Disease relevance of ATF3

• ATF3 expression was increased by LY294002, followed by the induction of apoptosis in several colorectal cancer cell lines [1].
• The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression [2].
• Here we demonstrated that the mechanism by which the ATF3 mRNA content is increased following amino acid limitation of human HepG2 hepatoma cells is mRNA stabilization [3].
• ATF3 may function as a cell survival factor of endothelial cells during vascular inflammation and atherogenesis [4].
• Nonrandom chromosomal imbalances in esophageal squamous cell carcinoma cell lines: possible involvement of the ATF3 and CENPF genes in the 1q32 amplicon [5].

High impact information on ATF3

• 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 [6].
• A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells [6].
• Thus, ATF3 is a novel stress-activated regulator of p53 protein stability/function providing the cell with a means of responding to a wide range of environmental insult, thus maintaining DNA integrity and protecting against cell transformation [7].
• Activating transcription factor 3 (ATF3) is rapidly induced by diverse environmental insults including genotoxic stress [7].
• In H2O2-stimulated NP31 cells as well as endothelial cells of glomerulus and aorta of Otsuka-Long-Evans-Tokushima-Fatty diabetic model rats, concomitantly enhanced expressions of ATF3, PAI-1, and p8 were observed [8].

Chemical compound and disease context of ATF3

• Previously, our laboratory identified activating transcription factor 3 (ATF3) as up-regulated by nonsteroidal anti-inflammatory drugs using microarray analysis of mRNA from human colorectal cancer cells treated with sulindac sulfide [9].
• Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.Oncogene (2007) 26, 284-289. doi:10.1038/sj.onc.1209781; published online 17 July 2006 [10].
• Because the etiology of hypospadias may include exposure to estrogenic compounds, the responsiveness of ATF3 to estrogen is also discussed [11].
• In this report, we show that ATF3 mRNA and protein expression are up-regulated in HCT-116 human colorectal cancer cells following treatment with NSAIDs, troglitazone, diallyl disulfide, and resveratrol [12].
• The expression of transcription factor activating transcription factor 3 in the human prostate and its regulation by androgen in prostate cancer [13].

Biological context of ATF3

• Genotoxic-stressed ATF3-null mouse embryonic fibroblasts, or cells in which ATF3 was reduced by small interference RNA, show inefficient p53 induction and impaired apoptosis compared with wild-type cells [7].
• ATF3, but not the Delta102-139 protein, binds the p53 carboxy-terminus and diminishes its ubiquitination and nuclear export [7].
• We also found that LY294002 increases ATF3 promoter activity and the transactivation is partly mediated by a GC-rich sequence located in the promoter [1].
• This is consistent with results showing that the down-regulation of the ATF3 gene by small interfering RNA suppressed LY294002-induced apoptosis in HCT-116 cells [1].
• Furthermore, phosphorylated EGR-1 was highly increased in LY294002-treated cells, indicating that EGR-1 phosphorylation induced by LY294002 may facilitate ATF3 transactivation [1].

Anatomical context of ATF3

• 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 [4].
• Treatment of HepG2 cells with thapsigargin, which causes endoplasmic reticulum stress, also increased the half-life of ATF3 mRNA [3].
• In this study, we investigated the functional role of ATF3 in doxorubicin (DOX=adriamycin)-treated neonatal rat cardiac myocytes [14].
• Intravenous infusion of paclitaxel induced a significant increase of ATF3 in mainly but not exclusively large and medium sensory neurons in all sensory ganglia [15].
• ATF3 enhances c-Jun-mediated neurite sprouting [16].

Associations of ATF3 with chemical compounds

• We showed that anisomycin at a low concentration activates the ATF3 promoter and stabilizes the ATF3 mRNA [17].
• Analysis of ATF3 mRNA turnover revealed that the half-life was increased from about 1 h in control cells to greater than 8 h in the histidine-deprived state, demonstrating mRNA stabilization in response to nutrient deprivation [3].
• Both amino acid limitation and activation of the endoplasmic reticulum stress response by glucose deprivation caused an increase in ATF3 mRNA content [18].
• 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 [4].
• A possible mechanism implicating the C-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) stress-inducible signaling pathway in the induction of the ATF3 gene is discussed [17].

Physical interactions of ATF3

• EGR-1 binds to the ATF3 promoter as assessed by gel shift assay [1].
• Immunoprecipitation of HuR-RNA complexes followed by reverse transcriptase-PCR analysis showed that HuR interacted with ATF3 mRNA in vivo and that this interaction increased following amino acid limitation [3].
• We recently reported that ATF3 interacts with the tumor suppressor p53 to increase its stability in the genotoxic response [19].
• The ability of ATF3 to stabilize p53-induced pathways thus represents a means of effectively countering DNA damage caused by environmental insult the latter leading to oncogene activation and ultimately malignant transformation [19].
• 1. LPS stimulation leads to an induction of ATF-3 and JunD factor binding to the CRE/AP-1 site [20].

Regulatory relationships of ATF3

• Thus, ATF3 represses MMP-2 expression by decreasing the trans-activation of this gene by p53 [2].
• The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells [21].
• Suppression of HuR expression by RNA interference partially blocked the accumulation of ATF3 mRNA following amino acid deprivation [3].
• These compounds induced phosphorylation of extracellular signal-regulated kinase1/2 (Erk1/2), whereas a dominant-negative inhibitor of mitogen-activate protein kinase kinase (MEK) 1 blocked the induction of ATF3 [9].
• Interleukin-10 induced activating transcription factor 3 transcriptional suppression of matrix metalloproteinase-2 gene expression in human prostate CPTX-1532 Cells [22].

Other interactions of ATF3

• Collectively, the results provide evidence for a potential role of multiple predicted ATF3 isoforms in the transcriptional regulation of the ASNS gene in response to nutrient deprivation [18].
• Assignment of UCK2, ATF3 and RGS18 from human chromosome 1 to porcine chromosomes 4, 9 and 10 with somatic and radiation hybrid panels [23].
• ATF3 and EGR-1 may provide a novel explanation for the antitumorigenic properties of LY294002 in human colorectal cancer cells [1].
• Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (-1659/-1622) necessary for the ATF3-mediated repression [2].
• Interaction of RNA-binding proteins HuR and AUF1 with the human ATF3 mRNA 3'-untranslated region regulates its amino acid limitation-induced stabilization [3].

Analytical, diagnostic and therapeutic context of ATF3

• Northern blot and nuclear run on assay showed that the transcription of tumor suppressor gene p53 was down-regulated in the ATF3-overexpressing cells [4].
• In contrast, ATF3 dramatically induced Tax-dependent transactivation, which was further enhanced by protein kinase A. Electrophoretic mobility shift assays with recombinant fusion proteins expressed and purified from bacteria indicate that the DNA-binding activity of ATF3 is also dramatically enhanced by Tax [24].
• DNA microarrays identified multiple mRNAs elevated 1.5 hours after suspension and re-adhesion including activation transcription factor 3 (ATF3) [25].
• Flow cytometry analysis and immunostaining analysis with TUNEL assay showed that ATF3/LRF-1 was highly expressed in cell death induced by these agents [26].
• Adenovirus-mediated expression of ATF3 protected cardiomyocytes from DOX-induced apoptosis, as determined by flow cytometry, cell viability, and TUNEL assay [14].

References