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Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.
Kamp F, Scheidt HA, Winkler E, Basset G, Heinel H, Hutchison JM, LaPointe LM, Sanders CR, Steiner H, Huster D
(2018) ACS Chem Neurosci 9: 1702-1713
MeSH Terms: Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Bexarotene, Cholesterol, HEK293 Cells, Humans, Liposomes, Molecular Structure, Neuroprotective Agents, Phosphatidylcholines, Protein Conformation, alpha-Helical, Protein Domains, Receptor, Notch1, Static Electricity
Show Abstract · Added November 21, 2018
Bexarotene is a pleiotropic molecule that has been proposed as an amyloid-β (Aβ)-lowering drug for the treatment of Alzheimer's disease (AD). It acts by upregulation of an apolipoprotein E (apoE)-mediated Aβ clearance mechanism. However, whether bexarotene induces removal of Aβ plaques in mouse models of AD has been controversial. Here, we show by NMR and CD spectroscopy that bexarotene directly interacts with and stabilizes the transmembrane domain α-helix of the amyloid precursor protein (APP) in a region where cholesterol binds. This effect is not mediated by changes in membrane lipid packing, as bexarotene does not share with cholesterol the property of inducing phospholipid condensation. Bexarotene inhibited the intramembrane cleavage by γ-secretase of the APP C-terminal fragment C99 to release Aβ in cell-free assays of the reconstituted enzyme in liposomes, but not in cells, and only at very high micromolar concentrations. Surprisingly, in vitro, bexarotene also inhibited the cleavage of Notch1, another major γ-secretase substrate, demonstrating that its inhibition of γ-secretase is not substrate specific and not mediated by acting via the cholesterol binding site of C99. Our data suggest that bexarotene is a pleiotropic molecule that interfere with Aβ metabolism through multiple mechanisms.
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14 MeSH Terms
Dodecyl-β-melibioside Detergent Micelles as a Medium for Membrane Proteins.
Hutchison JM, Lu Z, Li GC, Travis B, Mittal R, Deatherage CL, Sanders CR
(2017) Biochemistry 56: 5481-5484
MeSH Terms: Amyloid beta-Protein Precursor, Detergents, Diacylglycerol Kinase, Disaccharides, Dynamic Light Scattering, Enzyme Stability, Escherichia coli Proteins, Glucosides, Glycolipids, Hot Temperature, Humans, Micelles, Myelin Proteins, Nuclear Magnetic Resonance, Biomolecular, Particle Size, Peptide Fragments, Protein Interaction Domains and Motifs, Protein Stability, Receptor, Notch1
Show Abstract · Added November 21, 2018
There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-β-melibioside (β-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the β-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-β-maltoside (β-DDM). β-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into β-DDMB yielded activities that were 40% higher than those of DAGK purified into β-DDM. β-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. β-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.
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MeSH Terms
Identification of a Paralog-Specific Notch1 Intracellular Domain Degron.
Broadus MR, Chen TW, Neitzel LR, Ng VH, Jodoin JN, Lee LA, Salic A, Robbins DJ, Capobianco AJ, Patton JG, Huppert SS, Lee E
(2016) Cell Rep 15: 1920-9
MeSH Terms: Amino Acid Sequence, Animals, Cell Extracts, Embryo, Nonmammalian, F-Box Proteins, HEK293 Cells, Humans, Muscle Proteins, Mutation, Protein Binding, Protein Domains, Protein Stability, Proteolysis, Receptor, Notch1, Regulatory Sequences, Nucleic Acid, Sequence Homology, Amino Acid, Transcription, Genetic, Ubiquitin-Protein Ligases, Xenopus, Zebrafish
Show Abstract · Added February 13, 2017
Upon Notch pathway activation, the receptor is cleaved to release the Notch intracellular domain (NICD), which translocates to the nucleus to activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box). We show that mutations in the N1-Box inhibit NICD1 degradation and that the N1-Box is transferable for the promotion of degradation of heterologous proteins in Xenopus egg extracts and in cultured human cells. Mutation of the N1-Box enhances Notch1 activity in cultured human cells and zebrafish embryos. Human cancer mutations within the N1-Box enhance Notch1 signaling in transgenic zebrafish, highlighting the physiological relevance of this destruction signal. We find that binding of the Notch nuclear factor, CSL, to the N1-Box blocks NICD1 turnover. Our studies reveal a mechanism by which degradation of NICD1 is regulated by the N1-Box to minimize stochastic flux and to establish a threshold for Notch1 pathway activation.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Notch Transmembrane Domain: Secondary Structure and Topology.
Deatherage CL, Lu Z, Kim JH, Sanders CR
(2015) Biochemistry 54: 3565-8
MeSH Terms: Humans, Lipid Bilayers, Lysophosphatidylcholines, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Phosphatidylcholines, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Receptor, Notch1, Recombinant Proteins, Surface Properties
Show Abstract · Added February 5, 2016
The Notch signaling pathway is critical in development, neuronal maintenance, and hematopoiesis. An obligate step in the activation of this pathway is cleavage of its transmembrane (TM) domain by γ-secretase. While the soluble domains have been extensively studied, little has been done to characterize its TM and flanking juxtamembrane (JM) segments. Here, we present the results of nuclear magnetic resonance (NMR) studies of the human Notch1 TM/JM domain. The TM domain is largely α-helical. While the flanking JM segments do not adopt regular secondary structure, they interact with the membrane surface, suggesting membrane interactions may play a role in modulating its cleavage by γ-secretase and subsequent NOTCH signaling function.
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13 MeSH Terms
Requirement for ssbp2 in hematopoietic stem cell maintenance and stress response.
Li J, Kurasawa Y, Wang Y, Clise-Dwyer K, Klumpp SA, Liang H, Tailor RC, Raymond AC, Estrov Z, Brandt SJ, Davis RE, Zweidler-McKay P, Amin HM, Nagarajan L
(2014) J Immunol 193: 4654-62
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Marrow, Bone Marrow Transplantation, Cell Differentiation, DNA-Binding Proteins, Gene Expression, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Immunophenotyping, Mice, Mice, Knockout, Phenotype, Receptor, Notch1, Stress, Physiological
Show Abstract · Added February 14, 2015
Transcriptional mechanisms governing hematopoietic stem cell (HSC) quiescence, self-renewal, and differentiation are not fully understood. Sequence-specific ssDNA-binding protein 2 (SSBP2) is a candidate acute myelogenous leukemia (AML) suppressor gene located at chromosome 5q14. SSBP2 binds the transcriptional adaptor protein Lim domain-binding protein 1 (LDB1) and enhances LDB1 stability to regulate gene expression. Notably, Ldb1 is essential for HSC specification during early development and maintenance in adults. We previously reported shortened lifespan and greater susceptibility to B cell lymphomas and carcinomas in Ssbp2(-/-) mice. However, whether Ssbp2 plays a regulatory role in normal HSC function and leukemogenesis is unknown. In this study, we provide several lines of evidence to demonstrate a requirement for Ssbp2 in the function and transcriptional program of hematopoietic stem and progenitor cells (HSPCs) in vivo. We found that hematopoietic tissues were hypoplastic in Ssbp2(-/-) mice, and the frequency of lymphoid-primed multipotent progenitor cells in bone marrow was reduced. Other significant features of these mice were delayed recovery from 5-fluorouracil treatment and diminished multilineage reconstitution in lethally irradiated bone marrow recipients. Dramatic reduction of Notch1 transcripts and increased expression of transcripts encoding the transcription factor E2a and its downstream target Cdkn1a also distinguished Ssbp2(-/-) HSPCs from wild-type HSPCs. Finally, a tendency toward coordinated expression of SSBP2 and the AML suppressor NOTCH1 in a subset of the Cancer Genome Atlas AML cases suggested a role for SSBP2 in AML pathogenesis. Collectively, our results uncovered a critical regulatory function for SSBP2 in HSPC gene expression and function.
Copyright © 2014 by The American Association of Immunologists, Inc.
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16 MeSH Terms
Epigenetic regulation of the Ink4a-Arf (Cdkn2a) tumor suppressor locus in the initiation and progression of Notch1-driven T cell acute lymphoblastic leukemia.
Volanakis EJ, Boothby MR, Sherr CJ
(2013) Exp Hematol 41: 377-86
MeSH Terms: Animals, Binding Sites, Bone Marrow Cells, Cell Line, Cell Transformation, Neoplastic, Cells, Cultured, Coculture Techniques, Cyclin-Dependent Kinase Inhibitor p16, Disease Progression, Dogs, Epigenesis, Genetic, Flow Cytometry, Gene Expression, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes, Thymocytes, Tumor Suppressor Protein p14ARF
Show Abstract · Added December 10, 2013
Activating mutations of NOTCH1 and deletion of the INK4A-ARF (CDKN2A) tumor suppressor locus are two of the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL). In a murine model of T-ALL induced by the intracellular domain of Notch1 (ICN1), the genetic interaction between ICN1 signaling and Arf inactivation is developmentally stage-specific, with a more pronounced requirement for Arf deletion in thymocytes than in bone marrow precursors targeted for transformation. In the thymus, the target cell for transformation is a CD4 and CD8 double-negative progenitor that undergoes T cell receptor beta-chain rearrangement, a cell type in which polycomb silencing of Ink4a-Arf is normally requisite. Epigenetic remodeling during tumor progression licenses Arf as a tumor suppressor and in turn provides the selective pressure for Ink4a-Arf deletion in clonal T-ALLs that emerge.
Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
A novel technique for quantifying mouse heart valve leaflet stiffness with atomic force microscopy.
Sewell-Loftin MK, Brown CB, Baldwin HS, Merryman WD
(2012) J Heart Valve Dis 21: 513-20
MeSH Terms: Animals, Aortic Valve, Aortic Valve Insufficiency, Apolipoproteins E, Biomechanical Phenomena, Heterozygote, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microscopy, Atomic Force, Models, Cardiovascular, Receptor, Notch1, Stress, Mechanical, Swine
Show Abstract · Added February 12, 2015
BACKGROUND AND AIM OF THE STUDY - The use of genetically altered small animal models is a powerful strategy for elucidating the mechanisms of heart valve disease. However, while the ability to manipulate genes in rodent models is well established, there remains a significant obstacle in determining the functional mechanical properties of the genetically mutated leaflets. Hence, a feasibility study was conducted using micromechanical analysis via atomic force microscopy (AFM) to determine the stiffness of mouse heart valve leaflets in the context of age and disease states.
METHODS - A novel AFM imaging technique for the quantification of heart valve leaflet stiffness was performed on cryosectioned tissues. Heart valve leaflet samples were obtained from wild-type mice (2 and 17 months old) and genetically altered mice (10-month-old Notch1 heterozygous and 20-month-old ApoE homozygous). Histology was performed on adjacent sections to determine the extracellular matrix characteristics of the scanned areas.
RESULTS - The 17-month-old wild-type, 10-month-old Notch1, and 20-month-old ApoE aortic valve leaflets were all significantly stiffer than leaflets from 2-month-old wild-type mice. Notch1 leaflets were significantly stiffer than all other leaflets examined, indicating that the Notch1 heterozygous mutation may alter leaflet stiffness, both earlier and to a greater degree than the homozygous ApoE mutation. However, these conclusions must be considered only preliminary due to the small sample size used in this proof-of-concept study.
CONCLUSION - It is believed that this technique can provide a powerful end-point analysis for determining the mechanical properties of heart valve leaflets from genetically altered mice. Further, the technique is complementary to standard histological processing, and does not require excess tissue for mechanical testing. In this proof-of-concept study, AFM was shown to be a powerful tool for investigators of heart valve disease who develop genetically altered animals for their studies.
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14 MeSH Terms
Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients.
Humphreys R, Zheng W, Prince LS, Qu X, Brown C, Loomes K, Huppert SS, Baldwin S, Goudy S
(2012) Hum Mol Genet 21: 1374-83
MeSH Terms: Alagille Syndrome, Animals, Blotting, Western, Calcium-Binding Proteins, Cells, Cultured, Craniofacial Abnormalities, Embryo, Mammalian, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Integrases, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Membrane Proteins, Mesoderm, Mice, Mice, Inbred C57BL, Mice, Knockout, Morphogenesis, Neural Crest, Phenotype, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Serrate-Jagged Proteins, Wnt1 Protein
Show Abstract · Added December 16, 2011
JAGGED1 mutations cause Alagille syndrome, comprising a constellation of clinical findings, including biliary, cardiac and craniofacial anomalies. Jagged1, a ligand in the Notch signaling pathway, has been extensively studied during biliary and cardiac development. However, the role of JAGGED1 during craniofacial development is poorly understood. Patients with Alagille syndrome have midface hypoplasia giving them a characteristic 'inverted V' facial appearance. This study design determines the requirement of Jagged1 in the cranial neural crest (CNC) cells, which encompass the majority of mesenchyme present during craniofacial development. Furthermore, with this approach, we identify the autonomous and non-autonomous requirement of Jagged1 in a cell lineage-specific approach during midface development. Deleting Jagged1 in the CNC using Wnt1-cre; Jag1 Flox/Flox recapitulated the midfacial hypoplasia phenotype of Alagille syndrome. The Wnt1-cre; Jag1 Flox/Flox mice die at postnatal day 30 due to inability to masticate owing to jaw misalignment and poor occlusion. The etiology of midfacial hypoplasia in the Wnt1-cre; Jag1 Flox/Flox mice was a consequence of reduced cellular proliferation in the midface, aberrant vasculogenesis with decreased productive vessel branching and reduced extracellular matrix by hyaluronic acid staining, all of which are associated with midface anomalies and aberrant craniofacial growth. Deletion of Notch1 from the CNC using Wnt1-cre; Notch1 F/F mice did not recapitulate the midface hypoplasia of Alagille syndrome. These data demonstrate the requirement of Jagged1, but not Notch1, within the midfacial CNC population during development. Future studies will investigate the mechanism in which Jagged1 acts in a cell autonomous and cell non-autonomous manner.
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28 MeSH Terms
Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.
Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W, Proby CM, Leigh IM, Collisson EA, Gordon PB, Jakkula L, Pennypacker S, Zou Y, Sharma M, North JP, Vemula SS, Mauro TM, Neuhaus IM, Leboit PE, Hur JS, Park K, Huh N, Kwok PY, Arron ST, Massion PP, Bale AE, Haussler D, Cleaver JE, Gray JW, Spellman PT, South AP, Aster JC, Blacklow SC, Cho RJ
(2011) Proc Natl Acad Sci U S A 108: 17761-6
MeSH Terms: Base Sequence, Carcinoma, Squamous Cell, Cell Communication, Codon, Nonsense, Electrophoretic Mobility Shift Assay, Humans, Lod Score, Lung Neoplasms, Molecular Sequence Data, Receptor, Notch1, Receptor, Notch2, Sequence Analysis, DNA, Signal Transduction, Skin Neoplasms
Show Abstract · Added March 10, 2014
Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.
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14 MeSH Terms
Functional interactions between Lmo2, the Arf tumor suppressor, and Notch1 in murine T-cell malignancies.
Treanor LM, Volanakis EJ, Zhou S, Lu T, Sherr CJ, Sorrentino BP
(2011) Blood 117: 5453-62
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Transformation, Neoplastic, Cocarcinogenesis, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Disease Progression, Female, Gene Expression, LIM Domain Proteins, Loss of Heterozygosity, Male, Metalloproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Neoplastic Stem Cells, Precursor Cells, T-Lymphoid, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Promoter Regions, Genetic, Receptor, Notch1, Signal Transduction
Show Abstract · Added May 27, 2014
LMO2 is a target of chromosomal translocations in T-cell tumors and was activated by retroviral vector insertions in T-cell tumors from X-SCID patients in gene therapy trials. To better understand the cooperating genetic events in LMO2-associated T-cell acute lymphoblastic leukemia (T-ALL), we investigated the roles of Arf tumor suppressor loss and Notch activation in murine models of transplantation. Lmo2 overexpression enhanced the expansion of primitive DN2 thymocytes, eventually facilitating the stochastic induction of clonal CD4(+)/CD8(+) malignancies. Inactivation of the Arf tumor suppressor further increased the self-renewal capacity of the primitive, preleukemic thymocyte pool and accelerated the development of aggressive, Lmo2-induced T-cell lympholeukemias. Notch mutations were frequently detected in these Lmo2-induced tumors. The Arf promoter was not directly engaged by Lmo2 or mutant Notch, and use of a mouse model in which activation of a mutant Notch allele depends on previous engagement of the Arf promoter revealed that Notch activation could occur as a subsequent event in T-cell tumorigenesis. Therefore, Lmo2 cooperates with Arf loss to enhance self-renewal in primitive thymocytes. Notch mutation and Arf inactivation appear to independently cooperate in no requisite order with Lmo2 overexpression in inducing T-ALL, and all 3 events remained insufficient to guarantee immediate tumor development.
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24 MeSH Terms