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The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis.
Tsuda M, Fukuda A, Roy N, Hiramatsu Y, Leonhardt L, Kakiuchi N, Hoyer K, Ogawa S, Goto N, Ikuta K, Kimura Y, Matsumoto Y, Takada Y, Yoshioka T, Maruno T, Yamaga Y, Kim GE, Akiyama H, Ogawa S, Wright CV, Saur D, Takaori K, Uemoto S, Hebrok M, Chiba T, Seno H
(2018) J Clin Invest 128: 3475-3489
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, DNA Helicases, Female, Gene Expression Regulation, Humans, Male, Mice, Mice, Transgenic, Nuclear Proteins, Pancreatic Neoplasms, Response Elements, SOX9 Transcription Factor, Signal Transduction, Transcription Factors, Tumor Suppressor Protein p53
Show Abstract · Added August 7, 2018
Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
2 Communities
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17 MeSH Terms
Differential role of an NF-κB transcriptional response element in endothelial versus intimal cell VCAM-1 expression.
Milstone DS, Ilyama M, Chen M, O'Donnell P, Davis VM, Plutzky J, Brown JD, Haldar SM, Siu A, Lau AC, Zhu SN, Basheer MF, Collins T, Jongstra-Bilen J, Cybulsky MI
(2015) Circ Res 117: 166-77
MeSH Terms: 5' Untranslated Regions, Animals, Atherosclerosis, Carotid Artery Injuries, Cells, Cultured, Chemotaxis, Leukocyte, Cholesterol, Dietary, E-Selectin, Endothelial Cells, Endothelium, Vascular, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Protein Interaction Mapping, RNA Polymerase II, Receptors, LDL, Response Elements, Transcription Factor RelA, Transcription, Genetic, Tunica Intima, Vascular Cell Adhesion Molecule-1
Show Abstract · Added September 6, 2016
RATIONALE - Human and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown.
OBJECTIVE - Determine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene.
METHODS AND RESULTS - Homologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions.
CONCLUSIONS - This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.
© 2015 American Heart Association, Inc.
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23 MeSH Terms
PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells.
Teo AK, Tsuneyoshi N, Hoon S, Tan EK, Stanton LW, Wright CV, Dunn NR
(2015) Stem Cell Reports 4: 578-90
MeSH Terms: Binding Sites, Biomarkers, Cell Differentiation, Cell Line, Cluster Analysis, Computational Biology, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins, Human Embryonic Stem Cells, Humans, Liver, Nucleotide Motifs, Organ Specificity, Organogenesis, Pancreas, Position-Specific Scoring Matrices, Protein Binding, Response Elements, Trans-Activators, Transcription, Genetic
Show Abstract · Added April 7, 2015
Inactivation of the Pancreatic and Duodenal Homeobox 1 (PDX1) gene causes pancreatic agenesis, which places PDX1 high atop the regulatory network controlling development of this indispensable organ. However, little is known about the identity of PDX1 transcriptional targets. We simulated pancreatic development by differentiating human embryonic stem cells (hESCs) into early pancreatic progenitors and subjected this cell population to PDX1 chromatin immunoprecipitation sequencing (ChIP-seq). We identified more than 350 genes bound by PDX1, whose expression was upregulated on day 17 of differentiation. This group included known PDX1 targets and many genes not previously linked to pancreatic development. ChIP-seq also revealed PDX1 occupancy at hepatic genes. We hypothesized that simultaneous PDX1-driven activation of pancreatic and repression of hepatic programs underlie early divergence between pancreas and liver. In HepG2 cells and differentiating hESCs, we found that PDX1 binds and suppresses expression of endogenous liver genes. These findings rebrand PDX1 as a context-dependent transcriptional repressor and activator within the same cell type.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias.
Goodings C, Tripathi R, Cleveland SM, Elliott N, Guo Y, Shyr Y, Davé UP
(2015) Leuk Res 39: 100-9
MeSH Terms: Adaptor Proteins, Signal Transducing, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Transformation, Neoplastic, Humans, LIM Domain Proteins, Leukemia, T-Cell, Protein Multimerization, Proto-Oncogene Proteins, Response Elements, Transcription Factor 3
Show Abstract · Added February 19, 2015
LIM domain only-2 (LMO2) overexpression in T cells induces leukemia but the molecular mechanism remains to be elucidated. In hematopoietic stem and progenitor cells, Lmo2 is part of a protein complex comprised of class II basic helix loop helix proteins, Tal1and Lyl1. The latter transcription factors heterodimerize with E2A proteins like E47 and Heb to bind E boxes. LMO2 and TAL1 or LYL1 cooperate to induce T-ALL in mouse models, and are concordantly expressed in human T-ALL. Furthermore, LMO2 cooperates with the loss of E2A suggesting that LMO2 functions by creating a deficiency of E2A. In this study, we tested this hypothesis in Lmo2-induced T-ALL cell lines. We transduced these lines with an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen. We discovered that forced homodimerization induced growth arrest in 2 of the 4 lines tested. The lines sensitive to E47 homodimerization accumulated in G1 and had reduced S phase entry. We analyzed the transcriptome of a resistant and a sensitive line to discern the E47 targets responsible for the cellular effects. Our results suggest that E47 has diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T-ALL.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes.
Koh DI, Han D, Ryu H, Choi WI, Jeon BN, Kim MK, Kim Y, Kim JY, Parry L, Clarke AR, Reynolds AB, Hur MW
(2014) Proc Natl Acad Sci U S A 111: 15078-83
MeSH Terms: Acetylation, Animals, Apoptosis, Cell Cycle, Cell Line, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, DNA, DNA Damage, DNA Methylation, E1A-Associated p300 Protein, Female, Fibroblasts, HCT116 Cells, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Protein Binding, Response Elements, Transcription Factors, Tumor Suppressor Protein p53
Show Abstract · Added May 2, 2016
An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells.
1 Communities
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24 MeSH Terms
Interactions between NF-κB and SP3 connect inflammatory signaling with reduced FGF-10 expression.
Carver BJ, Plosa EJ, Stinnett AM, Blackwell TS, Prince LS
(2013) J Biol Chem 288: 15318-25
MeSH Terms: Active Transport, Cell Nucleus, Animals, CHO Cells, Cell Nucleus, Cricetinae, Fetus, Fibroblast Growth Factor 10, Gene Expression Regulation, Humans, Immunity, Innate, Inflammation, Lipopolysaccharides, Lung, Mice, Response Elements, Sp3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 7, 2014
Inflammation inhibits normal lung morphogenesis in preterm infants. Soluble inflammatory mediators present in the lungs of patients developing bronchopulmonary dysplasia disrupt expression of multiple genes critical for development. However, the mechanisms linking innate immune signaling and developmental programs are not clear. NF-κB activation inhibits expression of the critical morphogen FGF-10. Here, we show that interactions between the RELA subunit of NF-κB and SP3 suppress SP1-mediated FGF-10 expression. SP3 co-expression reduced SP1-mediated Fgf-10 promoter activity, suggesting antagonistic interactions between SP1 and SP3. Chromatin immunoprecipitation of LPS-treated primary mouse fetal lung mesenchymal cells detected increased interactions between SP3, RELA, and the Fgf-10 promoter. Expression of a constitutively active IκB kinase β mutant not only decreased Fgf-10 promoter activity but also increased RELA-SP3 nuclear interactions. Expression of a dominant-negative IκB, which blocks NF-κB nuclear translocation, prevented inhibition of FGF-10 by SP3. The inhibitory functions of SP3 required sequences located in the N-terminal region of the protein. These data suggested that inhibition of FGF-10 by inflammatory signaling involves the NF-κB-dependent interactions between RELA, SP3, and the Fgf-10 promoter. NF-κB activation may therefore lead to reduced gene expression by recruiting inhibitory factors to specific gene promoters following exposure to inflammatory stimuli.
1 Communities
2 Members
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17 MeSH Terms
Characterization of an apparently novel β-cell line-enriched 80-88 kDa transcriptional activator of the MafA and Pdx1 genes.
Hunter CS, Stein R
(2013) J Biol Chem 288: 3795-803
MeSH Terms: Animals, Cell Line, Gene Expression Regulation, Homeodomain Proteins, Insulin-Secreting Cells, Maf Transcription Factors, Large, Mice, Response Elements, Trans-Activators
Show Abstract · Added March 7, 2014
MafA and Pdx1 represent critical transcriptional regulators required for the maintenance of pancreatic islet β-cell function. The in vivo β-cell-enriched expression pattern of these genes is principally directed by islet transcription factors binding within conserved Region 3 (base pairs (bp) -8118/-7750) of MafA and Area II (bp -2153/-1923) of the Pdx1 gene. Comprehensive mutational analysis of conserved MafA Region 3 revealed two new β-cell line-specific cis-activation elements, termed Site 4 (bp -7997 to -7988) and Site 12 (bp -7835 to -7826). Gel mobility and antibody super-shift analysis identified Pdx1 as the Site 4 binding factor, while an 80-88 kilodalton (kDa) β-cell line-enriched protein complex bound Site 12 and similar aligned nucleotides within Pdx1 Area II. The 80-88 kDa activator was also found in adult mouse islet extract. Strikingly, the molecular weight, DNA binding, and antibody recognition properties of this activator were unique when compared with all other key islet transcription factors tested, including Prox1 (83 kDa), Hnf1α (67 kDa), FoxA2 (48 kDa), MafA (46 kDa), Isl1 (44 kDa), Pdx1 (42 kDa), and Nkx2.2 (30 kDa). Collectively, these data define an apparently novel MafA Region 3 and Pdx1 Area II activator contributing to expression in β-cells.
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9 MeSH Terms
Partial promoter substitutions generating transcriptional sentinels of diverse signaling pathways in embryonic stem cells and mice.
Serup P, Gustavsen C, Klein T, Potter LA, Lin R, Mullapudi N, Wandzioch E, Hines A, Davis A, Bruun C, Engberg N, Petersen DR, Peterslund JM, Macdonald RJ, Grapin-Botton A, Magnuson MA, Zaret KS
(2012) Dis Model Mech 5: 956-66
MeSH Terms: Activins, Animals, Base Sequence, Bone Morphogenetic Proteins, Embryo, Mammalian, Embryonic Stem Cells, Genetic Engineering, Genetic Loci, Humans, Mice, Molecular Sequence Data, Mutation, Promoter Regions, Genetic, Proteins, RNA, Untranslated, Rats, Receptors, Notch, Recombination, Genetic, Response Elements, Sequence Deletion, Signal Transduction, Transcription, Genetic, Tretinoin, Wnt Signaling Pathway
Show Abstract · Added November 6, 2013
Extracellular signals in development, physiology, homeostasis and disease often act by regulating transcription. Herein we describe a general method and specific resources for determining where and when such signaling occurs in live animals and for systematically comparing the timing and extent of different signals in different cellular contexts. We used recombinase-mediated cassette exchange (RMCE) to test the effect of successively deleting conserved genomic regions of the ubiquitously active Rosa26 promoter and substituting the deleted regions for regulatory sequences that respond to diverse extracellular signals. We thereby created an allelic series of embryonic stem cells and mice, each containing a signal-responsive sentinel with different fluorescent reporters that respond with sensitivity and specificity to retinoic acids, bone morphogenic proteins, activin A, Wnts or Notch, and that can be adapted to any pathway that acts via DNA elements.
3 Communities
2 Members
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24 MeSH Terms
Comparison of cAMP-responsive DNA sequences and their binding proteins associated with expression of the bovine CYP17 and CYP11A and human CYP21B genes.
Waterman MR, Kagawa N, Zanger UM, Momoi K, Lund J, Simpson ER
(1992) J Steroid Biochem Mol Biol 43: 931-5
MeSH Terms: Adrenal Cortex, Animals, Cattle, Cholesterol Side-Chain Cleavage Enzyme, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Gene Expression Regulation, Enzymologic, Humans, Isoenzymes, Response Elements, Steroid 17-alpha-Hydroxylase, Steroid 21-Hydroxylase
Show Abstract · Added February 12, 2015
Maintenance of optimal steriodogenic capacity in the adrenal cortex requires the action of the peptide hormone ACTH. Upon binding to its cell surface receptor ACTH activates adenylate cyclase leading to elevated levels of intracellular cAMP which in turn enhances transcription of the genes encoding the enzymes involved in the conversion of cholesterol to the steroid hormones. By deletion analysis of their upstream regions, the genes encoding the steroid hydroxylases P450c17, P450c21 and P450scc (CYP17, CYP21B and CYP11A, respectively) were found to contain unique cAMP-responsive sequences (CRSs). These sequences are unique in the sense that they have not previously been described to be associated with other genes whose transcription is regulated by cAMP. Furthermore they appear to bind unique nuclear proteins or transcription factors not previously associated with cAMP-dependent transcription. This review summarizes the relatedness of these CRSs in the bovine CYP17 and CYP11A genes and the human CYP12B gene and provides an up-to-date summary of the properties of their nuclear DNA-binding proteins.
Copyright © 1992. Published by Elsevier Ltd.
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12 MeSH Terms
Nuclear factor erythroid-derived factor 2-related factor 2 regulates transcription of CCAAT/enhancer-binding protein β during adipogenesis.
Hou Y, Xue P, Bai Y, Liu D, Woods CG, Yarborough K, Fu J, Zhang Q, Sun G, Collins S, Chan JY, Yamamoto M, Andersen ME, Pi J
(2012) Free Radic Biol Med 52: 462-72
MeSH Terms: 1-Methyl-3-isobutylxanthine, 3T3-L1 Cells, Adaptor Proteins, Signal Transducing, Adipogenesis, Animals, Antioxidants, CCAAT-Enhancer-Binding Protein-beta, Cell Nucleus, Cytoskeletal Proteins, Dexamethasone, Female, Gene Expression Regulation, Gene Knockdown Techniques, Genes, Reporter, Insulin, Kelch-Like ECH-Associated Protein 1, Luciferases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Oxidative Stress, Primary Cell Culture, Reactive Oxygen Species, Response Elements, Transcription, Genetic
Show Abstract · Added July 22, 2020
Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) is a cap-n-collar basic leucine zipper transcription factor that is involved in the cellular adaptive response to oxidative stress. Our previous study reported that targeted disruption of the Nrf2 gene in mice decreases adipose tissue mass and protects against obesity induced by a high-fat diet. Deficiency of Nrf2 in preadipocytes and mouse embryonic fibroblasts led to impaired adipogenesis. Consistent with these findings, the current study found that lack of Nrf2 in primary cultured mouse preadipocytes and 3T3-L1 cells hampered adipogenic differentiation induced by hormonal cocktails. Stable knockdown of Nrf2 in 3T3-L1 cells blocked the enhanced adipogenesis caused by deficiency of kelch-like ECH-associated protein 1 (Keap1), a Cul3-adapter protein that allows for Nrf2 to be ubiquinated and degraded by the 26S protesome complex. In addition, increased production of reactive oxygen species (ROS) and activation of Nrf2 occurred at the very early stage upon adipogenic hormonal challenge in 3T3-L1 cells, followed by an immediate induction of CCAAT/enhancer-binding protein β (C/EBPβ). Knockdown of Nrf2 led to reduced expression of C/EBPβ induced by adipogenic hormonal cocktails, chemical Nrf2 activators or Keap1 silencing. Cebpβ promoter-driven reporter assays and chromatin immunoprecipitation suggested that Nrf2 associates with a consensus antioxidant response element (ARE) binding site in the promoter of the Cebpβ gene during adipogenesis and upregulates its expression. These findings demonstrate a novel role of Nrf2 beyond xenobiotic detoxification and antioxidant response, and suggest that Nrf2 is one of the transcription factors that control the early events of adipogenesis by regulating expression of Cebpβ.
Copyright © 2011 Elsevier Inc. All rights reserved.
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