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Tsonwin Hai - One of the best experts on this subject based on the ideXlab platform.
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ATF3 deficiency promotes genome instability and spontaneous tumorigenesis in mice
Oncogene, 2017Co-Authors: Ziyan Wang, W. Deng, L. Lang, H. Yang, B. Jin, Ravindra Kolhe, Han-fei Ding, Junran Zhang, Tsonwin HaiAbstract:Mice lacking genes involving in the DNA-damage response (DDR) are often tumor prone owing to genome instability caused by oncogenic challenges. Previous studies demonstrate that activating transcription factor 3 (ATF3), a common stress sensor, can activate the tumor suppressor p53 and regulate expression of p53 target genes upon DNA damage. However, whether ATF3 contributes to the maintenance of genome stability and tumor suppression remains unknown. Here we report that ATF3-deficient (ATF3-/-) mice developed spontaneous tumors, and died significantly earlier than wild-type (ATF3+/+) mice. Consistent with these results, ATF3-/- mouse embryonic fibroblasts (MEFs) had more aberrant chromosomes and micronuclei, and were genetically unstable. Whereas we demonstrated that ATF3 activated p53 and promoted its pro-apoptotic activity in mouse thymi and small intestines, the chromosomal instability caused by ATF3 deficiency was largely dependent on the regulation of p53 by ATF3. Interestingly, loss of ATF3 also promoted spontaneous tumorigenesis in Trp53+/- mice, but did not affect tumor formation in Trp53-/- mice. Our results thus provide the first genetic evidence linking ATF3 to the suppression of the early development of cancer, and underscore the importance of ATF3 in the maintenance of genome integrity.
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Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model.
Oncogene, 2014Co-Authors: Ziyan Wang, Tsonwin Hai, Han-fei Ding, Junran Zhang, Jaejik Kim, Chunhong YanAbstract:Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.
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ATF3 is a novel regulator of mouse neutrophil migration
Blood, 2014Co-Authors: Nicholas D. Boespflug, Tsonwin Hai, Sachin Kumar, Jaclyn W. Mcalees, James D. Phelan, H. Leighton Grimes, Kasper Hoebe, Marie-dominique Filippi, Christopher L. KarpAbstract:Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven proinflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3−/− neutrophil recruitment to wild-type lungs. In vitro, ATF3−/− neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3−/− neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3−/− and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production but promotion of neutrophil chemotaxis.
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adult cardiac expression of the activating transcription factor 3 ATF3 promotes ventricular hypertrophy
PLOS ONE, 2013Co-Authors: Lilach Koren, Ofer Elhanani, Tsonwin Hai, Izhak Kehat, Ami AronheimAbstract:Cardiac hypertrophy is an adaptive response to various mechanophysical and pathophysiological stresses. However, when chronic stress is sustained, the beneficial response turns into a maladaptive process that eventually leads to heart failure. Although major advances in the treatment of patients have reduced mortality, there is a dire need for novel treatments for cardiac hypertrophy. Accordingly, considerable efforts are being directed towards developing mice models and understanding the processes that lead to cardiac hypertrophy. A case in point is ATF3, an immediate early transcription factor whose expression is induced in various cardiac stress models but has been reported to have conflicting functional significance in hypertrophy. To address this issue, we generated a transgenic mouse line with tetracycline-regulated ATF3 cardiac expression. These mice allowed us to study the consequence of ATF3 expression in the embryo or during the adult period, thus distinguishing the effect of ATF3 on development versus pathogenesis of cardiac dysfunction. Importantly, ATF3 expression in adult mice resulted in rapid ventricles hypertrophy, heart dysfunction, and fibrosis. When combined with a phenylephrine-infusion pressure overload model, the ATF3 expressing mice displayed a severe outcome and heart dysfunction. In a complementary approach, ATF3 KO mice displayed a lower level of heart hypertrophy in the same pressure overload model. In summary, ectopic expression of ATF3 is sufficient to promote cardiac hypertrophy and exacerbates the deleterious effect of chronic pressure overload; conversely, ATF3 deletion protects the heart. Therefore, ATF3 may serve as an important drug target to reduce the detrimental consequences of heart hypertrophy.
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Angiotensin II signaling up-regulates the immediate early transcription factor ATF3 in the left but not the right atrium
Basic Research in Cardiology, 2011Co-Authors: Tal Hasin, Ofer Elhanani, Tsonwin Hai, Zaid Abassi, Ami AronheimAbstract:The atria respond to various pathological stimuli including pressure and volume overload with remodeling and dilatation. Dilatation of the left atrium is associated with atrial fibrillation. The mechanisms involved in chamber-specific hypertrophy are largely unknown. Angiotensin II is hypothesized to take part in mediating this response. ATF3 is an immediate early gene found at the receiving end of multiple stress and growth stimuli. Here we characterize ATF3 as a direct target gene for angiotensin II. ATF3 expression is regulated by angiotensin receptor-mediated signaling in vivo and in vitro at the transcriptional level. ATF3 induction is mediated by cooperation between both the AT1A and AT2 receptor subtypes. While AT2R blocker (PD123319) efficiently blocks ATF3 induction in response to angiotensin II injection, it results in an increase in blood pressure indicating that the effect of angiotensin II on ATF3 is independent of its effect on blood pressure. In contrast to adrenergic stimulation that induces ATF3 in all heart chambers, ATF3 induction in response to angiotensin II occurs primarily in the left chambers. We hypothesize that the activation of differential signaling pathways accounts for the chamber-specific induction of ATF3 expression in response to angiotensin II stimulation. Angiotensin II injection rapidly activates the EGFR-dependent pathways including ERK and PI3K-AKT in the left but not the right atrium. EGF receptor inhibitor (Gefitinib/Iressa) as well as the AKT inhibitor (Triciribine) significantly abrogates ATF3 induction by angiotensin II in the left chambers. Collectively, our data strongly place ATF3 as a unique nuclear protein target in response to angiotensin II stimulation in the atria. The spatial expression of ATF3 may add to the understanding of the signaling pathways involved in cardiac response to neuro-hormonal stimulation, and in particular to the understanding of left atrial-generated pathology such as atrial fibrillation.
Chunhong Yan - One of the best experts on this subject based on the ideXlab platform.
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The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation
BMC Genomics, 2016Co-Authors: Jonathan Zhao, Mingxiong Guo, Jindan Yu, Xingyao Li, Chunhong YanAbstract:BackgroundDysregulation of the common stress responsive transcription factor ATF3 has been causally linked to many important human diseases such as cancer, atherosclerosis, infections, and hypospadias. Although it is believed that the ATF3 transcription activity is central to its cellular functions, how ATF3 regulates gene expression remains largely unknown. Here, we employed ATF3 wild-type and knockout isogenic cell lines to carry out the first comprehensive analysis of global ATF3-binding profiles in the human genome under basal and stressed (DNA damage) conditions.ResultsAlthough expressed at a low basal level, ATF3 was found to bind a large number of genomic sites that are often associated with genes involved in cellular stress responses. Interestingly, ATF3 appears to bind a large portion of genomic sites distal to transcription start sites and enriched with p300 and H3K27ac. Global gene expression profiling analysis indicates that genes proximal to these genomic sites were often regulated by ATF3. While DNA damage elicited by camptothecin dramatically altered the ATF3 binding profile, most of the genes regulated by ATF3 upon DNA damage were pre-bound by ATF3 before the stress. Moreover, we demonstrated that ATF3 was co-localized with the major stress responder p53 at genomic sites, thereby collaborating with p53 to regulate p53 target gene expression upon DNA damage.ConclusionsThese results suggest that ATF3 likely bookmarks genomic sites and interacts with other transcription regulators to control gene expression.
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the common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and h3k27ac for transcriptional regulation
BMC Genomics, 2016Co-Authors: Jonathan C Zhao, Mingxiong Guo, Chunhong YanAbstract:Dysregulation of the common stress responsive transcription factor ATF3 has been causally linked to many important human diseases such as cancer, atherosclerosis, infections, and hypospadias. Although it is believed that the ATF3 transcription activity is central to its cellular functions, how ATF3 regulates gene expression remains largely unknown. Here, we employed ATF3 wild-type and knockout isogenic cell lines to carry out the first comprehensive analysis of global ATF3-binding profiles in the human genome under basal and stressed (DNA damage) conditions. Although expressed at a low basal level, ATF3 was found to bind a large number of genomic sites that are often associated with genes involved in cellular stress responses. Interestingly, ATF3 appears to bind a large portion of genomic sites distal to transcription start sites and enriched with p300 and H3K27ac. Global gene expression profiling analysis indicates that genes proximal to these genomic sites were often regulated by ATF3. While DNA damage elicited by camptothecin dramatically altered the ATF3 binding profile, most of the genes regulated by ATF3 upon DNA damage were pre-bound by ATF3 before the stress. Moreover, we demonstrated that ATF3 was co-localized with the major stress responder p53 at genomic sites, thereby collaborating with p53 to regulate p53 target gene expression upon DNA damage. These results suggest that ATF3 likely bookmarks genomic sites and interacts with other transcription regulators to control gene expression.
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The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins.
Journal of Biological Chemistry, 2016Co-Authors: Hongmei Cui, Han-fei Ding, Junran Zhang, Chunhua Han, Qi-en Wang, Hongbo Wang, Chunhong YanAbstract:The response to UV irradiation is important for a cell to maintain its genetic integrity when challenged by environmental genotoxins. An immediate early response to UV irradiation is the rapid induction of activating transcription factor 3 (ATF3) expression. Although emerging evidence has linked ATF3 to stress pathways regulated by the tumor suppressor p53 and the histone acetyltransferase Tip60, the role of ATF3 in the UV response remains largely unclear. Here, we report that ATF3 mediated dichotomous UV responses. Although UV irradiation enhanced the binding of ATF3 to Tip60, knockdown of ATF3 expression decreased Tip60 stability, thereby impairing Tip60 induction by UV irradiation. In line with the role of Tip60 in mediating UV-induced apoptosis, ATF3 promoted the death of p53-defective cells in response to UV irradiation. However, ATF3 could also activate p53 and promote p53-mediated DNA repair, mainly through altering histone modifications that could facilitate recruitment of DNA repair proteins (such as DDB2) to damaged DNA sites. As a result, ATF3 rather protected the p53 wild-type cells from UV-induced apoptosis. Our results thus indicate that ATF3 regulates cell fates upon UV irradiation in a p53-dependent manner.
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Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model.
Oncogene, 2014Co-Authors: Ziyan Wang, Tsonwin Hai, Han-fei Ding, Junran Zhang, Jaejik Kim, Chunhong YanAbstract:Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.
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ATF3 represses 72 kda type iv collagenase mmp 2 expression by antagonizing p53 dependent trans activation of the collagenase promoter
Journal of Biological Chemistry, 2002Co-Authors: Chunhong Yan, Heng Wang, Douglas D BoydAbstract:Abstract The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression. The current study describes a novel mechanism by which ATF3 regulates transcription. Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (−1659/−1622) necessary for the ATF3-mediated repression. This region lacked CREB/AP-1 motifs but contained a consensus p53 motif shown previously to regulate MMP-2 expression. The activity of a p53 response element-driven luciferase reporter was reduced in ATF3-expressing HT1080 clones. Although MMP-2 promoter activity was not repressed by ATF3 inp53-deficient Saos-2 cells, p53 re-expression increased MMP-2 promoter activity and restored the sensitivity to ATF3. The activity of a GAL4-driven reporter in HT1080 cells co-expressing the full-length p53 sequence fused to the GAL4 DNA binding domain was diminished by ATF3. p53-ATF3 protein-protein interactions were demonstrated both in vivo and in vitro. Cell cycle analysis, performed as an independent assay of p53 function, revealed that γ-irradiation-induced slowed G2/M cell cycle progression (attributable to p53) was countered by ATF3. Thus, ATF3 represses MMP-2 expression by decreasing thetrans-activation of this gene by p53.
Shigetaka Kitajima - One of the best experts on this subject based on the ideXlab platform.
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ATF3 deficiency in chondrocytes alleviates osteoarthritis development.
The Journal of Pathology, 2016Co-Authors: Takashi Iezaki, Shigetaka Kitajima, Makoto Inoue, Kakeru Ozaki, Kazuya Fukasawa, Takeshi Muneta, Shu Takeda, Hiroyuki Fujita, Yuki Onishi, Tetsuhiro HorieAbstract:Activating transcription factor 3 (ATF3) has been implicated in the pathogenesis of various diseases, including cancer and inflammation, as well as in the regulation of cell proliferation and differentiation. However, the involvement of ATF3 in developmental skeletogenesis and joint disease has not been well studied to date. Here, we show that ATF3 is a critical mediator of osteoarthritis (OA) development through its expression in chondrocytes. ATF3 expression was markedly up-regulated in the OA cartilage of both mice and humans. Conditional deletion of ATF3 in chondrocytes did not result in skeletal abnormalities or affect the chondrogenesis, but alleviated the development of OA generated by surgically inducing knee joint instability in mice. Inflammatory cytokines significantly up-regulated ATF3 expression through the nuclear factor-kB (NF-kB) pathway, while cytokine-induced interleukin-6 (Il6) expression was repressed, in ATF3-deleted murine and human chondrocytes. Mechanistically, ATF3 deficiency decreased cytokine-induced Il6 transcription in chondrocytes through repressing NF-kB signalling by the attenuation of the phosphorylation status of IkB and p65. These findings suggest that ATF3 is implicated in the pathogenesis of OA through modulation of inflammatory cytokine expression in chondrocytes, and the feed-forward loop of inflammatory cytokines/NF-kB/ATF3 in chondrocytes may be a novel therapeutic target for the treatment for OA. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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role of activating transcription factor 3 ATF3 in endoplasmic reticulum er stress induced sensitization of p53 deficient human colon cancer cells to tumor necrosis factor tnf related apoptosis inducing ligand trail mediated apoptosis through up regul
Journal of Biological Chemistry, 2014Co-Authors: Makoto Edagawa, Hiroto Goshima, Makoto Inoue, Junya Kawauchi, Manabu Hirata, Tatsuro Okamoto, Akira Murakami, Yoshihiko Maehara, Shigetaka KitajimaAbstract:Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand, TNF-related apoptosis-inducing ligand (TRAIL), and a combination of TRAIL and agents that increase the expression of DR5 is expected to be a novel anticancer therapy. In this report, we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells. Both agents activated PERK-eIF2α kinases and induced the expression of activating transcription factor 4 (ATF4)-CCAAT enhancer-binding protein (C/EBP) homologous protein, which were remarkably suppressed by reactive oxygen species scavengers. In the absence of ATF3, the induction of DR5 mRNA and protein was abrogated significantly, and this was associated with reduced cell death by cotreatment of TRAIL with ZER or CCB. By contrast, exogenous expression of ATF3 caused a more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/ZER or TRAIL/CCB. A reporter assay demonstrated that at least two ATF/cAMP response element motifs as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter were required for ZER-induced DR5 gene transcription. Taken together, our results provide novel insights into the role of ATF3 as an essential transcription factor for p53-independent DR5 induction upon both ZER and CCB treatment, and this may be a useful biomarker for TRAIL-based anticancer therapy.
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role of ATF3 in synergistic cancer cell killing by a combination of hdac inhibitors and agonistic anti dr5 antibody through er stress in human colon cancer cells
Biochemical and Biophysical Research Communications, 2014Co-Authors: Jia Liu, Makoto Edagawa, Hiroto Goshima, Makoto Inoue, Hideo Yagita, Zhonghui Liu, Shigetaka KitajimaAbstract:Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy. However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fully elucidated. Death receptor 5 (DR5) is a transmembrane receptor containing death domain that triggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonistic anti-DR5 monoclonal antibody, and the combination of TRAIL/agonistic anti-DR5 monoclonal antibody and agents that increase the expression of DR5 is expected as a novel anticancer therapeutic strategy. Here we report that six different HDACIs activated endoplasmic reticulum (ER) stress sensor PERK and eIF2α and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increased expression of DR5 on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5 monoclonal antibody. Stress response gene ATF3 was required for efficient DR5 induction by HDACIs, and DR5 reporter assay showed that ATF3 play crucial role for the HDACIs-induced activation of DR5 gene transcription. These provide important mechanistic insight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatments when they are used in combination with other therapeutic strategies.
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expression of the transcriptional repressor ATF3 in gonadotrophs is regulated by egr 1 creb and atf2 after gonadotropin releasing hormone receptor stimulation
Endocrinology, 2008Co-Authors: Sabine I Mayer, Shigetaka Kitajima, Verena Dexheimer, Eisuke Nishida, Gerald ThielAbstract:Stimulation of GnRH receptors enhances expression of activating transcription factor (ATF) 3 in a pituitary gonadotroph cell line. The signaling pathway requires elevated cytosolic Ca2+ levels and activation of ERK and c-Jun N-terminal protein kinase. The signaling cascade was blocked by overexpression of either MAPK phosphatase (MKP)-1 or MAPK phosphatase-5 that dephosphorylate nuclear ERK and c-Jun N-terminal protein kinase. In addition, ATF3 biosynthesis was impaired after lentiviral-mediated expression of a constitutively active mutant of calcineurin A. Thus, MKP-1, MKP-5, and calcineurin may function as shut-off devices for GnRH receptor signaling. Expression of dominant-negative mutants of early growth response protein (Egr)-1, cAMP response element binding protein (CREB), and ATF2 blocked the biosynthesis of ATF3, indicating that these transcription factors connect the intracellular signaling cascade elicited by activation of GnRH receptors with transcription of the ATF3 gene. This view was corrobo...
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An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress stimuli.
Nucleic Acids Research, 2002Co-Authors: Yoshinori Hashimoto, Tsonwin Hai, Chun Zhang, Junya Kawauchi, Issei Imoto, Mimi T. Adachi, Johji Inazawa, Teruo Amagasa, Shigetaka KitajimaAbstract:Activating transcription factor 3 (ATF3) is a member of the ATF/CREB family of transcription factors and its expression is increased by various pathophysiological conditions and in several cancer cells. In this study, we describe two alternatively spliced ATF3∆Zip mRNAs: ATF3∆Zip2a and ATF3∆Zip2b. Both variants encoded the same truncated protein of 135 amino acids, which lacked the leucine zipper domain and was incapable of binding to the ATF/CRE motif. The ATF3∆Zip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3. Western blot analysis showed that ATF3∆Zip2 was expressed in cells exposed to A23187. Further study showed that, similar to the full-length ATF3, the expression of ATF3∆ Zip2 was induced by aw ide range of stress stimuli. However, its expression was not detectable in cancer cells that constitutively overexpressed ATF3. Taken together, our results suggest that ATF3∆Zip2, a protein derived from alternatively spliced mRNAs, is induced by various stress signals and may modulate the activity of the full-length ATF3 protein during stress response.
Ami Aronheim - One of the best experts on this subject based on the ideXlab platform.
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Response letter: "ATF3: A promoter or inhibitor of cardiac maladaptive remodeling"
International Journal of Cardiology, 2015Co-Authors: Lilach Koren, Yuval Shaked, Ami AronheimAbstract:We thankYang et al. for their important comments regarding our recent manuscript “ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling” by Koren et al. [1]. We completely agree with the authors that the discrepancy can be explained by the different models used in the studies. Our analysis is based on the phenylephrine (PE) infusion pressure overload model and ATF3 transgenic mice. The results from these studies are consistent with ATF3's role in promoting cardiac hypertrophy [1,2]. In contrast, studies using the transverse aortic constriction (TAC) model suggest a cardio-protective role for ATF3 [3–6]. The opposing functions of ATF3 observed in the two models may be explained by the timing and duration of ATF3 expression. In the PE model, ATF3 expression is induced transiently and involves the recruitment of macrophages to the heart in an ATF3 dependent manner [1]. In the TAC model, whereas the involvement of immune cells is yet to be determined, persistent ATF3 expression appears as cardioprotective [3]. However, prolonged adult cardiac ATF3 expression displays maladaptive cardiac remodeling [2]. So how can constitutive ATF3 expression lead to opposite outcome? Previously, we showed that ATF3 may switch between either an inhibition or an activation mode, depending on the cellular context and protein partner, i.e. ATF3 inhibits transcription as a homodimer from TPA response elements, but activates transcription as a heterodimer with CHOP10 [7]. Revealing whether ATF3 exhibits differential transcriptional activity in the TAC, ATF3-transgenic mice and PE models may provide an explanation for the resulting diverse outcomes. Collectively, in mice models, ATF3 can play either a promoting or an inhibiting role in cardiacmaladaptive remodeling processes. Significantly
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adult cardiac expression of the activating transcription factor 3 ATF3 promotes ventricular hypertrophy
PLOS ONE, 2013Co-Authors: Lilach Koren, Ofer Elhanani, Tsonwin Hai, Izhak Kehat, Ami AronheimAbstract:Cardiac hypertrophy is an adaptive response to various mechanophysical and pathophysiological stresses. However, when chronic stress is sustained, the beneficial response turns into a maladaptive process that eventually leads to heart failure. Although major advances in the treatment of patients have reduced mortality, there is a dire need for novel treatments for cardiac hypertrophy. Accordingly, considerable efforts are being directed towards developing mice models and understanding the processes that lead to cardiac hypertrophy. A case in point is ATF3, an immediate early transcription factor whose expression is induced in various cardiac stress models but has been reported to have conflicting functional significance in hypertrophy. To address this issue, we generated a transgenic mouse line with tetracycline-regulated ATF3 cardiac expression. These mice allowed us to study the consequence of ATF3 expression in the embryo or during the adult period, thus distinguishing the effect of ATF3 on development versus pathogenesis of cardiac dysfunction. Importantly, ATF3 expression in adult mice resulted in rapid ventricles hypertrophy, heart dysfunction, and fibrosis. When combined with a phenylephrine-infusion pressure overload model, the ATF3 expressing mice displayed a severe outcome and heart dysfunction. In a complementary approach, ATF3 KO mice displayed a lower level of heart hypertrophy in the same pressure overload model. In summary, ectopic expression of ATF3 is sufficient to promote cardiac hypertrophy and exacerbates the deleterious effect of chronic pressure overload; conversely, ATF3 deletion protects the heart. Therefore, ATF3 may serve as an important drug target to reduce the detrimental consequences of heart hypertrophy.
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the bzip repressor proteins c jun dimerization protein 2 and activating transcription factor 3 recruit multiple hdac members to the ATF3 promoter
Biochimica et Biophysica Acta, 2012Co-Authors: Ilona Darlyuksaadon, Keren Weidenfeldbaranboim, Kazunari K. Yokoyama, Ami AronheimAbstract:Abstract JDP2, is a basic leucine zipper (bZIP) protein displaying a high degree of homology with the stress inducible transcription factor, ATF3. Both proteins bind to cAMP and TPA response elements and repress transcription by multiple mechanisms. Histone deacetylases (HDACs) play a key role in gene inactivation by deacetylating lysine residues on histones. Here we describe the association of JDP2 and ATF3 with HDACs 1, 2–6 and 10. Association of HDAC3 and HDAC6 with JDP2 and ATF3 occurs via direct protein–protein interactions. Only part of the N-terminal bZIP motif of JDP2 and ATF3 basic domain is necessary and sufficient for the interaction with HDACs in a manner that is independent of coiled-coil dimerization. Class I HDACs associate with the bZIP repressors via the DAC conserved domain whereas the Class IIb HDAC6 associates through its C-terminal unique binder of ubiquitin Zn finger domain. Both JDP2 and ATF3 are known to bind and repress the ATF3 promoter. MEF cells treated with histone deacetylase inhibitor, trichostatin A (TSA) display enhanced ATF3 transcription. ATF3 enhanced transcription is significantly reduced in MEF cells lacking both ATF3 and JDP2. Collectively, we propose that the recruitment of multiple HDAC members to JDP2 and ATF3 is part of their transcription repression mechanism.
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Angiotensin II signaling up-regulates the immediate early transcription factor ATF3 in the left but not the right atrium
Basic Research in Cardiology, 2011Co-Authors: Tal Hasin, Ofer Elhanani, Tsonwin Hai, Zaid Abassi, Ami AronheimAbstract:The atria respond to various pathological stimuli including pressure and volume overload with remodeling and dilatation. Dilatation of the left atrium is associated with atrial fibrillation. The mechanisms involved in chamber-specific hypertrophy are largely unknown. Angiotensin II is hypothesized to take part in mediating this response. ATF3 is an immediate early gene found at the receiving end of multiple stress and growth stimuli. Here we characterize ATF3 as a direct target gene for angiotensin II. ATF3 expression is regulated by angiotensin receptor-mediated signaling in vivo and in vitro at the transcriptional level. ATF3 induction is mediated by cooperation between both the AT1A and AT2 receptor subtypes. While AT2R blocker (PD123319) efficiently blocks ATF3 induction in response to angiotensin II injection, it results in an increase in blood pressure indicating that the effect of angiotensin II on ATF3 is independent of its effect on blood pressure. In contrast to adrenergic stimulation that induces ATF3 in all heart chambers, ATF3 induction in response to angiotensin II occurs primarily in the left chambers. We hypothesize that the activation of differential signaling pathways accounts for the chamber-specific induction of ATF3 expression in response to angiotensin II stimulation. Angiotensin II injection rapidly activates the EGFR-dependent pathways including ERK and PI3K-AKT in the left but not the right atrium. EGF receptor inhibitor (Gefitinib/Iressa) as well as the AKT inhibitor (Triciribine) significantly abrogates ATF3 induction by angiotensin II in the left chambers. Collectively, our data strongly place ATF3 as a unique nuclear protein target in response to angiotensin II stimulation in the atria. The spatial expression of ATF3 may add to the understanding of the signaling pathways involved in cardiac response to neuro-hormonal stimulation, and in particular to the understanding of left atrial-generated pathology such as atrial fibrillation.
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the ubiquitously expressed bzip inhibitor jdp2 suppresses the transcription of its homologue immediate early gene counterpart ATF3
Nucleic Acids Research, 2009Co-Authors: Keren Weidenfeldbaranboim, Tal Hasin, Ofer Elhanani, Kazunari K. Yokoyama, Ilona Darlyuk, Ronit Heinrich, Jianzhi Pan, Ami AronheimAbstract:JDP2 is a ubiquitously expressed bZIP repressor protein. JDP2 binds TPA response element and cyclic AMP response element located within various promoters. JDP2 displays a high degree of homology to the immediate early gene ATF3. ATF3 plays a crucial role in the cellular adaptive response to multiple stress insults as well as growth stimuli. We have identified ATF3 as a potential target gene for JDP2 repression. JDP2 regulates the ATF3 promoter potentially through binding to both the consensus ATF/CRE site and a non-consensus ATF3 auto-repression DNA-binding element. Expression of ATF3 protein in wild-type mouse embryo fibroblast (MEF) cells is below the detectable levels, whereas, JDP2 disrupted MEF cells display noticeable level of ATF3 protein. Following either serum or ER stress stimulation, ATF3 expression is potentiated in JDP2-KO fibroblast cells as compared with wild-type cells. Mice with either JDP2 over-expression or JDP2 disruption display undetectable level of ATF3 protein. However, ATF3 induction in response to either growth or stress signals is dependent on JDP2 expression level. ATF3 induction is attenuated in JDP2 over-expressing mice whereas is potentiated in JDP2-KO mice as compared with the corresponding wild-type mice. Collectively, the data presented strongly suggest that JDP2 plays a role in the determination of the ATF3 adaptive cellular threshold response to different stress insults and growth stimuli.
Benjamin P C Chen - One of the best experts on this subject based on the ideXlab platform.
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gadd153/Chop10, a potential target gene of the transcriptional repressor ATF3.
Molecular and Cellular Biology, 1997Co-Authors: Curt D. Wolfgang, Benjamin P C Chen, Jennifer L. Martindale, Nikki J. Holbrook, Tsonwin HaiAbstract: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, ATF3 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.
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gadd153 chop10 a potential target gene of the transcriptional repressor ATF3
Molecular and Cellular Biology, 1997Co-Authors: Curt D. Wolfgang, Benjamin P C Chen, Jennifer L. Martindale, Nikki J. Holbrook, Tsonwin HaiAbstract: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, ATF3 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.
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Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10.
Molecular and Cellular Biology, 1996Co-Authors: Benjamin P C Chen, Curt D. Wolfgang, Tsonwin HaiAbstract:We demonstrate that ATF3, a member of the ATF/CREB family of transcription factors, is induced in a variety of stressed tissues: mechanically injured liver, toxin-injured liver, blood-deprived heart, and postseizure brain. We also demonstrate that an ATF3-interacting protein, gadd153/Chop10, forms a nonfunctional heterodimer with ATF3: the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. Interestingly, ATF3 and gadd153/Chop10 are expressed in inverse but overlapping manners during the liver's response to carbon tetrachloride (CCl4): the level of gadd153/Chop10 mRNA is high in the normal liver and greatly decreases upon CCl4 treatment; the level of ATF3 mRNA, on the other hand, is low in the normal liver and greatly increases upon CCl4 treatment. We hypothesize that in nonstressed liver, gadd153/Chop10 inhibits the limited amount of ATF3 by forming an inactive heterodimer with it, whereas in CCl4-injured liver, the synthesis of gadd153/Chop10 is repressed, allowing the induced ATF3 to function.
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analysis of ATF3 a transcription factor induced by physiological stresses and modulated by gadd153 chop10
Molecular and Cellular Biology, 1996Co-Authors: Benjamin P C Chen, Curt D. Wolfgang, Tsonwin HaiAbstract:We demonstrate that ATF3, a member of the ATF/CREB family of transcription factors, is induced in a variety of stressed tissues: mechanically injured liver, toxin-injured liver, blood-deprived heart, and postseizure brain. We also demonstrate that an ATF3-interacting protein, gadd153/Chop10, forms a nonfunctional heterodimer with ATF3: the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. Interestingly, ATF3 and gadd153/Chop10 are expressed in inverse but overlapping manners during the liver's response to carbon tetrachloride (CCl4): the level of gadd153/Chop10 mRNA is high in the normal liver and greatly decreases upon CCl4 treatment; the level of ATF3 mRNA, on the other hand, is low in the normal liver and greatly increases upon CCl4 treatment. We hypothesize that in nonstressed liver, gadd153/Chop10 inhibits the limited amount of ATF3 by forming an inactive heterodimer with it, whereas in CCl4-injured liver, the synthesis of gadd153/Chop10 is repressed, allowing the induced ATF3 to function.
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ATF3 gene. Genomic organization, promoter, and regulation.
Journal of Biological Chemistry, 1996Co-Authors: Guosheng Liang, Curt D. Wolfgang, Benjamin P C Chen, Tsu Hua Chen, Tsonwin HaiAbstract:Abstract ATF3 gene, which encodes a member of the activating transcription factor/cAMP responsive element binding protein (ATF/CREB) family of transcription factors, is induced by many physiological stresses. As a step toward understanding the induction mechanisms, we isolated the human ATF3 gene and analyzed its genome organization and 5′-flanking region. We found that the human ATF3 mRNA is derived from four exons distributed over 15 kilobases. Sequence analysis of the 5′-flanking region revealed a consensus TATA box and a number of transcription factor binding sites including the AP-1, ATF/CRE, NF-κB, E2F, and Myc/Max binding sites. As another approach to understanding the mechanisms by which the ATF3 gene is induced by stress signals, we studied the regulation of the ATF3 gene in tissue culture cells by anisomycin, an approach that has been used to study the stress responses in tissue culture cells. We showed that anisomycin at a low concentration activates the ATF3 promoter and stabilizes the ATF3 mRNA. Significantly, co-transfection of DNAs expressing ATF2 and c-Jun activates the ATF3 promoter. A possible mechanism implicating the C-Jun NH-terminal kinase/stress-activated protein kinase (JNK/SAPK) stress-inducible signaling pathway in the induction of the ATF3 gene is discussed.