicate that ATF3 represses transcription as a homodimer;however, ATF3 can activate transcription when coexpressed with its heterodimeric partners or other proteins. Therefore, it is possible that, when induced during stress responses, ATF3 activates some target genes but represses others, depending on the p

摘要： Recently, we demonstrated that the function of ATF3, a stress-inducible transcriptional repressor, is negatively regulated by a bZip protein, gadd153/Chop10. In this report, we present evidence that ATF3 can repress the expression of its own inhibitor, gadd153/Chop10. First, ATF3 represses a chloramphenicol acetyltransferase reporter gene driven by the gadd153/Chop10 promoter when assayed by a transfection assay in vivo and a transcription assay in vitro, Second, the gadd153/Chop10 promoter contains two functionally important binding sites for ATF3: an AP-1 site and a C/EBP-ATF composite site, a previously unidentified binding site for ATF3, The absence of either site reduces the ability of ATF3 to repress the promoter, Third, overexpression of ATF3 by transient transfection results in a reduction of the endogenous gadd153/Chop10 mRNA level. Fourth, as described previously, ATM is induced in the liver upon CCl4 treatment. Intriguingly, we show in this report that gadd153/Chop10 mRNA is not present in areas where ATF3 is induced, Taken together, these results strongly suggest that ATF3 represses the expression of gadd153/Chop10. The mutual negative regulation between ATF3 and gadd153/Chop10 is discussed.

摘要： We have previously identified a 20-bp sequence that mediates induced transcription in response to EGF, Ras, and Raf but not after TPA or UV stimulation, This composite response element, present in a long terminal repeat of a member within the VL30 family of retrotransposons, contains an AP-l-like site that cooperates in function with a juxtaposed sequence unrelated to known transcription factor-binding sites, Using in vitro translated proteins, we here demonstrate that the AP-l-like site preferentially binds ATF3/c-Jun and ATF3/JunD heterodimers, Results from a functional analysis indicate that the ATF3/c-Jun heterodimer, together with factors interacting with the 3' element, are most likely the important mediators of the response because overexpression of JunD, alone or in combination with ATF3, abolishes Ras-induced transcription, Partial purification by phosphocellulose and DNA-affinity chromatography in combination with Southwestern analyses reveals a 52-kDa protein that specifically binds to the sequence juxtaposed to the AP-l-like site, Scatchard analyses show that this sequence, TTAGTTAC, forms two different complexes with K(d)s of 1.9 x 10(-10) and 2.3 x 10(-9) M, respectively, Together, these results suggest that EGF/Ras/Raf induces transcription via combined activation of ATF3/c-Jun and a 52-kDa nuclear factor, whereas JunD acts as a repressor of this response.

摘要： Recently, we demonstrated that the liver's response to stress signals entails a cascade of regulation of gene expression. One transcription factor involved in this regulation is the basic region-leucine zipper (bZip) protein, Activating Transcription Factor 3 (ATF3). In contrast to its name, ATF3 is a transcriptional repressor rather than an activator. We discovered that ATF3 is induced in the liver by toxic agents such as acetaminophen, alcohol, and carbon tetrachloride. In addition, ATF3 is induced by stress signals in other tissues such as the heart, brain and kidney. Preliminary results suggest that this induction, at least in part, is due to the activation of ihe stress-inducible JNK/SAPK signal transdtiction pathway. Significantly, the expression of ATF3 correlates with cell injury and cell death. Furthermore, ATF3 is involved in a complicated interplay with another bZip prtoein, gadd153/ChoplO, in the liver upon exposure to stress signals. In light of the correlation between the expression of ATF3 and cell death, we generated transgenic flies that express human ATF3 in various regions of the fly during different stages of fly development using specific GAL4 drivers. Preliminary results indicate that over-expression of ATF3 in early embryonic stages results in a high incidence of embryonic lethality, suggesting that ATF3 may contribute to cell death. Therefore, ATF3 provides a handle to study signal transduction pathways, alteration of gene expression and the molecular basis for cell death induced by stress signals. (This work is supported by an NfH grant given to T. Hai.).

关键词： IFN gamma   IL-4   LRF-1   ATF3   c-Jun   c-Fos  

摘要： To study macrophage genes activated by lipopolysaccharide (LPS) we have constructed a cDNA library using the mouse macrophage cell line, RAW 264.7. By differential screening, a gene, designated LRG-21, was identified that showed nucleic acid sequence homology to rat liver regenerating factor-1 (LRF-1) and human activating transcription factor-3 (ATF3). Both LRG-21 and LRF-1 are transcribed within an hour following stimulation and in the absence of protein synthesis. The predicted protein sequence of LRG-21 consists of 181 amino acids with a molecular weight of 20.7 kDa. All three sequences contain basic and leucine zipper regions characteristic of the c-Fos and c-Jun family of transcription factors, but the remainder of the sequences are unrelated to this family. Recombinant LRG-21 has been shown to bind to a phorbol ester promoter element. Additional experiments have shown that LRG-21 is also induced by interferon-gamma (IFN-gamma) and by interleukin-4 (IL-4) in both RAW264.7 cells and murine peritoneal macrophages. Based on these observations, it is likely that LRG-21 plays an important role in macrophage activation. Copyright (C) 1996 Elsevier Science Ltd

关键词： LRF1   ATF   cJun   E1A  

摘要： The adenovirus (Ad) E1A proteins alter the expression level and activity of AP-1/ATF transcription factors. Previously we have shown that in AdE1-transformed cells cJun is hyperphosphorylated in its N-terminal transactivation domain, which parallels enhanced transactivation function. To find out whether the interaction between cJun and other cellular proteins is altered, we have searched for proteins which would physically associate with cJun. In this report we show that in AdE1-transformed cells cJun specifically associates with two proteins of 21 and 23 kD. These proteins are not expressed at detectable levels in the parental cells or in cells transformed by oncogenes other than AdE1. The cJun-associated proteins represent different forms of the bZIP transcription factor ATF3, the human homolog of rat LRF1. The expression of ATF3 is induced in AdE1-transformed cells and is a direct effect of the expression of E1A. Through induction of ATF3 expression and the subsequent formation of cJun/ATF3 heterodimers, E1A alters the repertoire of AP-1/ATF factors and may thereby redirect the corresponding gene-expression program. Since the induction of ATF3 is a function of sequences within the transforming 12S-E1A protein, cJun/ATF3 complexes might be involved in establishing cellular transformation by AdE1A.