The Experts below are selected from a list of 26616 Experts worldwide ranked by ideXlab platform
Diego Haro - One of the best experts on this subject based on the ideXlab platform.
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Activating Transcription Factor 4 dependent induction of fgf21 during amino acid deprivation
Biochemical Journal, 2012Co-Authors: Ana Luisa De Sousacoelho, Pedro F Marrero, Diego HaroAbstract:Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation Factor 2), global protein synthesis reduction and increased ATF4 (Activating Transcription Factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth Factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5′ regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent Transcriptional activation of this gene. These results add FGF21 gene induction to the Transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation. Abbreviations: AARE, amino acid-response element; AMPK, AMP-activated protein kinase; ATF4, Activating Transcription Factor 4; BAT, brown adipose tissue; C/EBP, CCAAT/enhancer-binding protein; CARE, C/EBP/ATF-response element; ChIP, chromatin immunoprecipitation; eIF2, eukaryotic initiation Factor 2; EMSA, electrophoretic mobility-shift assay; FGF, fibroblast growth Factor; GCN2, general control non-derepressible 2; HisOH, histidinol; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; hnRNA, heterogeneous nuclear RNA; MEM, minimal essential medium; PPAR, peroxisome-proliferator-activated receptor; PGC-1α, PPARγ co-activator-1α; siRNA, small interfering RNA; SREBP1c, sterol-regulatory-element-binding protein 1c; UCP1, uncoupling protein 1; WAT, white adipose tissue
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Activating Transcription Factor 4 dependent induction of fgf21 during amino acid deprivation
Biochemical Journal, 2012Co-Authors: Ana Luisa De Sousacoelho, Pedro F Marrero, Diego HaroAbstract:Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation Factor 2), global protein synthesis reduction and increased ATF4 (Activating Transcription Factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth Factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent Transcriptional activation of this gene. These results add FGF21 gene induction to the Transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.
Chunhong Yan - One of the best experts on this subject based on the ideXlab platform.
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the Activating Transcription Factor 3 protein suppresses the oncogenic function of mutant p53 proteins
Journal of Biological Chemistry, 2014Co-Authors: Saisai Wei, Hongbo Wang, Chunhong Yan, Sarah Malmut, Jianqiao Zhang, Shumei Ren, Wei Wang, Dale D TangAbstract:Mutant p53 proteins (mutp53) often acquire oncogenic activities, conferring drug resistance and/or promoting cancer cell migration and invasion. Although it has been well established that such a gain of function is mainly achieved through interaction with Transcriptional regulators, thereby modulating cancer-associated gene expression, how the mutp53 function is regulated remains elusive. Here we report that Activating Transcription Factor 3 (ATF3) bound common mutp53 (e.g. R175H and R273H) and, subsequently, suppressed their oncogenic activities. ATF3 repressed mutp53-induced NFKB2 expression and sensitized R175H-expressing cancer cells to cisplatin and etoposide treatments. Moreover, ATF3 appeared to suppress R175H- and R273H-mediated cancer cell migration and invasion as a consequence of preventing the Transcription Factor p63 from inactivation by mutp53. Accordingly, ATF3 promoted the expression of the metastasis suppressor SHARP1 in mutp53-expressing cells. An ATF3 mutant devoid of the mutp53-binding domain failed to disrupt the mutp53-p63 binding and, thus, lost the activity to suppress mutp53-mediated migration, suggesting that ATF3 binds to mutp53 to suppress its oncogenic function. In line with these results, we found that down-regulation of ATF3 expression correlated with lymph node metastasis in TP53-mutated human lung cancer. We conclude that ATF3 can suppress mutp53 oncogenic function, thereby contributing to tumor suppression in TP53-mutated cancer.
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MDM2 mediates ubiquitination and degradation of Activating Transcription Factor 3
The Journal of biological chemistry, 2010Co-Authors: Hongbo Wang, Douglas D Boyd, Chunhong YanAbstract:Activating Transcription Factor 3 (ATF3) is a common stress sensor, and its rapid induction by cellular stresses (e.g. DNA damage) is crucial for cells to mount appropriate responses (e.g. Activating the tumor suppressor p53) and maintain homeostasis. Although emerging evidence suggests that dysregulation of ATF3 contributes to occurrences of human diseases including cancer, the mechanism(s) by which ATF3 expression is regulated is largely unknown. Here, we demonstrate that mouse double minute 2 (MDM2) is a bona fide E3 ubiquitin ligase for ATF3 and regulates ATF3 expression by promoting its degradation. MDM2 via its C-terminal RING finger can bind to the Basic region of ATF3 and mediate the addition of ubiquitin moieties to the ATF3 leucine zipper domain. As a consequence, ATF3, but not a mutant deficient in MDM2 binding (Δ80–100), is degraded by MDM2-mediated proteolysis. Consistent with these results, ablation of MDM2 in cells not only increases basal ATF3 levels, but results in stabilization of ATF3 in late stages of DNA damage responses. Because ATF3 was recently identified as a p53 activator, these results suggest that MDM2 could inactivate p53 through an additional feedback mechanism involving ATF3. Therefore, we provide the first evidence demonstrating that ATF3 is regulated by a posttranslational mechanism.
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Activating Transcription Factor 3 activates p53 by preventing e6 associated protein from binding to e6
Journal of Biological Chemistry, 2010Co-Authors: Hongbo Wang, Shumei Ren, Chunhong YanAbstract:Genomic integration of human papillomavirus (HPV) DNA accounts for more than 90% of cervical cancers. High-risk genital HPVs encode E6 proteins that can interact with a cellular ubiquitin ligase E6-associated protein (E6AP) and target the tumor suppressor p53 for ubiquitin-mediated proteolysis. Currently, how this critical event is regulated is largely unknown. Here we report that Activating Transcription Factor 3 (ATF3), a broad DNA damage sensor whose expression is frequently downregulated in cervical cancer, interacted with E6 and prevented p53 from ubiquitination and degradation mediated by the viral protein. Consistent with its role as a potent E6 antagonist, ATF3 expressed enforcedly in HPV-positive SiHa cells activated p53, leading to expression of p53-target genes (e.g. p21 and PUMA), cell cycle arrest and apoptotic cell death. The leucine zipper domain of ATF3 appears indispensable for these effects as an ATF3 mutant lacking this domain failed to interact with E6 and activate p53 in the cervical cancer cells. The prevention of p53 degradation was unlikely caused by binding of ATF3 to the tumor suppressor, but rather was a consequence of disruption of the E6-E6AP interaction by ATF3. These results indicate that ATF3 plays a key role in a mechanism defending against HPV-induced carcinogenesis, and could serve as a novel therapeutic target for HPV-positive cancers.
Hongbo Wang - One of the best experts on this subject based on the ideXlab platform.
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the Activating Transcription Factor 3 protein suppresses the oncogenic function of mutant p53 proteins
Journal of Biological Chemistry, 2014Co-Authors: Saisai Wei, Hongbo Wang, Chunhong Yan, Sarah Malmut, Jianqiao Zhang, Shumei Ren, Wei Wang, Dale D TangAbstract:Mutant p53 proteins (mutp53) often acquire oncogenic activities, conferring drug resistance and/or promoting cancer cell migration and invasion. Although it has been well established that such a gain of function is mainly achieved through interaction with Transcriptional regulators, thereby modulating cancer-associated gene expression, how the mutp53 function is regulated remains elusive. Here we report that Activating Transcription Factor 3 (ATF3) bound common mutp53 (e.g. R175H and R273H) and, subsequently, suppressed their oncogenic activities. ATF3 repressed mutp53-induced NFKB2 expression and sensitized R175H-expressing cancer cells to cisplatin and etoposide treatments. Moreover, ATF3 appeared to suppress R175H- and R273H-mediated cancer cell migration and invasion as a consequence of preventing the Transcription Factor p63 from inactivation by mutp53. Accordingly, ATF3 promoted the expression of the metastasis suppressor SHARP1 in mutp53-expressing cells. An ATF3 mutant devoid of the mutp53-binding domain failed to disrupt the mutp53-p63 binding and, thus, lost the activity to suppress mutp53-mediated migration, suggesting that ATF3 binds to mutp53 to suppress its oncogenic function. In line with these results, we found that down-regulation of ATF3 expression correlated with lymph node metastasis in TP53-mutated human lung cancer. We conclude that ATF3 can suppress mutp53 oncogenic function, thereby contributing to tumor suppression in TP53-mutated cancer.
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MDM2 mediates ubiquitination and degradation of Activating Transcription Factor 3
The Journal of biological chemistry, 2010Co-Authors: Hongbo Wang, Douglas D Boyd, Chunhong YanAbstract:Activating Transcription Factor 3 (ATF3) is a common stress sensor, and its rapid induction by cellular stresses (e.g. DNA damage) is crucial for cells to mount appropriate responses (e.g. Activating the tumor suppressor p53) and maintain homeostasis. Although emerging evidence suggests that dysregulation of ATF3 contributes to occurrences of human diseases including cancer, the mechanism(s) by which ATF3 expression is regulated is largely unknown. Here, we demonstrate that mouse double minute 2 (MDM2) is a bona fide E3 ubiquitin ligase for ATF3 and regulates ATF3 expression by promoting its degradation. MDM2 via its C-terminal RING finger can bind to the Basic region of ATF3 and mediate the addition of ubiquitin moieties to the ATF3 leucine zipper domain. As a consequence, ATF3, but not a mutant deficient in MDM2 binding (Δ80–100), is degraded by MDM2-mediated proteolysis. Consistent with these results, ablation of MDM2 in cells not only increases basal ATF3 levels, but results in stabilization of ATF3 in late stages of DNA damage responses. Because ATF3 was recently identified as a p53 activator, these results suggest that MDM2 could inactivate p53 through an additional feedback mechanism involving ATF3. Therefore, we provide the first evidence demonstrating that ATF3 is regulated by a posttranslational mechanism.
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Activating Transcription Factor 3 activates p53 by preventing e6 associated protein from binding to e6
Journal of Biological Chemistry, 2010Co-Authors: Hongbo Wang, Pingli MoAbstract:Genomic integration of human papillomavirus (HPV) DNA accounts for more than 90% of cervical cancers. High-risk genital HPVs encode E6 proteins that can interact with a cellular ubiquitin ligase E6-associated protein (E6AP) and target the tumor suppressor p53 for ubiquitin-mediated proteolysis. Currently, how this critical event is regulated is largely unknown. Here we report that Activating Transcription Factor 3 (ATF3), a broad DNA damage sensor whose expression is frequently downregulated in cervical cancer, interacted with E6 and prevented p53 from ubiquitination and degradation mediated by the viral protein. Consistent with its role as a potent E6 antagonist, ATF3 expressed enforcedly in HPV-positive SiHa cells activated p53, leading to expression of p53-target genes (e.g. p21 and PUMA), cell cycle arrest and apoptotic cell death. The leucine zipper domain of ATF3 appears indispensable for these effects as an ATF3 mutant lacking this domain failed to interact with E6 and activate p53 in the cervical cancer cells. The prevention of p53 degradation was unlikely caused by binding of ATF3 to the tumor suppressor, but rather was a consequence of disruption of the E6-E6AP interaction by ATF3. These results indicate that ATF3 plays a key role in a mechanism defending against HPV-induced carcinogenesis, and could serve as a novel therapeutic target for HPV-positive cancers.
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Activating Transcription Factor 3 activates p53 by preventing e6 associated protein from binding to e6
Journal of Biological Chemistry, 2010Co-Authors: Hongbo Wang, Shumei Ren, Chunhong YanAbstract:Genomic integration of human papillomavirus (HPV) DNA accounts for more than 90% of cervical cancers. High-risk genital HPVs encode E6 proteins that can interact with a cellular ubiquitin ligase E6-associated protein (E6AP) and target the tumor suppressor p53 for ubiquitin-mediated proteolysis. Currently, how this critical event is regulated is largely unknown. Here we report that Activating Transcription Factor 3 (ATF3), a broad DNA damage sensor whose expression is frequently downregulated in cervical cancer, interacted with E6 and prevented p53 from ubiquitination and degradation mediated by the viral protein. Consistent with its role as a potent E6 antagonist, ATF3 expressed enforcedly in HPV-positive SiHa cells activated p53, leading to expression of p53-target genes (e.g. p21 and PUMA), cell cycle arrest and apoptotic cell death. The leucine zipper domain of ATF3 appears indispensable for these effects as an ATF3 mutant lacking this domain failed to interact with E6 and activate p53 in the cervical cancer cells. The prevention of p53 degradation was unlikely caused by binding of ATF3 to the tumor suppressor, but rather was a consequence of disruption of the E6-E6AP interaction by ATF3. These results indicate that ATF3 plays a key role in a mechanism defending against HPV-induced carcinogenesis, and could serve as a novel therapeutic target for HPV-positive cancers.
Ana Luisa De Sousacoelho - One of the best experts on this subject based on the ideXlab platform.
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Activating Transcription Factor 4 dependent induction of fgf21 during amino acid deprivation
Biochemical Journal, 2012Co-Authors: Ana Luisa De Sousacoelho, Pedro F Marrero, Diego HaroAbstract:Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation Factor 2), global protein synthesis reduction and increased ATF4 (Activating Transcription Factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth Factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5′ regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent Transcriptional activation of this gene. These results add FGF21 gene induction to the Transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation. Abbreviations: AARE, amino acid-response element; AMPK, AMP-activated protein kinase; ATF4, Activating Transcription Factor 4; BAT, brown adipose tissue; C/EBP, CCAAT/enhancer-binding protein; CARE, C/EBP/ATF-response element; ChIP, chromatin immunoprecipitation; eIF2, eukaryotic initiation Factor 2; EMSA, electrophoretic mobility-shift assay; FGF, fibroblast growth Factor; GCN2, general control non-derepressible 2; HisOH, histidinol; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; hnRNA, heterogeneous nuclear RNA; MEM, minimal essential medium; PPAR, peroxisome-proliferator-activated receptor; PGC-1α, PPARγ co-activator-1α; siRNA, small interfering RNA; SREBP1c, sterol-regulatory-element-binding protein 1c; UCP1, uncoupling protein 1; WAT, white adipose tissue
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Activating Transcription Factor 4 dependent induction of fgf21 during amino acid deprivation
Biochemical Journal, 2012Co-Authors: Ana Luisa De Sousacoelho, Pedro F Marrero, Diego HaroAbstract:Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation Factor 2), global protein synthesis reduction and increased ATF4 (Activating Transcription Factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth Factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent Transcriptional activation of this gene. These results add FGF21 gene induction to the Transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.
Marina Pasca Di Magliano - One of the best experts on this subject based on the ideXlab platform.
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Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer
Oncogene, 2021Co-Authors: Nawab Azizi, Jelena Toma, Mickenzie Martin, Muhammad Faran Khalid, Nina Steele, Jiaqi Shi, Marina Pasca Di Magliano, Fatemeh Mousavi, Phyo Wei Win, Maria Teresa BorrelloAbstract:The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR that promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized that ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germline mutation of Atf3 ( Atf3 ^ −/− ) combined with acinar-specific induction of oncogenic KRAS ( Ptf1a ^ creERT/+ Kras ^ G12D/+ ). Atf3 ^ −/− mice with (termed APK ) and without KRAS^G12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3 ^ −/− mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia (PanIN) formation and PDAC in Ptf1a ^ creERT/+ Kras ^ G12D/+ mice. In response to injury, KRAS^G12D bypassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. Compared to Ptf1a ^ creERT/+ Kras ^ G12D/+ mice, APK mice exhibited a significant decrease in pancreatic and total body weight, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.
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loss of Activating Transcription Factor 3 prevents kras mediated pancreatic cancer
bioRxiv, 2020Co-Authors: Nawab Azizi, Jelena Toma, Mickenzie Martin, Muhammad Faran Khalid, Nina Steele, Jiaqi Shi, Marina Pasca Di Magliano, Christopher L PinAbstract:The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+KrasLSL-G12D mice. In response to injury, KRASG12D bipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlike Ptf1acreERT/+KrasLSL-G12D mice, APK mice exhibited a cachexia-like phenotype, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.
