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The chromosome 3q25 genomic region is associated with measures of adiposity in newborns in a multi-ethnic genome-wide association study.
Urbanek M, Hayes MG, Armstrong LL, Morrison J, Lowe LP, Badon SE, Scheftner D, Pluzhnikov A, Levine D, Laurie CC, McHugh C, Ackerman CM, Mirel DB, Doheny KF, Guo C, Scholtens DM, Dyer AR, Metzger BE, Reddy TE, Cox NJ, Lowe WL, HAPO Study Cooperative Research Group
(2013) Hum Mol Genet 22: 3583-96
MeSH Terms: Adiposity, African Continental Ancestry Group, Asian Continental Ancestry Group, Birth Weight, Body Mass Index, Caribbean Region, Chromosomes, Human, Pair 3, Cohort Studies, Continental Population Groups, Cyclins, Ethnic Groups, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Infant, Newborn, Linear Models, Male, Mexican Americans, Pregnancy, Proteinase Inhibitory Proteins, Secretory, Serine Peptidase Inhibitor Kazal-Type 5, Thailand
Show Abstract · Added February 22, 2016
Newborns characterized as large and small for gestational age are at risk for increased mortality and morbidity during the first year of life as well as for obesity and dysglycemia as children and adults. The intrauterine environment and fetal genes contribute to the fetal size at birth. To define the genetic architecture underlying the newborn size, we performed a genome-wide association study (GWAS) in 4281 newborns in four ethnic groups from the Hyperglycemia and Adverse Pregnancy Outcome Study. We tested for association with newborn anthropometric traits (birth length, head circumference, birth weight, percent fat mass and sum of skinfolds) and newborn metabolic traits (cord glucose and C-peptide) under three models. Model 1 adjusted for field center, ancestry, neonatal gender, gestational age at delivery, parity, maternal age at oral glucose tolerance test (OGTT); Model 2 adjusted for Model 1 covariates, maternal body mass index (BMI) at OGTT, maternal height at OGTT, maternal mean arterial pressure at OGTT, maternal smoking and drinking; Model 3 adjusted for Model 2 covariates, maternal glucose and C-peptide at OGTT. Strong evidence for association was observed with measures of newborn adiposity (sum of skinfolds model 3 Z-score 7.356, P = 1.90×10⁻¹³, and to a lesser degree fat mass and birth weight) and a region on Chr3q25.31 mapping between CCNL and LEKR1. These findings were replicated in an independent cohort of 2296 newborns. This region has previously been shown to be associated with birth weight in Europeans. The current study suggests that association of this locus with birth weight is secondary to an effect on fat as opposed to lean body mass.
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23 MeSH Terms
Cyclin-dependent kinase 9-cyclin K functions in the replication stress response.
Yu DS, Zhao R, Hsu EL, Cayer J, Ye F, Guo Y, Shyr Y, Cortez D
(2010) EMBO Rep 11: 876-82
MeSH Terms: Cell Cycle, Cell Line, Tumor, Chromatin, Cyclin-Dependent Kinase 9, Cyclins, DNA, DNA Replication, Gene Silencing, Humans, Hydroxyurea, Protein Binding, Replication Protein A, Stress, Physiological
Show Abstract · Added February 13, 2014
Cyclin-dependent kinase 9 (CDK9) is a well-characterized subunit of the positive transcription elongation factor b complex in which it regulates transcription elongation in cooperation with cyclin T. However, CDK9 also forms a complex with cyclin K, the function of which is less clear. Using a synthetic lethal RNA interference screen in human cells, we identified CDK9 as a component of the replication stress response. Loss of CDK9 activity causes an increase in spontaneous levels of DNA damage signalling in replicating cells and a decreased ability to recover from a transient replication arrest. This activity is restricted to CDK9-cyclin K complexes and is independent of CDK9-cyclin T complex. CDK9 accumulates on chromatin in response to replication stress and limits the amount of single-stranded DNA in cells under stress. Furthermore, we show that CDK9 and cyclin K interact with ataxia telangiectasia and Rad3-related protein and other checkpoint signalling proteins. These results reveal an unexpectedly direct role for CDK9-cyclin K in checkpoint pathways that maintain genome integrity in response to replication stress.
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13 MeSH Terms
Tob1 is a constitutively expressed repressor of liver regeneration.
Ho KJ, Do NL, Otu HH, Dib MJ, Ren X, Enjyoji K, Robson SC, Terwilliger EF, Karp SJ
(2010) J Exp Med 207: 1197-208
MeSH Terms: Animals, CCAAT-Enhancer-Binding Protein-alpha, Carrier Proteins, Cell Proliferation, Cyclin-Dependent Kinases, Cyclins, Dependovirus, Gene Expression Regulation, Gene Regulatory Networks, Hepatectomy, Hepatocytes, Intracellular Signaling Peptides and Proteins, Liver, Liver Regeneration, Mice, Mice, Inbred C57BL, Organ Size, Protein Binding, Proteins, RNA, Messenger, Repressor Proteins, Ribonucleases, Signal Transduction, Smad Proteins, Transcription, Genetic
Show Abstract · Added May 22, 2014
How proliferative and inhibitory signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified transducer of ErbB2.1 (Tob1), a member of the PC3/BTG1 family of mito-inhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hepatectomy in mice secondary to posttranscriptional mechanisms. Deletion of Tob1 increases hepatocyte proliferation and accelerates restoration of liver mass after hepatectomy. Down-regulation of Tob1 is required for normal liver regeneration, and Tob1 controls hepatocyte proliferation in a dose-dependent fashion. Tob1 associates directly with both Caf1 and cyclin-dependent kinase (Cdk) 1 and modulates Cdk1 kinase activity. In addition, Tob1 has significant effects on the transcription of critical cell cycle components, including E2F target genes and genes involved in p53 signaling. We provide direct evidence that levels of an inhibitory factor control the rate of liver regeneration, and we identify Tob1 as a crucial check point molecule that modulates the expression and activity of cell cycle proteins.
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25 MeSH Terms
Down-regulation of p57Kip2 induces prostate cancer in the mouse.
Jin RJ, Lho Y, Wang Y, Ao M, Revelo MP, Hayward SW, Wills ML, Logan SK, Zhang P, Matusik RJ
(2008) Cancer Res 68: 3601-8
MeSH Terms: Animals, Cell Differentiation, Cell Line, Tumor, Cell Transformation, Neoplastic, Cyclin D, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p57, Cyclins, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Prostatic Neoplasms, Retinoblastoma Protein
Show Abstract · Added December 10, 2013
p57(Kip2) has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57(Kip2) in tumorigenesis and cancer progression. Here, we show that the expression of p57(Kip2) is significantly decreased in human prostate cancer, and the overexpression of p57(Kip2) in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57(Kip2) in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57(Kip2) knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57(Kip2) is an important gene in prostate cancer tumorigenesis, and the p57(Kip2) pathway may be a potential target for prostate cancer prevention and therapy.
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16 MeSH Terms
Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina.
Barton KM, Levine EM
(2008) Dev Dyn 237: 672-82
MeSH Terms: Animals, Cell Cycle, Cell Cycle Proteins, Cyclin A, Cyclin A2, Cyclin B, Cyclin B1, Cyclin D, Cyclins, Histones, Mice, Minichromosome Maintenance Complex Component 6, Phosphorylation, Proliferating Cell Nuclear Antigen, Retina
Show Abstract · Added November 2, 2015
A challenge in studying organogenesis is the ability to identify progenitor cell populations. To address this problem, we characterized the expression patterns of cell cycle proteins during mouse retinal development and used flow cytometry to determine the expression profiles in the cell cycle. We found that MCM6 and PCNA are expressed in essentially all retinal progenitor cells throughout the proliferative period and these proteins are readily detectable in all cell cycle phases. Furthermore, their expression levels are downregulated as cells exit the cell cycle and differentiate. We also analyzed the expression of Cyclins D1, A2, and B1, and phosphorylated Histone H3 and found unexpected expression patterns and cell cycle profiles. The combined utilization of the markers tested and the use of flow cytometry should further facilitate the study of stem and progenitor cell behavior during development and in adult tissues.
(c) 2008 Wiley-Liss, Inc.
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15 MeSH Terms
Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression.
Liao HJ, Carpenter G
(2007) Mol Biol Cell 18: 1064-72
MeSH Terms: Animals, Cell Nucleus, Cyclin D, Cyclins, Endoplasmic Reticulum, Epidermal Growth Factor, ErbB Receptors, Gene Expression, Gene Expression Regulation, HeLa Cells, Humans, Membrane Proteins, Mice, Models, Biological, Protein Binding, Protein Transport, RNA, Messenger, SEC Translocation Channels
Show Abstract · Added August 23, 2013
The epidermal growth factor (EGF)-dependent trafficking of the intact EGF receptor to the nucleus and its requirement for growth factor induction of cyclin D and other genes has been reported. Unresolved is the mechanism by which this or other transmembrane proteins are excised from a lipid bilayer before nuclear translocalization. We report that, after the addition of EGF, the cell surface EGF receptor is trafficked to the endoplasmic reticulum (ER) where it associates with Sec61beta, a component of the Sec61 translocon, and is retrotranslocated from the ER to the cytoplasm. Abrogation of Sec61beta expression prevents EGF-dependent localization of EGF receptors to the nucleus and expression of cyclin D. This indicates that EGF receptors are trafficked from the ER to the nucleus by a novel pathway that involves the Sec61 translocon.
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18 MeSH Terms
Identification of novel and conserved functional and structural elements of the G1 cyclin Cln3 important for interactions with the CDK Cdc28 in Saccharomyces cerevisiae.
Miller ME, Cross FR, Groeger AL, Jameson KL
(2005) Yeast 22: 1021-36
MeSH Terms: Amino Acid Sequence, CDC28 Protein Kinase, S cerevisiae, Cyclin G, Cyclins, Gene Expression Regulation, Fungal, Molecular Sequence Data, Mutagenesis, Insertional, Mutation, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Structure-Activity Relationship
Show Abstract · Added October 22, 2013
Regions of the budding yeast G1 cyclin Cln3 were characterized using mutational analysis and viability assays to identify functionally relevant and novel mutant alleles of CLN3. Cyclin proteins are conserved, and Cln3 contains a region with homology to the cyclin box, which is thought to mediate physical interactions with the cyclin-dependent kinase. CLN3 was found to have characteristics similar to the conserved cyclin fold found in higher eukaryotic cyclin boxes, which consist of five alpha-helices. Peptide linker sequences inserted within helices 1, 2, 3 and 5 resulted in a loss of Cln3 function, showing cyclin fold structure similar to that previously observed for the G1 cyclin Cln2. A clustered-charge-to-alanine scan mutagenesis revealed two regions of Cln3 important for Cln3-dependent viability. The first region encompasses the conserved cyclin box. The second region is identified with alanine substitutions located well past the cyclin box, just prior to the C-terminal region of Cln3 important for protein stability. Cln3 with mutational changes in each of these regions are expressed at steady-state levels higher than wild-type Cln3, and show some defect in binding to Cdc28. The conserved hydrophobic patch domain (HPD) of cyclins is present within the first helix of the cyclin box. Alanine substitutions introduced into the HPD of Cln3 and Cln2 show functional defects while maintaining physical interaction with Cdc28 as measured by co-immunoprecipitation assay.
Copyright (c) 2005 John Wiley & Sons, Ltd.
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11 MeSH Terms
Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas.
Thompson MA, Stumph J, Henrickson SE, Rosenwald A, Wang Q, Olson S, Brandt SJ, Roberts J, Zhang X, Shyr Y, Kinney MC
(2005) Hum Pathol 36: 494-504
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Cell Cycle Proteins, Child, Cyclin D3, Cyclin-Dependent Kinase Inhibitor p19, Cyclins, Female, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, Lymphoma, Large B-Cell, Diffuse, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added March 5, 2014
Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown. This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules (SYK , LYN , CDC37) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates. Genes highly expressed in both ALK- and ALK+ ALCLs included kinases (LCK, protein kinase C, vav2, and NKIAMRE) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.
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22 MeSH Terms
Constitutively active K-cyclin/cdk6 kinase in Kaposi sarcoma-associated herpesvirus-infected cells.
Van Dross R, Yao S, Asad S, Westlake G, Mays DJ, Barquero L, Duell S, Pietenpol JA, Browning PJ
(2005) J Natl Cancer Inst 97: 656-66
MeSH Terms: Blotting, Western, CDC2-CDC28 Kinases, Cell Cycle Proteins, Cell Line, Tumor, Cyclin D, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Cyclins, Enzyme Inhibitors, Half-Life, Herpesviridae Infections, Herpesvirus 8, Human, Humans, Immunoprecipitation, Lymphoma, Phosphorylation, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Tumor Suppressor Proteins
Show Abstract · Added February 15, 2016
BACKGROUND - Kaposi sarcoma-associated human herpesvirus (KSHV) encodes K-cyclin, a homologue of D-type cellular cyclins, which binds cyclin-dependent kinases to phosphorylate various substrates. K-cyclin/cdk phosphorylates a subset of substrates normally targeted by cyclins D, E, and A. We used cells naturally infected with KSHV to further characterize the biochemical features of K-cyclin.
METHODS - We used immunoprecipitation with K-cyclin antibodies to examine the association of K-cyclin with cdk2, cdk6, p21Cip1, and p27Kip1 proteins in BC3 cells. We separated populations of BC3 cells enriched in cells in G1, S, or G2/M phases by elutriation and measured K-cyclin protein and the kinase activity of K-cyclin/cdk6 complexes. The half-life of K-cyclin and cyclin D2 proteins was determined by blocking protein synthesis with cycloheximide and measuring proteins in cell lysates by western blot analysis. We fused the entire K-cyclin sequence to the carboxyl-terminal sequence of cellular cyclin D that contains the PEST degradation sequence to produce K-cyclin/D2 and transfected K-cyclin/D2 into K-cyclin-negative cells to investigate the effect of the PEST sequence on K-cyclin's stability.
RESULTS - Viral K-cyclin interacted with cyclin-dependent kinases cdk2, cdk4, and cdk6 and with the cyclin/cdk inhibitory proteins p21Cip1 and p27Kip1 in BC3 cell lysates. Unlike D-type cyclins, whose expression is cell cycle dependent, the level of K-cyclin was stable throughout the cell cycle, and the kinase associated with the K-cyclin/cdk6 complex was constitutively active. The half-life of K-cyclin (6.9 hours) was much longer than that of cellular cyclin D2 (0.6 hour) and that of K-cyclin/D2 (0.5 hour), probably because K-cyclin lacks the PEST degradation sequence present in D-type cyclins.
CONCLUSION - The constitutive activation of K-cyclin/cdk complexes in KSHV-infected cells appears to result from the extended half-life of K-cyclin and may explain its role in Kaposi sarcoma.
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23 MeSH Terms
Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5.
de Bruin RA, McDonald WH, Kalashnikova TI, Yates J, Wittenberg C
(2004) Cell 117: 887-98
MeSH Terms: Amino Acid Sequence, Amino Acid Substitution, Cell Size, Chromatin, Consensus Sequence, Cyclins, G1 Phase, Gene Expression Regulation, Fungal, Models, Genetic, Molecular Sequence Data, Phosphorylation, Precipitin Tests, Promoter Regions, Genetic, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Show Abstract · Added March 20, 2014
G1-specific transcriptional activation by Cln3/CDK initiates the budding yeast cell cycle. To identify targets of Cln3/CDK, we analyzed the SBF and MBF transcription factor complexes by multidimensional protein interaction technology (MudPIT). Whi5 was identified as a stably bound component of SBF but not MBF. Inactivation of Whi5 leads to premature expression of G1-specific genes and budding, whereas overexpression retards those processes. Whi5 inactivation bypasses the requirement for Cln3 both for transcriptional activation and cell cycle initiation. Whi5 associates with G1-specific promoters via SBF during early G1 phase, then dissociates coincident with transcriptional activation. Dissociation of Whi5 is promoted by Cln3 in vivo. Cln/CDK phosphorylation of Whi5 in vitro promotes its dissociation from SBF complexes. Mutation of putative CDK phosphorylation sites, at least five of which are phosphorylated in vivo, strongly reduces SBF-dependent transcription and delays cell cycle initiation. Like mammalian Rb, Whi5 is a G1-specific transcriptional repressor antagonized by CDK.
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20 MeSH Terms