scholarly journals Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity

2021 ◽  
Vol 22 (21) ◽  
pp. 11400
Author(s):  
Chiung-Min Wang ◽  
William Harry Yang ◽  
Leticia Cardoso ◽  
Ninoska Gutierrez ◽  
Richard Henry Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Stress ◽  
Tumor Development ◽  
Cellular Stress Response ◽  
Luciferase Reporter ◽  
Activating Transcription Factor 3 ◽  
Post Translational Modifications ◽  
Complex Processes ◽  
Activating Transcription Factor ◽  
Atf3 Expression

Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X chromosome, is a novel transcriptional repressor for several oncogenes. However, it remains unknown whether ATF3 is the target protein of FOXP3. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. Firstly, we observed that overexpression of FOXP3 reduced ATF3 protein level. Moreover, knockdown FOXP3 by siRNA increased ATF3 expression. Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in the luciferase reporter assay. Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) significantly abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, the FOXP3 binding site was found on ATF3 promoter region by deletion and mutagenesis analysis. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and that this novel event may be involved in tumor development and progression.

scholarly journals Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

2008 ◽  
Vol 158 (5) ◽  
pp. 729-739 ◽  
Author(s):  
Ana Beleza-Meireles ◽  
Virpi Töhönen ◽  
Cilla Söderhäll ◽  
Christian Schwentner ◽  
Christian Radmayr ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mutation Screening ◽  
Activating Transcription Factor 3 ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Genital Development ◽  
Responsive Gene ◽  
Activating Transcription Factor ◽  
Atf3 Expression ◽  
Transcription Factor 3

IntroductionHypospadias is a common inborn error of the genital development, whose complex etiology remains elusive. Defects of the androgen metabolism and activity have been found in a subset of boys with hypospadias. Moreover, the balance between androgens and estrogens seems to be important to the proper male genital development. Activating transcription factor 3 (ATF3), an estrogen responsive gene, has been reported to be expressed during sexual development and up-regulated in hypospadic genital skin. We investigated ATF3 as a candidate gene for hypospadias.Material and methodsGenotyping of eight-tagged single nucleotide polymorphisms (SNP)s was performed in 330 boys with hypospadias and in 380 healthy controls. Screening for mutations in ATF3 was conducted in a subset of boys with hypospadias. ATF3 expression was evaluated in the foreskin of boys with hypospadias and in healthy controls and in the human fetal genitalia by immunohistochemistry.ResultsThree common SNPs, spanning a region of about 16 kb in intron 1 of ATF3, are associated with hypospadias. These SNPs are not linked and their effects are independent. The combination of the three risk SNPs yields the highest significance. Mutation screening identified the gene variant c536A>G in one patient and c817C>T in the 3′-UTR in two other patients. ATF3 expression was evidenced in the developing male urethra.ConclusionsATF3 gene variants influence the risk of hypospadias. Its hormonal responsiveness may underlie this risk effect. But also other ATF3-dependent biological aspects, such as cell survival and death, response to stress stimuli, or the control of epithelial–mesenchymal interactions, may be of importance.

Abstract P795: Activating Transcription Factor 3 Improves Stroke Recovery Through Reduction of Neuronal Damage and Neuroinflammation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Zhanqiang Wang ◽  
Peipei Pan ◽  
Rich Liang ◽  
Qifeng Li ◽  
Janothon Pan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Ischemic Stroke ◽  
Neuronal Damage ◽  
Stroke Recovery ◽  
Activating Transcription Factor 3 ◽  
Double Labeling ◽  
Activating Transcription Factor ◽  
Adhesive Removal ◽  
Atf3 Expression ◽  
Transcription Factor 3

Background and Purpose: Activating transcription factor 3 (ATF3), a member of the ATF/CREB family, is upregulated in the early phase of various stresses including ischemic stroke. The role of ATF3 in ischemic stroke injury has not been fully elucidated. Hypothesis: ATF3 improves stroke outcomes through reduction of neuronal damage and neuroinflammation. Methods: Permanent distal middle cerebral artery occlusion (pMCAO) was performed in 8-week-old male and female C57BL/6J (WT) and ATF3 knockout (ATF3 -/- ) mice. The sensorimotor functions were analyzed 3 days after pMCAO through adhesive removal and corner tests. Infarct volumes and injured neurons were quantified on Nissl stained and Fluoro-Jade C (FJC) stained sections. The cell-specific expression of ATF3 was analyzed by co-staining ATF3 antibody with antibodies specific to NeuN (Neuron), CD68 (microglia/macrophage) and GFAP (astrocyte). The expression of ATF3 in injured neurons was analyzed by ATF3 and FJC double labeling. Results: ATF3 expression was detected exclusively in neurons in the infarct area 1 day after pMCAO. There were a few ATF3 + CD68 + microglia/macrophages at the peri-infarct regions 2 and 3 days after pMCAO. Almost all FJC + neurons were ATF3 positive. No ATF3 expression was detected in astrocytes. Compared to WT mice, ATF3 -/- mice took longer time to remove the adhesive from their right paws (p<0.001) in adhesive removal test and more left turns in corner test (p<0.001) 3 days after pMCAO. ATF3 -/- mice also had a larger infarct volume (p = 0.014), more FJC + neurons (p=0.002) and CD68 + microglia/macrophages (p=0.003) in the peri-infarct regions than WT mice. Conclusions: Deletion of ATF3 exacerbates neuronal injury, neuroinflammation, and sensorimotor dysfunction in stroke mice, suggesting that upregulation of ATF3 at early stage of stroke improves ischemic stroke recovery through reduction of neuronal damage and neuroinflammation.

scholarly journals Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity

2020 ◽  
Vol 21 (4) ◽  
pp. 1429
Author(s):  
Natsuko Emura ◽  
Chiung-Min Wang ◽  
William Harry Yang ◽  
Wei-Hsiung Yang
Keyword(s):  
Site Directed Mutagenesis ◽  
Activating Transcription Factor 3 ◽  
Dependent Manner ◽  
Orphan Nuclear Receptor ◽  
Steroidogenic Factor 1 ◽  
Post Translational Modifications ◽  
Endocrine Organs ◽  
Activating Transcription Factor ◽  
Dose Dependent ◽  
Atf3 Expression

Steroidogenic Factor 1 (SF-1/NR5A1), an orphan nuclear receptor, is important for sexual differentiation and the development of multiple endocrine organs, as well as cell proliferation in cancer cells. Activating transcription factor 3 (ATF3) is a transcriptional repressor, and its expression is rapidly induced by DNA damage and oncogenic stimuli. Since both NR5A1 and ATF3 can regulate and cooperate with several transcription factors, we hypothesized that NR5A1 may interact with ATF3 and plays a functional role in cancer development. First, we found that NR5A1 physically interacts with ATF3. We further demonstrated that ATF3 expression is up-regulated by NR5A1. Moreover, the promoter activity of the ATF3 is activated by NR5A1 in a dose-dependent manner in several cell lines. By mapping the ATF3 promoter as well as the site-directed mutagenesis analysis, we provide evidence that NR5A1 response elements (−695 bp and −665 bp) are required for ATF3 expression by NR5A1. It is well known that the transcriptional activities of NR5A1 are modulated by post-translational modifications, such as small ubiquitin-related modifier (SUMO) modification and phosphorylation. Notably, we found that both SUMOylation and phosphorylation of NR5A1 play roles, at least in part, for NR5A1-mediated ATF3 expression. Overall, our results provide the first evidence of a novel relationship between NR5A1 and ATF3.

scholarly journals ASBEL–TCF3 complex is required for the tumorigenicity of colorectal cancer cells

2016 ◽  
Vol 113 (45) ◽  
pp. 12739-12744 ◽  
Author(s):  
Kenzui Taniue ◽  
Akiko Kurimoto ◽  
Yasuko Takeda ◽  
Takeshi Nagashima ◽  
Mariko Okada-Hatakeyama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Noncoding Rna ◽  
Cancer Development ◽  
Activating Transcription Factor 3 ◽  
Colorectal Cancer Cells ◽  
Activating Transcription Factor ◽  
Atf3 Expression ◽  
Transcription Factor 3

Wnt/β-catenin signaling plays a key role in the tumorigenicity of colon cancer. Furthermore, it has been reported that lncRNAs are dysregulated in several steps of cancer development. Here we show that β-catenin directly activates the transcription of the long noncoding RNA (lncRNA) ASBEL [antisense ncRNA in the ANA (Abundant in neuroepithelium area)/BTG3 (B-cell translocation gene 3) locus] and transcription factor 3 (TCF3), both of which are required for the survival and tumorigenicity of colorectal cancer cells. ASBEL interacts with and recruits TCF3 to the activating transcription factor 3 (ATF3) locus, where it represses the expression of ATF3. Furthermore, we demonstrate that ASBEL–TCF3–mediated down-regulation of ATF3 expression is required for the proliferation and tumorigenicity of colon tumor cells. ATF3, in turn, represses the expression of ASBEL. Our results reveal a pathway involving an lncRNA and two transcription factors that plays a key role in Wnt/β–catenin–mediated tumorigenesis. These results may provide insights into the variety of biological and pathological processes regulated by Wnt/β-catenin signaling.

scholarly journals Cardiac Fibroblast–Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling

Circulation ◽  
2017 ◽  
Vol 135 (21) ◽  
pp. 2041-2057 ◽  
Author(s):  
Yulin Li ◽  
Zhenya Li ◽  
Congcong Zhang ◽  
Ping Li ◽  
Yina Wu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Transforming Growth Factor Β ◽  
Cardiac Fibroblast ◽  
Activating Transcription Factor 3 ◽  
Activating Transcription Factor ◽  
Atf3 Expression

Background: Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood. Methods: We used a discovery-driven/nonbiased approach to identify increased activating transcription factor 3 (ATF3) expression in hypertensive heart. We used loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examined the mechanisms through transcriptome, chromatin immunoprecipitation sequencing analysis, and in vivo and in vitro experiments. Results: ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast–selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell–specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene–associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the profibrotic/hypertrophic phenotype in ATF3KO cells. Last, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the profibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced transforming growth factor-β signaling-related profibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells. Conclusions: Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects the heart by suppressing Map2K3 expression and subsequent p38-transforming growth factor-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling.

Activating Transcription Factor 3 (ATF3) Is Overexpressed in Classical Hodgkin Lymphoma and Is Required for Survival of Hodgkin and Reed-Sternberg Cells in Response to Cellular Stress.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3116-3116
Author(s):  
M. Janz ◽  
M. Hummel ◽  
M. Truss ◽  
B. Wollert-Wulf ◽  
S. Mathas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Staining Pattern ◽  
Large Cell ◽  
Activating Transcription Factor 3 ◽  
Classical Hodgkin Lymphoma ◽  
Activating Transcription Factor ◽  
Atf3 Expression ◽  
Selection Of

Abstract Hodgkin and Reed-Sternberg (HRS) cells display aberrant activity of several transcription factors, including nuclear factor kappa B (NF-kB) and members of the activator protein-1 (AP-1) family, that promote cytokine expression, cellular survival and proliferation. Using oligonucleotide microarrays, we set out to identify additional factors which are responsible for the malignant phenotype of HRS cells. Microarray analysis and subsequent Northern and Western blotting revealed that activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors that is involved in the cellular response to stress signals, shows a strong constitutive expression in Hodgkin-derived cell lines. In contrast, ATF3 expression could not be detected in several Non-Hodgkin cell lines of distinct differentiation stages, ranging from pre-B cell lines to plasma B cell lines. To investigate the expression pattern of ATF3 in primary tumor cells, we performed immunohistochemistry on tissue microarrays. Immunohistochemistry confirmed a strong expression of ATF3 in primary HRS cells with a nuclear staining pattern. ATF3 expression was observed in almost all cases of classical Hodgkin lymphoma examined (69/71), whereas ATF3 expression was not detected in lymphocyte-predominant Hodgkin lymphoma. In addition, a significant number of anaplastic large cell lymphomas revealed a nuclear ATF3 staining pattern. In contrast, among all other B and T cell Non-Hodgkin lymphomas, ATF3 expression was observed only in rare cases (7/244), indicating that ATF3 expression is almost exclusively restricted to classical Hodgkin lymphoma and to a subset of anaplastic large cell lymphomas. To investigate the role of ATF3 for proliferation and survival of HRS cells, we generated vector-based siRNA constructs to downregulate ATF3 expression. Our vector system carries a puromycin-resistance gene thus allowing selection of siRNA expressing cells. Transfection of Hodgkin-derived cell lines with ATF3 siRNA constructs and subsequent selection of siRNA-expressing cells demonstrated a dramatic loss of viable cells. Our observations indicate that ATF3 is required for the survival of HRS cells exposed to the environmental stress imposed by antibiotic selection.

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