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A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells.
Shih HP, Seymour PA, Patel NA, Xie R, Wang A, Liu PP, Yeo GW, Magnuson MA, Sander M
(2015) Cell Rep 13: 326-36
MeSH Terms: Animals, Cell Lineage, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Homeodomain Proteins, Intestinal Mucosa, Intestines, Mice, Pancreas, SOX9 Transcription Factor, Trans-Activators, Transcriptional Activation
Show Abstract · Added November 3, 2015
The generation of pancreas, liver, and intestine from a common pool of progenitors in the foregut endoderm requires the establishment of organ boundaries. How dorsal foregut progenitors activate pancreatic genes and evade the intestinal lineage choice remains unclear. Here, we identify Pdx1 and Sox9 as cooperative inducers of a gene regulatory network that distinguishes the pancreatic from the intestinal lineage. Genetic studies demonstrate dual and cooperative functions for Pdx1 and Sox9 in pancreatic lineage induction and repression of the intestinal lineage choice. Pdx1 and Sox9 bind to regulatory sequences near pancreatic and intestinal differentiation genes and jointly regulate their expression, revealing direct cooperative roles for Pdx1 and Sox9 in gene activation and repression. Our study identifies Pdx1 and Sox9 as important regulators of a transcription factor network that initiates pancreatic fate and sheds light on the gene regulatory circuitry that governs the development of distinct organs from multi-lineage-competent foregut progenitors.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
1 Members
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13 MeSH Terms
A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor.
Yi Y, Polosukhina D, Love HD, Hembd A, Pickup M, Moses HL, Lovvorn HN, Zent R, Clark PE
(2015) J Urol 194: 1762-70
MeSH Terms: Animals, Disease Models, Animal, E2F1 Transcription Factor, Gene Expression Regulation, Neoplastic, Genotype, Kidney, Kidney Neoplasms, Mice, Mice, Mutant Strains, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins p21(ras), Transcriptional Activation, Transcriptome, Tumor Suppressor Protein p53, Up-Regulation, Wilms Tumor, beta Catenin
Show Abstract · Added October 1, 2015
PURPOSE - Wilms tumor is the most common renal neoplasm of childhood. We previously found that restricted activation of the WNT/β-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial Wilms tumor. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. We sought to define the molecular pathways activated in this process and their relationship to human renal malignancies.
MATERIALS AND METHODS - Affymetrix® expression microarray data from murine kidneys with activation of K-ras and/or Ctnnb1 (β-catenin) restricted to renal epithelium were analyzed and compared to publicly available expression data on normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry.
RESULTS - Mouse kidney tumors with activation of K-ras and Ctnnb1, and human renal malignancies had similar mRNA expression signatures and were associated with activation of networks centered on β-catenin and TP53. Up-regulation of WNT/β-catenin targets (MYC, Survivin, FOXA2, Axin2 and Cyclin D1) was confirmed by immunoblot. K-RAS/β-catenin murine kidney tumors were more similar to human Wilms tumor than to other renal malignancies and demonstrated activation of a TP53 dependent network of genes, including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in murine and human Wilms tumor samples.
CONCLUSIONS - Simultaneous activation of K-RAS and β-catenin in embryonic renal epithelium leads to neoplasms similar to human Wilms tumor and associated with activation of TP53 and up-regulation of E2F1. Further studies are warranted to evaluate the role of TP53 and E2F1 in human Wilms tumor.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
1 Communities
3 Members
0 Resources
17 MeSH Terms
Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm.
Lippmann ES, Williams CE, Ruhl DA, Estevez-Silva MC, Chapman ER, Coon JJ, Ashton RS
(2015) Stem Cell Reports 4: 632-44
MeSH Terms: Fibroblast Growth Factors, Gene Expression Regulation, Developmental, Homeodomain Proteins, Humans, Neural Plate, Organ Specificity, Pluripotent Stem Cells, Signal Transduction, Stem Cells, Transcriptional Activation, Transcriptome, Tretinoin, Wnt Proteins, beta Catenin
Show Abstract · Added August 19, 2015
Colinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/β-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2(+)/Brachyury(+) neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2(+)/PAX6(+) neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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1 Members
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14 MeSH Terms
An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.
Williams CH, Hempel JE, Hao J, Frist AY, Williams MM, Fleming JT, Sulikowski GA, Cooper MK, Chiang C, Hong CC
(2015) Cell Rep 11: 43-50
MeSH Terms: Animals, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 4, Hedgehog Proteins, Phosphodiesterase 4 Inhibitors, Pyrimidinones, Receptors, G-Protein-Coupled, Signal Transduction, Small Molecule Libraries, Smoothened Receptor, Thiophenes, Transcriptional Activation, Zebrafish, Zebrafish Proteins
Show Abstract · Added April 5, 2015
Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
3 Members
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14 MeSH Terms
Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis.
Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W
(2015) Gut 64: 1028-39
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Growth Inhibitors, Immunohistochemistry, Mice, Mice, Knockout, Peptides, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, Stomach Neoplasms, Transcriptional Activation, Trefoil Factor-1, beta Catenin
Show Abstract · Added February 19, 2015
OBJECTIVE - In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-catenin signalling using in vivo and in vitro models of gastric tumorigenesis.
DESIGN - Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on β-catenin signalling pathway.
RESULTS - Nuclear localisation of β-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the β-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of β-catenin in stages of human gastric tumorigenesis.
CONCLUSIONS - Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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2 Members
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17 MeSH Terms
Activation of epidermal growth factor receptor mediates mucin production stimulated by p40, a Lactobacillus rhamnosus GG-derived protein.
Wang L, Cao H, Liu L, Wang B, Walker WA, Acra SA, Yan F
(2014) J Biol Chem 289: 20234-44
MeSH Terms: Animals, Apoptosis, Bacterial Proteins, Cell Line, Colon, ErbB Receptors, Humans, Intestinal Mucosa, Lactobacillus rhamnosus, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucin-2, Mucins, Probiotics, RNA, Small Interfering, Transcriptional Activation, Up-Regulation
Show Abstract · Added October 8, 2015
The mucus layer coating the gastrointestinal tract serves as the first line of intestinal defense against infection and injury. Probiotics promote mucin production by goblet cells in the intestine. p40, a Lactobacillus rhamnosus GG-derived soluble protein, has been shown to transactivate the EGF receptor (EGFR) in intestinal epithelial cells, which is required for inhibition of apoptosis and preservation of barrier function in the colon, thereby ameliorating intestinal injury and colitis. Because activation of EGFR has been shown to up-regulate mucin production in goblet cells, the purpose of this study was to investigate the effects and mechanisms of p40 regulation of mucin production. p40 activated EGFR and its downstream target, Akt, in a concentration-dependent manner in LS174T cells. p40 stimulated Muc2 gene expression and mucin production in LS174T cells, which were abolished by inhibition of EGFR kinase activity, down-regulation of EGFR expression by EGFR siRNA transfection, or suppression of Akt activation. Treatment with p40 increased mucin production in the colonic epithelium, thus thickening the mucus layer in the colon of wild type, but not of Egfr(wa5) mice, which have a dominant negative mutation in the EGFR kinase domain. Furthermore, inhibition of mucin-type O-linked glycosylation suppressed the effect of p40 on increasing mucin production and protecting intestinal epithelial cells from TNF-induced apoptosis in colon organ culture. Thus, these results suggest that p40-stimulated activation of EGFR mediates up-regulation of mucin production, which may contribute to the mechanisms by which p40 protects the intestinal epithelium from injury.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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1 Members
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18 MeSH Terms
Redox control of p53 in the transcriptional regulation of TGF-β1 target genes through SMAD cooperativity.
Overstreet JM, Samarakoon R, Meldrum KK, Higgins PJ
(2014) Cell Signal 26: 1427-36
MeSH Terms: Acetylation, Animals, Cell Line, DNA-Binding Proteins, Enzyme Activation, Epithelial Cells, Fibroblasts, Fibrosis, Gene Expression Regulation, Humans, Keratinocytes, Kidney Diseases, Kidney Tubules, Mice, Mice, Knockout, NADPH Oxidases, Phosphorylation, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Signal Transduction, Smad3 Protein, Transcriptional Activation, Transforming Growth Factor beta1, Tumor Suppressor Protein p53
Show Abstract · Added April 19, 2016
Transforming growth factor-β1 (TGF-β1) regulates the tissue response to injury and is the principal driver of excessive scarring leading to fibrosis and eventual organ failure. The TGF-β1 effectors SMAD3 and p53 are major contributors to disease progression. While SMAD3 is an established pro-fibrotic factor, the role of p53 in the TGF-β1-induced fibrotic program is not clear. p53 gene silencing, genetic ablation/subsequent rescue, and pharmacological inhibition confirmed that p53 was required for expression of plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1 target gene and a key causative element in fibrotic disorders. TGF-β1 regulated p53 activity by stimulating p53(Ser15 and 9) phosphorylation and acetylation, promoting interactions with activated SMADs and subsequent binding of p53/SMAD3 to the PAI-1 promoter in HK-2 human renal tubular epithelial cells and HaCaT human keratinocytes. Immunohistochemistry revealed prominent co-induction of SMAD3, p53 and PAI-1 in the tubular epithelium of the obstructed kidney consistent with a potential in vivo role for p53 and SMADs in TGF-β1-driven renal fibrosis. TGF-β1-initiated phosphorylation of p53(Ser15) and up-regulation of expression of several pro-fibrotic genes, moreover, was dependent on the rapid generation of reactive oxygen species (ROS). shRNA silencing of the p22(Phox) subunit of NADP(H) oxidases in HK-2 cells partially attenuated (over 50%) p53(Ser15) phosphorylation and PAI-1 induction. These studies highlight the role of free radicals in p53 activation and subsequent pro-fibrotic reprogramming by TGF-β1 via the SMAD3-p53 transcriptional axis. Present findings provide a rationale for therapeutic targeting of SMAD3-p53 in aberrant TGF-β1 signaling associated with renal fibrosis.
Copyright © 2014 Elsevier Inc. All rights reserved.
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1 Members
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27 MeSH Terms
CITED1 confers stemness to Wilms tumor and enhances tumorigenic responses when enriched in the nucleus.
Murphy AJ, Pierce J, de Caestecker C, Ayers GD, Zhao A, Krebs JR, Saito-Diaz VK, Lee E, Perantoni AO, de Caestecker MP, Lovvorn HN
(2014) Oncotarget 5: 386-402
MeSH Terms: Animals, Apoptosis Regulatory Proteins, Carcinogenesis, Cell Nucleus, Disease Models, Animal, Female, HEK293 Cells, Humans, Kidney Neoplasms, Mice, Mice, SCID, Neoplastic Stem Cells, Nuclear Proteins, Trans-Activators, Transcription Factors, Transcriptional Activation, Transfection, Wilms Tumor, Xenograft Model Antitumor Assays
Show Abstract · Added February 26, 2014
Wilms tumor (WT) is the most common childhood kidney cancer and retains gene expression profiles reminiscent of the embryonic kidney. We have shown previously that CITED1, a transcriptional regulator that labels the self-renewing, multipotent nephron progenitor population of the developing kidney, is robustly expressed across all major WT disease and patient characteristics. In this malignant context, CITED1 becomes enriched in the nucleus, which deviates from its cytosolic predominance in embryonic nephron progenitors. We designed the current studies to test the functional and mechanistic effects of differential CITED1 subcellular localization on WT behavior. To mimic its subcellular distribution observed in clinical WT specimens, CITED1 was misexpressed ectopically in the human WT cell line, WiT49, as either a wild-type (predominantly cytosolic) or a mutant, but transcriptionally active, protein (two point mutations in its nuclear export signal, CITED1ΔNES; nuclear-enriched). In vitro analyses showed that CITED1ΔNES enhanced WiT49 proliferation and colony formation in soft agar relative to wild-type CITED1 and empty vector controls. The nuclear-enriched CITED1ΔNES cell line showed the greatest tumor volumes after xenotransplantation into immunodeficient mice (n=15 animals per cell line). To elucidate CITED1 gene targets in this model, microarray profiling showed that wild-type CITED1 foremost upregulated LGR5 (stem cell marker), repressed CDH6 (early marker of epithelial commitment of nephron progenitors), and altered expression of specific WNT pathway participants. In summary, forced nuclear enrichment of CITED1 in a human WT cell line appears to enhance tumorigenicity, whereas ectopic cytosolic expression confers stem-like properties and an embryonic phenotype, analogous to the developmental context.
2 Communities
5 Members
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19 MeSH Terms
Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.
Schultz MA, Hagan SS, Datta A, Zhang Y, Freeman ML, Sikka SC, Abdel-Mageed AB, Mondal D
(2014) PLoS One 9: e87204
MeSH Terms: Analysis of Variance, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA Primers, Dihydrotestosterone, Electrophoretic Mobility Shift Assay, Humans, Immunoblotting, Luciferases, Male, NF-E2-Related Factor 2, Nuclear Respiratory Factor 1, Prostatic Neoplasms, Castration-Resistant, Real-Time Polymerase Chain Reaction, Receptors, Androgen, Transcriptional Activation
Show Abstract · Added March 13, 2014
Despite androgen deprivation therapy (ADT), persistent androgen receptor (AR) signaling enables outgrowth of castration resistant prostate cancer (CRPC). In prostate cancer (PCa) cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP) and castration resistant (C4-2B) PCa cells. Dihydrotestosterone (DHT) stimulated transactivation of the androgen response element (ARE) was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.
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16 MeSH Terms
Transforming growth factor β regulates P-body formation through induction of the mRNA decay factor tristetraprolin.
Blanco FF, Sanduja S, Deane NG, Blackshear PJ, Dixon DA
(2014) Mol Cell Biol 34: 180-95
MeSH Terms: 3' Untranslated Regions, AU Rich Elements, Animals, Binding Sites, Cell Line, Cell Proliferation, Cellular Senescence, Colon, Cytoplasmic Structures, Intestinal Mucosa, Mice, Mice, Knockout, Promoter Regions, Genetic, RNA Processing, Post-Transcriptional, RNA Stability, RNA, Messenger, Rats, Signal Transduction, Smad3 Protein, Transcriptional Activation, Transforming Growth Factor beta, Tristetraprolin
Show Abstract · Added March 7, 2014
Transforming growth factor β (TGF-β) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3' untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-β inhibited ARE-mRNA expression. This effect of TGF-β was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-β/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-β induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-β-dependent P-body formation and promoted growth inhibition by TGF-β. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-β/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-β's antiproliferative properties and identify TGF-β as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.
1 Communities
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22 MeSH Terms