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BET bromodomain inhibitors suppress EWS-FLI1-dependent transcription and the IGF1 autocrine mechanism in Ewing sarcoma.
Loganathan SN, Tang N, Fleming JT, Ma Y, Guo Y, Borinstein SC, Chiang C, Wang J
(2016) Oncotarget 7: 43504-43517
MeSH Terms: Animals, Antineoplastic Agents, Autocrine Communication, Azepines, Bone Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Survival, Epigenesis, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor I, Mice, Mice, Nude, NIH 3T3 Cells, Oncogene Proteins, Fusion, Proteins, Proto-Oncogene Protein c-fli-1, Proto-Oncogene Proteins c-akt, RNA-Binding Protein EWS, Receptors, Somatomedin, Sarcoma, Ewing, Signal Transduction, Transcription, Genetic, Triazoles, Xenograft Model Antitumor Assays
Show Abstract · Added November 19, 2016
Ewing sarcoma is driven by characteristic chromosomal translocations between the EWSR1 gene with genes encoding ETS family transcription factors (EWS-ETS), most commonly FLI1. However, direct pharmacological inhibition of transcription factors like EWS-FLI1 remains largely unsuccessful. Active gene transcription requires orchestrated actions of many epigenetic regulators, such as the bromodomain and extra-terminal domain (BET) family proteins. Emerging BET bromodomain inhibitors have exhibited promising antineoplastic activities via suppression of oncogenic transcription factors in various cancers. We reasoned that EWS-FLI1-mediated transcription activation might be susceptible to BET inhibition. In this study, we demonstrated that small molecule BET bromodomain inhibitors repressed EWS-FLI1-driven gene signatures and downregulated important target genes. However, expression of EWS-FLI1 was not significantly affected. Repression of autocrine IGF1 by BET inhibitors led to significant inhibition of the IGF1R/AKT pathway critical to Ewing sarcoma cell proliferation and survival. Consistently, BET inhibitors impaired viability and clonogenic survival of Ewing sarcoma cell lines and blocked EWS-FLI1-induced transformation of mouse NIH3T3 fibroblast cells. Selective depletion of individual BET genes partially phenocopied the actions of BET inhibitors. Finally, the prototypical BET inhibitor, JQ1, significantly repressed Ewing sarcoma xenograft tumor growth. These findings suggest therapeutic potential of BET inhibitors in Ewing sarcoma and highlight an emerging paradigm of using epigenetic agents to treat cancers driven by fusion transcription factors.
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28 MeSH Terms
WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma.
Wen J, Lee J, Malhotra A, Nahta R, Arnold AR, Buss MC, Brown BD, Maier C, Kenney AM, Remke M, Ramaswamy V, Taylor MD, Castellino RC
(2016) Oncogene 35: 5552-5564
MeSH Terms: Animals, Biomarkers, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cerebellar Neoplasms, Gene Knockdown Techniques, Hedgehog Proteins, Humans, Medulloblastoma, Mice, Mice, Transgenic, NIH 3T3 Cells, Neural Stem Cells, Protein Phosphatase 2C, Signal Transduction, Tumor Suppressor Protein p53
Show Abstract · Added April 25, 2016
High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.
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18 MeSH Terms
MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer.
Edmonds MD, Boyd KL, Moyo T, Mitra R, Duszynski R, Arrate MP, Chen X, Zhao Z, Blackwell TS, Andl T, Eischen CM
(2016) J Clin Invest 126: 349-64
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Animals, Cell Line, Tumor, Female, Humans, Lung Neoplasms, MAP Kinase Signaling System, Male, Mice, MicroRNAs, Mutation, NIH 3T3 Cells, Proto-Oncogene Proteins p21(ras), ras Proteins
Show Abstract · Added February 22, 2016
MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
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15 MeSH Terms
Vinculin controls talin engagement with the actomyosin machinery.
Atherton P, Stutchbury B, Wang DY, Jethwa D, Tsang R, Meiler-Rodriguez E, Wang P, Bate N, Zent R, Barsukov IL, Goult BT, Critchley DR, Ballestrem C
(2015) Nat Commun 6: 10038
MeSH Terms: Actin Cytoskeleton, Actins, Actomyosin, Animals, Cell Polarity, Focal Adhesions, Mice, NIH 3T3 Cells, Protein Binding, Protein Structure, Tertiary, Talin, Vinculin
Show Abstract · Added February 4, 2016
The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs.
1 Communities
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12 MeSH Terms
Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif.
Thomas LR, Foshage AM, Weissmiller AM, Popay TM, Grieb BC, Qualls SJ, Ng V, Carboneau B, Lorey S, Eischen CM, Tansey WP
(2016) Oncogene 35: 3613-8
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Cell Transformation, Neoplastic, Conserved Sequence, Evolution, Molecular, HEK293 Cells, Host Cell Factor C1, Humans, Immunoprecipitation, Mice, Mutation, NIH 3T3 Cells, Protein Binding, Proto-Oncogene Proteins c-myc, Sequence Homology, Amino Acid
Show Abstract · Added March 26, 2019
The MYC family of oncogenes encodes a set of three related transcription factors that are overexpressed in many human tumors and contribute to the cancer-related deaths of more than 70,000 Americans every year. MYC proteins drive tumorigenesis by interacting with co-factors that enable them to regulate the expression of thousands of genes linked to cell growth, proliferation, metabolism and genome stability. One effective way to identify critical co-factors required for MYC function has been to focus on sequence motifs within MYC that are conserved throughout evolution, on the assumption that their conservation is driven by protein-protein interactions that are vital for MYC activity. In addition to their DNA-binding domains, MYC proteins carry five regions of high sequence conservation known as Myc boxes (Mb). To date, four of the Mb motifs (MbI, MbII, MbIIIa and MbIIIb) have had a molecular function assigned to them, but the precise role of the remaining Mb, MbIV, and the reason for its preservation in vertebrate Myc proteins, is unknown. Here, we show that MbIV is required for the association of MYC with the abundant transcriptional coregulator host cell factor-1 (HCF-1). We show that the invariant core of MbIV resembles the tetrapeptide HCF-binding motif (HBM) found in many HCF-interaction partners, and demonstrate that MYC interacts with HCF-1 in a manner indistinguishable from the prototypical HBM-containing protein VP16. Finally, we show that rationalized point mutations in MYC that disrupt interaction with HCF-1 attenuate the ability of MYC to drive tumorigenesis in mice. Together, these data expose a molecular function for MbIV and indicate that HCF-1 is an important co-factor for MYC.
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MeSH Terms
Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC.
Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, Olejniczak ET, Clark T, Dey S, Lorey S, Alicie B, Howard GC, Cawthon B, Ess KC, Eischen CM, Zhao Z, Fesik SW, Tansey WP
(2015) Mol Cell 58: 440-52
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Anisotropy, Binding Sites, Carcinogenesis, Chromatin, Fluorescence Polarization, HEK293 Cells, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Sequence Data, Mutation, NIH 3T3 Cells, Protein Binding, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins c-myc, Sequence Homology, Amino Acid, Two-Hybrid System Techniques
Show Abstract · Added May 15, 2015
MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved "MYC box IIIb" motif that engages a shallow, hydrophobic cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC at ∼80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anticancer therapies against MYC-driven tumors.
Copyright © 2015 Elsevier Inc. All rights reserved.
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3 Members
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22 MeSH Terms
Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.
Ohnuma K, Hatano R, Aune TM, Otsuka H, Iwata S, Dang NH, Yamada T, Morimoto C
(2015) J Immunol 194: 3697-712
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Caveolin 1, Cord Blood Stem Cell Transplantation, Dermis, Dipeptidyl Peptidase 4, Graft vs Host Disease, Graft vs Leukemia Effect, Humans, Interleukins, Lung, Lung Diseases, Mice, Mice, Inbred NOD, Mice, Knockout, NIH 3T3 Cells, Receptors, Fc, Recombinant Fusion Proteins
Show Abstract · Added July 17, 2019
Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγ(null) mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26(+)CD26(+)CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26(+)CD26(+)CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.
Copyright © 2015 by The American Association of Immunologists, Inc.
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MeSH Terms
Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.
Huang J, Zhong Z, Wang M, Chen X, Tan Y, Zhang S, He W, He X, Huang G, Lu H, Wu P, Che Y, Yan YL, Postlethwait JH, Chen W, Wang H
(2015) J Neurosci 35: 2572-87
MeSH Terms: Animals, Animals, Genetically Modified, Attention Deficit Disorder with Hyperactivity, Avoidance Learning, Behavior, Animal, Circadian Rhythm, Dopamine, Dopaminergic Neurons, Impulsive Behavior, Larva, Mice, Motor Activity, NIH 3T3 Cells, Period Circadian Proteins, Tyrosine 3-Monooxygenase, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 20, 2015
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine β hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder.
Copyright © 2015 the authors 0270-6474/15/352572-16$15.00/0.
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17 MeSH Terms
Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles.
Sarett SM, Kilchrist KV, Miteva M, Duvall CL
(2015) J Biomed Mater Res A 103: 3107-16
MeSH Terms: Animals, Biocompatible Materials, Biological Transport, Active, Drug Delivery Systems, Endosomes, Gene Silencing, HEK293 Cells, Humans, Materials Testing, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, NIH 3T3 Cells, Nanoparticles, Palmitic Acid, Polymers, RNA, Small Interfering
Show Abstract · Added March 14, 2018
Clinical translation of siRNA therapeutics has been limited by the inability to effectively overcome the rigorous delivery barriers associated with intracellular-acting biologics. Here, to address both potency and longevity of siRNA gene silencing, pH-responsive micellar nanoparticle (NP) carriers loaded with siRNA conjugated to palmitic acid (siRNA-PA) were investigated as a combined approach to improve siRNA endosomal escape and stability. Conjugation to hydrophobic PA improved NP loading efficiency relative to unmodified siRNA, enabling complete packaging of siRNA-PA at a lower polymer:siRNA ratio. PA conjugation also increased intracellular uptake of the nucleic acid cargo by 35-fold and produced a 3.1-fold increase in intracellular half-life. The higher uptake and improved retention of siRNA-PA NPs correlated to a 2- and 11-fold decrease in gene silencing IC50 in comparison to siRNA NPs in fibroblasts and mesenchymal stem cells, respectively, for both the model gene luciferase and the therapeutically relevant gene prolyl hydroxylase domain protein 2 (PHD2) . PA conjugation also significantly increased longevity of silencing activity following a single treatment in fibroblasts. Thus, conjugation of PA to siRNA paired with endosomolytic NPs is a promising approach to enhance the functional efficacy of siRNA in tissue regenerative and other applications.
Copyright © 2015 Wiley Periodicals, Inc.
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17 MeSH Terms
The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.
Waters AM, Asfahani R, Carroll P, Bicknell L, Lescai F, Bright A, Chanudet E, Brooks A, Christou-Savina S, Osman G, Walsh P, Bacchelli C, Chapgier A, Vernay B, Bader DM, Deshpande C, O' Sullivan M, Ocaka L, Stanescu H, Stewart HS, Hildebrandt F, Otto E, Johnson CA, Szymanska K, Katsanis N, Davis E, Kleta R, Hubank M, Doxsey S, Jackson A, Stupka E, Winey M, Beales PL
(2015) J Med Genet 52: 147-56
MeSH Terms: Animals, Centrioles, Chromosomal Proteins, Non-Histone, Cilia, Exome, Female, Fetus, Genetics, Medical, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Male, Mice, Microcephaly, Microfilament Proteins, Mutation, NIH 3T3 Cells, Pedigree, Pregnancy, Zebrafish
Show Abstract · Added September 28, 2015
BACKGROUND - Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.
METHODS AND RESULTS - Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.
CONCLUSIONS - Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.
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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20 MeSH Terms