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Sequence Characteristics Distinguish Transcribed Enhancers from Promoters and Predict Their Breadth of Activity.
Colbran LL, Chen L, Capra JA
(2019) Genetics 211: 1205-1217
MeSH Terms: Base Composition, Enhancer Elements, Genetic, Histone Code, Humans, Models, Genetic, Promoter Regions, Genetic, Support Vector Machine, Transcription Factors, Transcriptional Activation
Show Abstract · Added March 3, 2020
Enhancers and promoters both regulate gene expression by recruiting transcription factors (TFs); however, the degree to which enhancer promoter activity is due to differences in their sequences or to genomic context is the subject of ongoing debate. We examined this question by analyzing the sequences of thousands of transcribed enhancers and promoters from hundreds of cellular contexts previously identified by cap analysis of gene expression. Support vector machine classifiers trained on counts of all possible 6-bp-long sequences (6-mers) were able to accurately distinguish promoters from enhancers and distinguish their breadth of activity across tissues. Classifiers trained to predict enhancer activity also performed well when applied to promoter prediction tasks, but promoter-trained classifiers performed poorly on enhancers. This suggests that the learned sequence patterns predictive of enhancer activity generalize to promoters, but not vice versa. Our classifiers also indicate that there are functionally relevant differences in enhancer and promoter GC content beyond the influence of CpG islands. Furthermore, sequences characteristic of broad promoter or broad enhancer activity matched different TFs, with predicted ETS- and RFX-binding sites indicative of promoters, and AP-1 sites indicative of enhancers. Finally, we evaluated the ability of our models to distinguish enhancers and promoters defined by histone modifications. Separating these classes was substantially more difficult, and this difference may contribute to ongoing debates about the similarity of enhancers and promoters. In summary, our results suggest that high-confidence transcribed enhancers and promoters can largely be distinguished based on biologically relevant sequence properties.
Copyright © 2019 by the Genetics Society of America.
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MeSH Terms
ROCK-nmMyoII, Notch and gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche.
Bankaitis ED, Bechard ME, Gu G, Magnuson MA, Wright CVE
(2018) Development 145:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Movement, Endocrine Cells, Gene Dosage, Mice, Mice, Transgenic, Nerve Tissue Proteins, Organogenesis, Pancreas, Receptors, Notch, Stem Cells, Transcriptional Activation, rho-Associated Kinases
Show Abstract · Added August 24, 2018
During mouse pancreas organogenesis, endocrine cells are born from progenitors residing in an epithelial plexus niche. After a period in a lineage-primed state, progenitors become endocrine committed via upregulation of We find that the to transition is associated with distinct stages of an epithelial egression process: narrowing the apical surface of the cell, basalward cell movement and eventual cell-rear detachment from the apical lumen surface to allow clustering as nascent islets under the basement membrane. Apical narrowing, basalward movement and transcriptional upregulation still occur without Neurog3 protein, suggesting that morphogenetic cues deployed within the plexus initiate endocrine commitment upstream or independently of Neurog3. Neurog3 is required for cell-rear detachment and complete endocrine-cell birth. The ROCK-nmMyoII pathway coordinates epithelial-cell morphogenesis and the progression through -expressing states. NmMyoII is necessary for apical narrowing, basalward cell displacement and upregulation, but all three are limited by ROCK activity. We propose that ROCK-nmMyoII activity, gene-dose and Notch signaling integrate endocrine fate allocation with epithelial plexus growth and morphogenesis, representing a feedback control circuit that coordinates morphogenesis with lineage diversification in the endocrine-birth niche.
© 2018. Published by The Company of Biologists Ltd.
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15 MeSH Terms
Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes.
Shen X, Liu L, Peek RM, Acra SA, Moore DJ, Wilson KT, He F, Polk DB, Yan F
(2018) Mucosal Immunol 11: 1316-1328
MeSH Terms: Animals, Bacterial Proteins, Cell Differentiation, Cell Proliferation, Epithelial Cells, ErbB Receptors, Female, Hydrogels, Immunity, Innate, Immunoglobulin A, Intestinal Mucosa, Lactobacillus rhamnosus, Mice, Mice, Inbred C57BL, Probiotics, T-Lymphocytes, Regulatory, Tight Junctions, Time, Transcriptional Activation
Show Abstract · Added June 8, 2018
The beneficial effects of the gut microbiota on growth in early life are well known. However, knowledge about the mechanisms underlying regulating intestinal development by the microbiota is limited. p40, a Lactobacillus rhamnosus GG-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells for protecting the intestinal epithelium against injury and inflammation. Here, we developed p40-containing pectin/zein hydrogels for targeted delivery of p40 to the small intestine and the colon. Treatment with p40-containing hydrogels from postnatal day 2 to 21 significantly enhanced bodyweight gain prior to weaning and functional maturation of the intestine, including intestinal epithelial cell proliferation, differentiation, and tight junction formation, and IgA production in early life in wild-type mice. These p40-induced effects were abolished in mice with specific deletion of EGFR in intestinal epithelial cells, suggesting that transactivation of EGFR in intestinal epithelial cells may mediate p40-regulated intestinal development. Furthermore, neonatal p40 treatment reduced the susceptibility to intestinal injury and colitis and promoted protective immune responses, including IgA production and differentiation of regulatory T cells, in adult mice. These findings reveal novel roles of neonatal supplementation of probiotic-derived factors in promoting EGFR-mediated maturation of intestinal functions and innate immunity, which likely promote long-term beneficial outcomes.
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19 MeSH Terms
Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth.
Zhao G, Liu L, Peek RM, Hao X, Polk DB, Li H, Yan F
(2016) J Biol Chem 291: 20462-72
MeSH Terms: Animals, Cell Line, Tumor, ErbB Receptors, Gastrointestinal Neoplasms, Gene Expression Regulation, Neoplastic, Heparin-binding EGF-like Growth Factor, Humans, Interleukin-4, Macrophages, Peritoneal, Mice, Mice, Knockout, RAW 264.7 Cells, Transcriptional Activation
Show Abstract · Added April 6, 2017
EGF receptor (EGFR) in tumor cells serves as a tumor promoter. However, information about EGFR activation in macrophages in regulating M2 polarization and tumor development is limited. This study aimed to investigate the effects of EGFR activation in macrophages on M2 polarization and development of gastrointestinal tumors. IL-4, a cytokine to elicit M2 polarization, stimulated release of an EGFR ligand, HB-EGF, and transactivation and down-regulation of EGFR in Raw 264.7 cells and peritoneal macrophages from WT mice. Knockdown of HB-EGF in macrophages inhibited EGFR transactivation by IL-4. IL-4-stimulated STAT6 activation, Arg1 and YM1 gene expression, and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr(wa5) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr(fl/fl) LysM-Cre mice with myeloid cell-specific EGFR deletion. Chitin induced a higher level of M2 polarization in peritoneal macrophages in Egfr(fl/fl) LysM-Cre mice than that in Egfr(fl/fl) mice. Accordingly, IL-4-conditioned medium stimulated growth and epithelial-to-mesenchymal transition in gastric epithelial and colonic tumor cells, which were suppressed by that from Raw 264.7 cells with HB-EGF knockdown but promoted by that from Egfr(wa5) and Egfr(fl/fl) LysM-Cre peritoneal macrophages. Clinical assessment revealed that the number of macrophages with EGFR expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers. Thus, IL-4-stimulated HB-EGF-dependent transactivation of EGFR in macrophages may mediate inhibitory feedback for M2 polarization and HB-EGF production, thereby inhibiting gastrointestinal tumor growth.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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13 MeSH Terms
Interaction of Gcn4 with target gene chromatin is modulated by proteasome function.
Howard GC, Tansey WP
(2016) Mol Biol Cell 27: 2735-41
MeSH Terms: Adenosine Triphosphatases, Basic-Leucine Zipper Transcription Factors, Cell Cycle Proteins, Chromatin, DNA-Binding Proteins, Molecular Chaperones, Proteasome Endopeptidase Complex, Proteolysis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factors, Transcriptional Activation, Ubiquitin, Ubiquitination, Valosin Containing Protein
Show Abstract · Added March 26, 2019
The ubiquitin-proteasome system (UPS) influences gene transcription in multiple ways. One way in which the UPS affects transcription centers on transcriptional activators, the function of which can be stimulated by components of the UPS that also trigger their destruction. Activation of transcription by the yeast activator Gcn4, for example, is attenuated by mutations in the ubiquitin ligase that mediates Gcn4 ubiquitylation or by inhibition of the proteasome, leading to the idea that ubiquitin-mediated proteolysis of Gcn4 is required for its activity. Here we probe the steps in Gcn4 activity that are perturbed by disruption of the UPS. We show that the ubiquitylation machinery and the proteasome control different steps in Gcn4 function and that proteasome activity is required for the ability of Gcn4 to bind to its target genes in the context of chromatin. Curiously, the effect of proteasome inhibition on Gcn4 activity is suppressed by mutations in the ubiquitin-selective chaperone Cdc48, revealing that proteolysis per se is not required for Gcn4 activity. Our data highlight the role of Cdc48 in controlling promoter occupancy by Gcn4 and support a model in which ubiquitylation of activators-not their destruction-is important for function.
© 2016 Howard and Tansey. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells.
Wang Y, Liu L, Moore DJ, Shen X, Peek RM, Acra SA, Li H, Ren X, Polk DB, Yan F
(2017) Mucosal Immunol 10: 373-384
MeSH Terms: Animals, Antibody Formation, B-Lymphocytes, Bacterial Proteins, Cells, Cultured, Epithelial Cells, ErbB Receptors, Immunoglobulin A, Intestine, Small, Lactobacillus rhamnosus, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, RNA, Small Interfering, Transcriptional Activation, Tumor Necrosis Factor Ligand Superfamily Member 13, Up-Regulation
Show Abstract · Added June 30, 2016
p40, a Lactobacillus rhamnosus GG (LGG)-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells, leading to amelioration of intestinal injury and inflammation. To elucidate mechanisms by which p40 regulates mucosal immunity to prevent inflammation, this study aimed to determine the effects and mechanisms of p40 on regulation of a proliferation-inducing ligand (APRIL) expression in intestinal epithelial cells for promoting immunoglobulin A (IgA) production. p40 upregulated April gene expression and protein production in mouse small intestine epithelial (MSIE) cells, which were inhibited by blocking EGFR expression and kinase activity. Enteroids from Egfr, but not Egfr-Vil-Cre mice with EGFR specifically deleted in intestinal epithelial cells, exhibited increased April gene expression by p40 treatment. p40-conditioned media from MSIE cells increased B-cell class switching to IgA cells and IgA production, which was suppressed by APRIL receptor-neutralizing antibodies. Treatment of B cells with p40 did not show any effects on IgA production. p40 treatment increased April gene expression and protein production in small intestinal epithelial cells, fecal IgA levels, IgAB220, IgACD19, and IgA plasma cells in lamina propria of Egfr, but not of Egfr-Vil-Cre, mice. Thus p40 upregulates EGFR-dependent APRIL production in intestinal epithelial cells, which may contribute to promoting IgA production.
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18 MeSH Terms
A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1.
Nnamani MC, Ganguly S, Erkenbrack EM, Lynch VJ, Mizoue LS, Tong Y, Darling HL, Fuxreiter M, Meiler J, Wagner GP
(2016) Cell Rep 15: 2097-2108
MeSH Terms: Allosteric Regulation, Amino Acid Sequence, Amino Acid Substitution, Animals, Biological Evolution, CREB-Binding Protein, DNA-Activated Protein Kinase, Forkhead Box Protein O1, HeLa Cells, Homeodomain Proteins, Humans, Intrinsically Disordered Proteins, Mice, Models, Biological, Models, Molecular, Phosphorylation, Protein Binding, Protein Domains, Protein Structure, Secondary, Transcriptional Activation
Show Abstract · Added April 8, 2017
Transcription factors (TFs) play multiple roles in development. Given this multifunctionality, it has been assumed that TFs are evolutionarily highly constrained. Here, we investigate the molecular mechanisms for the origin of a derived functional interaction between two TFs, HOXA11 and FOXO1. We have previously shown that the regulatory role of HOXA11 in mammalian endometrial stromal cells requires interaction with FOXO1, and that the physical interaction between these proteins evolved before their functional cooperativity. Here, we demonstrate that the derived functional cooperativity between HOXA11 and FOXO1 is due to derived allosteric regulation of HOXA11 by FOXO1. This study shows that TF function can evolve through changes affecting the functional output of a pre-existing protein complex.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis.
Astudillo L, Da Silva TG, Wang Z, Han X, Jin K, VanWye J, Zhu X, Weaver K, Oashi T, Lopes PE, Orton D, Neitzel LR, Lee E, Landgraf R, Robbins DJ, MacKerell AD, Capobianco AJ
(2016) Cancer Res 76: 3593-603
MeSH Terms: Animals, Cell Line, Tumor, DNA-Binding Proteins, Humans, Mice, Neoplasms, Receptors, Notch, Somites, Thiazolidines, Transcription Factors, Transcriptional Activation, Zebrafish
Show Abstract · Added February 13, 2017
In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593-603. ©2016 AACR.
©2016 American Association for Cancer Research.
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12 MeSH Terms
Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions.
Choi E, Hendley AM, Bailey JM, Leach SD, Goldenring JR
(2016) Gastroenterology 150: 918-30.e13
MeSH Terms: Animals, Anticarcinogenic Agents, Benzimidazoles, Cell Differentiation, Cell Lineage, Cell Proliferation, Cell Transformation, Neoplastic, Chief Cells, Gastric, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Genes, ras, Genetic Predisposition to Disease, Humans, Macrophages, Male, Metaplasia, Mice, Inbred C57BL, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, Mutation, Phenotype, Protein Kinase Inhibitors, Signal Transduction, Stomach Neoplasms, Time Factors, Transcriptional Activation
Show Abstract · Added March 28, 2016
BACKGROUND & AIMS - Gastric cancer develops in the context of parietal cell loss, spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM). We investigated whether expression of the activated form of Ras in gastric chief cells of mice leads to the development of SPEM, as well as progression of metaplasia.
METHODS - We studied Mist1-CreERT2Tg/+;LSL-K-Ras(G12D)Tg/+ (Mist1-Kras) mice, which express the active form of Kras in chief cells on tamoxifen exposure. We studied Mist1-CreERT2Tg/+;LSL-KRas (G12D)Tg/+;R26RmTmG/+ (Mist1-Kras-mTmG) mice to examine whether chief cells that express active Kras give rise to SPEM and IM. Some mice received intraperitoneal injections of the Mitogen-activated protein kinase kinase (MEK) inhibitor, selumetinib, for 14 consecutive days. Gastric tissues were collected and analyzed by immunohistochemistry, immunofluorescence, and quantitative polymerase chain reaction.
RESULTS - Mist1-Kras mice developed metaplastic glands, which completely replaced normal fundic lineages and progressed to IM within 3-4 months after tamoxifen injection. The metaplastic glands expressed markers of SPEM and IM, and were infiltrated by macrophages. Lineage tracing studies confirmed that the metaplasia developed directly from Kras (G12D)-induced chief cells. Selumetinib induced persistent regression of SPEM and IM, and re-established normal mucosal cells, which were derived from normal gastric progenitor cells.
CONCLUSIONS - Expression of activated Ras in chief cells of Mist1-Kras mice led to the full range of metaplastic lineage transitions, including SPEM and IM. Inhibition of Ras signaling by inhibition of MEK might reverse preneoplastic metaplasia in the stomach.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
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27 MeSH Terms
LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding.
Layer JH, Alford CE, McDonald WH, Davé UP
(2016) Mol Cell Biol 36: 488-506
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amino Acid Substitution, Cell Line, DNA-Binding Proteins, Humans, Jurkat Cells, LIM Domain Proteins, Leukemia, T-Cell, Molecular Sequence Data, Mutation, Protein Interaction Domains and Motifs, Protein Interaction Maps, Protein Stability, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation
Show Abstract · Added January 26, 2016
LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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17 MeSH Terms