Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 21

Publication Record


DNA methyltransferase 3a and mitogen-activated protein kinase signaling regulate the expression of fibroblast growth factor-inducible 14 (Fn14) during denervation-induced skeletal muscle atrophy.
Tajrishi MM, Shin J, Hetman M, Kumar A
(2014) J Biol Chem 289: 19985-99
MeSH Terms: Animals, Base Sequence, Conserved Sequence, CpG Islands, DNA, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Gene Expression, Gene Knockdown Techniques, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Models, Biological, Molecular Sequence Data, Muscle Denervation, Muscle, Skeletal, Muscular Atrophy, Promoter Regions, Genetic, RNA, Small Interfering, Receptors, Tumor Necrosis Factor, Sequence Homology, Nucleic Acid, Sp1 Transcription Factor, TWEAK Receptor, Transcription Factor AP-1
Show Abstract · Added October 30, 2014
The TWEAK-fibroblast growth factor-inducible 14 (Fn14) system is a critical regulator of denervation-induced skeletal muscle atrophy. Although the expression of Fn14 is a rate-limiting step in muscle atrophy on denervation, mechanisms regulating gene expression of Fn14 remain unknown. Methylation of CpG sites within promoter region is an important epigenetic mechanism for gene silencing. Our study demonstrates that Fn14 promoter contains a CpG island close to transcription start site. Fn14 promoter also contains multiple consensus DNA sequence for transcription factors activator protein 1 (AP1) and specificity protein 1 (SP1). Denervation diminishes overall genomic DNA methylation and causes hypomethylation at specific CpG sites in Fn14 promoter leading to the increased gene expression of Fn14 in skeletal muscle. Abundance of DNA methyltransferase 3a (Dnmt3a) and its interaction with Fn14 promoter are repressed in denervated skeletal muscle of mice. Overexpression of Dnmt3a inhibits the gene expression of Fn14 and attenuates skeletal muscle atrophy upon denervation. Denervation also causes the activation of ERK1/2, JNK1/2, and ERK5 MAPKs and AP1 and SP1, which stimulate the expression of Fn14 in skeletal muscle. Collectively, our study provides novel evidence that Dnmt3a and MAPK signaling regulate the levels of Fn14 in skeletal muscle on denervation.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin.
Goswami S, Yee SW, Stocker S, Mosley JD, Kubo M, Castro R, Mefford JA, Wen C, Liang X, Witte J, Brett C, Maeda S, Simpson MD, Hedderson MM, Davis RL, Roden DM, Giacomini KM, Savic RM
(2014) Clin Pharmacol Ther 96: 370-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Glycated Hemoglobin A, Hepatocyte Nuclear Factor 4, Homozygote, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Models, Biological, Multivariate Analysis, PPAR alpha, Pharmacogenetics, Phenotype, Polymorphism, Single Nucleotide, Retrospective Studies, Sp1 Transcription Factor, Transcription Factors, Treatment Outcome, United States, Young Adult
Show Abstract · Added June 26, 2014
One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.
0 Communities
1 Members
0 Resources
27 MeSH Terms
NADPH oxidase deficiency results in reduced alveolar macrophage 5-lipoxygenase expression and decreased leukotriene synthesis.
Coffey MJ, Serezani CH, Phare SM, Flamand N, Peters-Golden M
(2007) J Leukoc Biol 82: 1585-91
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Arachidonic Acid, Cells, Cultured, Culture Media, Conditioned, Early Growth Response Protein 1, Leukotrienes, Macrophages, Alveolar, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidases, Onium Compounds, Rats, Reactive Oxygen Species, Sp1 Transcription Factor
Show Abstract · Added May 4, 2017
Reactive oxygen intermediates (ROI) play an important role in cell signaling in addition to their role in microbial killing. We have shown previously that exogenous ROI regulate activity of the enzyme 5-lipoxygenase (5-LO) in alveolar macrophages (AM). Here, we examined the role of endogenous ROI, specifically generated by NADPH oxidase, in the regulation of leukotriene (LT) synthetic capacity in AM, which from NADPH oxidase knockout (KO) mice, was significantly less than that from wild-type (WT) AM. The decrease in LT synthesis could not be explained by reduced release of the substrate for 5-LO, arachidonic acid. However, the expression of 5-LO was reduced approximately 50% in AM from NADPH oxidase KO mice compared with WT mice. Reduced 5-LO expression could be reproduced by treating WT AM with ROI scavengers and with selective pharmacologic inhibitors of NADPH oxidase. Furthermore, conditioned media from WT AM augmented 5-LO metabolism in AM from NADPH oxidase KO mice. This decrease in 5-LO expression in NADPH oxidase KO cells was associated with decreased expression of the transcription factors, specificity protein-1 and early growth response-1, both of which are known to regulate 5-LO mRNA expression. These data reveal a previously unrecognized influence of endogenous ROI generated by NADPH oxidase on expression of the key LT biosynthetic protein, 5-LO. In view of the antimicrobial actions of LT, a reduction in LT synthetic capacity by AM from NADPH oxidase KO mice may contribute to the susceptibility of these animals to infection.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Functional zinc finger/sleeping beauty transposase chimeras exhibit attenuated overproduction inhibition.
Wilson MH, Kaminski JM, George AL
(2005) FEBS Lett 579: 6205-9
MeSH Terms: Carrier Proteins, Gene Transfer Techniques, Humans, Mutation, Recombinant Fusion Proteins, Repressor Proteins, Sp1 Transcription Factor, Transposases, Zinc Fingers
Show Abstract · Added March 14, 2018
The sleeping beauty (SB) transposon system has potential utility in gene transfer applications but lacks specificity for genomic integration and exhibits overproduction inhibition which limits in vivo activity. Targeting transposition may be possible by coupling a specific DNA binding domain to the SB transposase, but it is not known if this strategy will preserve or disrupt activity of the system. We engineered and tested chimeric SB transposases with two different human zinc finger DNA binding domain elements, Sp1 and zinc finger 202 (ZNF202). Addition of Sp1 to the C-terminus abolished transposase activity whereas N-terminal addition of either Sp1 or ZNF202 did not. Transposition activity exhibited by N-terminal chimeras was increased to levels similar to native SB through the use of a hyperactive transposase (SB12) and activating transposon mutations. Importantly, addition of DNA binding domains to the transposase N-terminus resulted in attenuation of overproduction inhibition, a major limitation of this system. These findings suggest that SB transposase chimeras may have specific advantages over the native enzyme.
0 Communities
1 Members
0 Resources
9 MeSH Terms
A G/C element mediates repression of the SM22alpha promoter within phenotypically modulated smooth muscle cells in experimental atherosclerosis.
Wamhoff BR, Hoofnagle MH, Burns A, Sinha S, McDonald OG, Owens GK
(2004) Circ Res 95: 981-8
MeSH Terms: Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Becaplermin, Cell Differentiation, Cells, Cultured, Crosses, Genetic, Extracellular Matrix Proteins, Gene Silencing, Genes, Reporter, Hypercholesterolemia, Lac Operon, Mice, Mice, Inbred CBA, Mice, Transgenic, Microfilament Proteins, Muscle Proteins, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Phenotype, Platelet-Derived Growth Factor, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-sis, Rats, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Serum Response Element, Sp1 Transcription Factor
Show Abstract · Added May 5, 2016
A hallmark of smooth muscle cell (SMC) phenotypic switching in atherosclerotic lesions is suppression of SMC differentiation marker gene expression. Yet little is known regarding the molecular mechanisms that control this process. Here we show that transcription of the SMC differentiation marker gene SM22alpha is reduced in atherosclerotic lesions and identify a cis regulatory element in the SM22alpha promoter required for this process. Transgenic mice carrying the SM22alpha promoter-beta-galactosidase (beta-gal) reporter transgene were crossed to apolipoprotein E (ApoE)-/- mice. Cells of the fibrous cap, intima, and underlying media showed complete loss of beta-gal activity in advanced atherosclerotic lesions. Of major significance, mutation of a G/C-rich cis element in the SM22alpha promoter prevented the decrease in SM22alpha promoter-beta-gal reporter transgene expression, including in cells that compose the fibrous cap of the lesion and in medial cells in proximity to the lesion. To begin to assess mechanisms whereby the G/C repressor element mediates suppression of SM22alpha in atherosclerosis, we tested the hypothesis that effects may be mediated by platelet-derived growth factor (PDGF)-BB-induced increases in the G/C binding transcription factor Sp1. Consistent with this hypothesis, results of studies in cultured SMCs showed that: (1) PDGF-BB increased expression of Sp1; (2) PDGF-BB and Sp1 profoundly suppressed SM22alpha promoter activity as well as smooth muscle myosin heavy chain promoter activity through mechanisms that were at least partially dependent on the G/C cis element; and (3) a short interfering RNA to Sp1 increased basal expression and attenuated PDGF-BB induced suppression of SM22alpha. Together, these results support a model whereby a G/C repressor element within the SM22alpha promoter mediates transcriptional repression of this gene within phenotypically modulated SMCs in experimental atherosclerosis and provide indirect evidence implicating PDGF-BB and Sp1 as possible mediators of these effects.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Common variants at the PCOL2 and Sp1 binding sites of the COL1A1 gene and their interactive effect influence bone mineral density in Caucasians.
Liu PY, Lu Y, Long JR, Xu FH, Shen H, Recker RR, Deng HW
(2004) J Med Genet 41: 752-7
MeSH Terms: Binding Sites, Bone Density, Bone and Bones, Collagen Type I, European Continental Ancestry Group, Female, Genetic Variation, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Response Elements, Sp1 Transcription Factor
Show Abstract · Added December 10, 2013
BACKGROUND - Osteoporosis, mainly characterised by low bone mineral density (BMD), is a serious public health problem. The collagen type I alpha 1 (COL1A1) gene is a prominent candidate gene for osteoporosis. Here, we examined whether genetic variants at the COL1A1 gene can influence BMD variation.
METHODS - BMD was measured at nine skeletal sites in 313 Caucasian males and 308 Caucasian females. We screened four single nucleotide polymorphisms (SNPs) at the COL1A1 gene: PCOL2 (-1997 G/T) in the promoter, Sp1 (1546 G/T) in the intron 1, Gly19Cys (3911 G/A) in exon 8, and Ala897Thr (13 773 G/A) in exon 45. Univariate and multivariate association approaches were used in the analyses.
RESULTS - In multivariate analyses, we found a strong association between the PCOL2 SNP and BMD (p = 0.007 to 0.024) and a suggestive association between the Sp1 SNP and BMD (p = 0.023 to 0.048) in elderly Caucasian females. Interestingly, the interaction of these two SNPs was highly significantly associated with BMD variation (p = 0.001 to 0.003). The haplotype GG at the two SNPs had, on average, 2.7% higher BMD than non-carriers (p = 0.006 to 0.026).
CONCLUSIONS - Our data suggested that the common genetic variants at the PCOL2 and Sp1 sites, and importantly, their interactive effects, may contribute to BMD variation in elderly Caucasian females. Further studies are necessary to delineate the mechanisms underlying the effects of these common variants on BMD variation and to test their clinical relevance for general populations. In addition, our study highlighted the importance of multivariate analyses when multiple correlated phenotypes are under study.
0 Communities
1 Members
0 Resources
14 MeSH Terms
TGF-beta1 induction of the adenine nucleotide translocator 1 in astrocytes occurs through Smads and Sp1 transcription factors.
Law AK, Gupta D, Levy S, Wallace DC, McKeon RJ, Buck CR
(2004) BMC Neurosci 5: 1
MeSH Terms: Adenine Nucleotide Translocator 1, Animals, Astrocytes, Binding Sites, Cells, Cultured, Cerebral Cortex, Collodion, DNA-Binding Proteins, Electrophoretic Mobility Shift Assay, Gene Expression Regulation, Implants, Experimental, Mice, Mutagenesis, Site-Directed, Promoter Regions, Genetic, Response Elements, Sequence Deletion, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Sp1 Transcription Factor, Trans-Activators, Transforming Growth Factor beta, Transforming Growth Factor beta1
Show Abstract · Added February 28, 2014
BACKGROUND - The adenine nucleotide translocator 1 (Ant1) is an inner mitochondrial membrane protein involved with energy mobilization during oxidative phosphorylation. We recently showed that rodent Ant1 is upregulated by transforming growth factor-beta (TGF-beta) in reactive astrocytes following CNS injury. In the present study, we describe the molecular mechanisms by which TGF-beta1 regulates Ant1 gene expression in cultured primary rodent astrocytes.
RESULTS - Transcription reporter analysis verified that TGF-beta1 regulates transcription of the mouse Ant1 gene, but not the gene encoding the closely related Ant2 isoform. A 69 basepair TGF-beta1 responsive element of the Ant1 promoter was also identified. Electrophoretic mobility shift assays demonstrated that astrocyte nuclear proteins bind to this response element and TGF-beta1 treatment recruits additional nuclear protein binding to this element. Antibody supershift and promoter deletion analyses demonstrated that Sp1 consensus binding sites in the RE are important for TGF-beta1 regulation of Ant1 in astrocytes. Additionally, we demonstrate that Smad 2, 3 and 4 transcription factors are expressed in injured cerebral cortex and in primary astrocyte cultures. TGF-beta1 activated Smad transcription factors also contribute to Ant1 regulation since transcription reporter assays in the presence of dominant negative (DN)-Smads 3 and 4 significantly reduced induction of Ant1 by TGF-beta1.
CONCLUSION - The specific regulation of Ant1 by TGF-beta1 in astrocytes involves a cooperative interaction of both Smad and Sp1 binding elements located immediately upstream of the transcriptional start site. The first report of expression of Smads 2, 3 and 4 in astrocytes provided here is consistent with a regulation of Ant1 gene expression by these transcription factors in reactive astrocytes. Given the similarity in TGF-beta1 regulation of Ant1 with other genes that are thought to promote neuronal survival, this interaction may represent a general mechanism that underlies the neuroprotective effects of TGF-beta1.
0 Communities
1 Members
0 Resources
24 MeSH Terms
High glucose and insulin promote O-GlcNAc modification of proteins, including alpha-tubulin.
Walgren JL, Vincent TS, Schey KL, Buse MG
(2003) Am J Physiol Endocrinol Metab 284: E424-34
MeSH Terms: Acetylglucosamine, Animals, Cells, Cultured, Glucose, Glycosylation, HSP70 Heat-Shock Proteins, Hypoglycemic Agents, Insulin, Insulin Resistance, Mass Spectrometry, Membrane Proteins, Muscle Cells, Sp1 Transcription Factor, Tubulin
Show Abstract · Added May 27, 2014
Increased flux through the hexosamine biosynthesis pathway has been implicated in the development of glucose-induced insulin resistance and may promote the modification of certain proteins with O-linked N-acetylglucosamine (O-GlcNAc). L6 myotubes (a model of skeletal muscle) were incubated for 18 h in 5 or 25 mM glucose with or without 10 nM insulin. As assessed by immunoblotting with an O-GlcNAc-specific antibody, high glucose and/or insulin enhanced O-GlcNAcylation of numerous proteins, including the transcription factor Sp1, a known substrate for this modification. To identify novel proteins that may be O-GlcNAc modified in a glucose concentration/insulin-responsive manner, total cell membranes were separated by one- or two-dimensional gel electrophoresis. Selected O-GlcNAcylated proteins were identified by mass spectrometry (MS) analysis. MS sequencing of tryptic peptides identified member(s) of the heat shock protein 70 (HSP70) family and rat alpha-tubulin. Immunoprecipitation/immunoblot studies demonstrated several HSP70 isoforms and/or posttranslational modifications, some with selectively enhanced O-GlcNAcylation following exposure to high glucose plus insulin. In conclusion, in L6 myotubes, Sp1, membrane-associated HSP70, and alpha-tubulin are O-GlcNAcylated; the modification is markedly enhanced by sustained increased glucose flux.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1.
Datta PK, Blake MC, Moses HL
(2000) J Biol Chem 275: 40014-9
MeSH Terms: Animals, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Humans, Plasminogen Activator Inhibitor 1, Smad3 Protein, Smad4 Protein, Sp1 Transcription Factor, Trans-Activators, Transforming Growth Factor beta
Show Abstract · Added February 17, 2014
Members of the transforming growth factor-beta (TGF-beta) superfamily mediate a broad range of biological activities by regulating the expression of target genes. Smad proteins play a critical role in this process by binding directly to the promoter elements and/or associating with other transcription factors. TGF-beta1 up-regulates several genes transcriptionally through Sp1 binding sites; however, the mechanism of TGF-beta induction of gene expression through Sp1 sites is largely unknown. Here we report the identification of a novel 38-base pair TGF-beta-responsive element in the human plasminogen activator inhibitor-1 (PAI-1) promoter, which contains two Sp1 binding sites, and is required for TGF-beta-induced Smad-dependent transcriptional activation. Three canonical Sp1 binding sites also support strong transcriptional activation by TGF-beta and Smads from a minimal heterologous promoter. TGF-beta induction of PAI-1 and p21 is blocked by the Sp1 inhibitor mithramycin, implicating Sp1 in the in vivo regulation of these genes by TGF-beta. We show that the association between endogenous Sp1 and Smad3 is induced by TGF-beta in several cell lines; however, Smad4 shows constitutive interaction with Sp1. These data provide novel insights into the mechanism by which TGF-beta up-regulates several gene expression by activating Sp1-dependent transcription through the induction of Smad/Sp1 complex formation.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Dynamic expression and activity of NF-kappaB during post-natal mammary gland morphogenesis.
Brantley DM, Yull FE, Muraoka RS, Hicks DJ, Cook CM, Kerr LD
(2000) Mech Dev 97: 149-55
MeSH Terms: Animals, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Female, Humans, I-kappa B Proteins, Mammary Glands, Animal, Mice, Mice, Inbred C57BL, Morphogenesis, NF-KappaB Inhibitor alpha, NF-kappa B, NF-kappa B p50 Subunit, Pregnancy, Protein Precursors, Sp1 Transcription Factor, Transcription Factor RelA, Tubulin
Show Abstract · Added March 5, 2014
The Rel/NF-kappaB family of transcription factors has been implicated in such diverse cellular processes as proliferation, differentiation, and apoptosis. As each of these processes occurs during post-natal mammary gland morphogenesis, the expression and activity of NF-kappaB factors in the murine mammary gland were examined. Immunohistochemical and immunoblot analyses revealed expression of the p105/p50 and RelA subunits of NF-kappaB, as well as the major inhibitor, IkappaBalpha, in the mammary epithelium during pregnancy, lactation, and involution. Electrophoretic mobility shift assay (EMSA) demonstrated that DNA-binding complexes containing p50 and RelA were abundant during pregnancy and involution, but not during lactation. Activity of an NF-kappaB-dependent luciferase reporter in transgenic mice was highest during pregnancy, decreased to near undetectable levels during lactation, and was elevated during involution. This highly regulated pattern of activity was consistent with the modulated expression of p105/p50, RelA, and IkappaBalpha.
0 Communities
3 Members
0 Resources
19 MeSH Terms