Disease relevance of Atf3

• Because ATF3 is a stress-inducible gene, these mice may provide a model to investigate the molecular mechanisms of some stress-associated liver diseases [1].
• In this report, we demonstrate that expression of ATF3 is induced by cardiac ischemia coupled with reperfusion (ischemia-reperfusion) in both cultured cells and an animal model [2].
• The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer [3].
• Topical lysolecithin application causes focal demyelination of afferent nerve A-fibers without axonal loss, as assessed either by electron and light microscopy or by immunohistochemical analysis of dorsal root ganglia (DRG) for a neuronal injury marker, activating transcription factor 3 [4].

High impact information on Atf3

• Surprisingly, the majority of these transcripts were derived from stromal cells rather than the TCR-cross-linked CD4+CD8+TCRlow thymocytes including the macrophage products IL-1, the chemokine Mig and the transcription factor LRG-21 [5].
• Role for activating transcription factor 3 in stress-induced beta-cell apoptosis [6].
• Second, induction of ATF3 is mediated in part by the NF-kappaB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes [6].
• First, ATF3 is induced in beta cells by signals relevant to beta-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate [6].
• These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases [7].

Chemical compound and disease context of Atf3

• The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression [1].
• In this report, we demonstrate that transgenic mice expressing ATF3 in the liver had symptoms of liver dysfunction such as high levels of serum bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bile acids [1].
• The roles of ATF3 in glucose homeostasis. A transgenic mouse model with liver dysfunction and defects in endocrine pancreas [8].
• In this report, we demonstrate that ATF3 is induced in the pancreas by partial pancreatectomy, streptozotocin treatment, and ischemia coupled with reperfusion [8].

Biological context of Atf3

• This domain, when fused to the ATF3 heterologous phosphoacceptor site, can direct its phosphorylation by JNK [9].
• Taken together, our results are consistent with the model that the expression of ATF3 in the liver results in defects in glucose homeostasis by repressing gluconeogenesis [1].
• Furthermore, transient transfection assays indicated that ATF3 repressed the activity of the PEPCK promoter [1].
• A conserved sequence in the promoters of the Atf3 and Gadd45gamma genes contains a CCAAT/enhancer-binding protein (C/EBP) site previously observed in the Gadd45gamma promoter, suggesting a novel corresponding C/EBP site in the Atf3 promoter [10].
• Furthermore, ATF3 is induced in cultured islet cells by oxidative stress [8].

Anatomical context of Atf3

• This is accompanied by increased Atf3 promoter activity in cytochalasin D-treated chondrocytes [11].
• Analyses of embryos indicated that the ATF3 transgene is expressed in the ductal epithelium in the developing pancreas, and the transgenic pancreas has fewer mitotic cells than the non-transgenic counterpart, providing a potential explanation for the reduction of endocrine cells [8].
• Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors [12].
• Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway [7].
• Diabetes-induced expression of activating transcription factor 3 in mouse primary sensory neurons [13].

Associations of Atf3 with chemical compounds

• Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop [12].
• Transcript profiling of immediate early genes reveals a unique role for activating transcription factor 3 in mediating activation of the glycoprotein hormone alpha-subunit promoter by gonadotropin-releasing hormone [14].
• Increased expression of the activating transcription factor 3 by urea was newly detected via expression array and confirmed via immunoblot analysis [15].
• 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 [16].
• Diabetes was induced using streptozotocin in C57BL/6 mice, and ATF3 expression in lumbar dorsal root ganglia was assessed at different time points and correlated with the markers of unmyelinated and myelinated neuronal populations [13].

Regulatory relationships of Atf3

• Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-kappaB binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray [12].
• ATF3 seems to inhibit Il6 and Il12b transcription by altering chromatin structure, thereby restricting access to transcription factors [12].

Other interactions of Atf3

• Nevertheless, ATF3 does not serve as a JNK substrate in vitro or in vivo [9].
• Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) [1].
• ATF3 and Rel (a component of NF-kappaB) were shown to bind to the regulatory regions of these genes upon macrophage activation [12].
• Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 [12].
• Activated Ha-Ras but not TPA induces transcription through binding sites for activating transcription factor 3/Jun and a novel nuclear factor [17].

References