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Spatiotemporal regulation of the Dma1-mediated mitotic checkpoint coordinates mitosis with cytokinesis.
Cullati SN, Gould KL
(2019) Curr Genet 65: 663-668
MeSH Terms: Cell Cycle Checkpoints, Cell Cycle Proteins, Cytokinesis, Mitosis, Phosphorylation, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Spatio-Temporal Analysis, Ubiquitination
Show Abstract · Added April 10, 2019
During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In fission yeast, the septation initiation network (SIN) is responsible for this coordination, and a mitotic checkpoint dependent on the E3 ubiquitin ligase Dma1 and the protein kinase CK1 controls SIN signaling to delay cytokinesis when there are errors in mitosis. The participation of kinases and ubiquitin ligases in cell cycle checkpoints that maintain genome integrity is conserved from yeast to human, making fission yeast an excellent model system in which to study checkpoint mechanisms. In this review, we highlight recent advances and remaining questions related to checkpoint regulation, which requires the synchronized modulation of protein ubiquitination, phosphorylation, and subcellular localization.
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9 MeSH Terms
lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer.
Wang Z, Yang B, Zhang M, Guo W, Wu Z, Wang Y, Jia L, Li S, Cancer Genome Atlas Research Network, Xie W, Yang D
(2018) Cancer Cell 33: 706-720.e9
MeSH Terms: Animals, Binding Sites, Breast Neoplasms, Cell Cycle, Cell Line, Tumor, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasm Transplantation, Prognosis, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, RNA, Long Noncoding, Up-Regulation
Show Abstract · Added October 30, 2019
We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Genomic and Functional Approaches to Understanding Cancer Aneuploidy.
Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, Schumacher SE, Wang C, Hu H, Liu J, Lazar AJ, Cancer Genome Atlas Research Network, Cherniack AD, Beroukhim R, Meyerson M
(2018) Cancer Cell 33: 676-689.e3
MeSH Terms: Aneuploidy, Carcinoma, Squamous Cell, Cell Cycle, Cell Proliferation, Chromosome Aberrations, Chromosome Deletion, Chromosomes, Human, Pair 3, Databases, Genetic, Genomics, Humans, Mutation Rate, Tumor Suppressor Protein p53
Show Abstract · Added October 30, 2019
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Cdk1-dependent phosphoinhibition of a formin-F-BAR interaction opposes cytokinetic contractile ring formation.
Willet AH, Bohnert KA, Gould KL
(2018) Mol Biol Cell 29: 713-721
MeSH Terms: Actin Cytoskeleton, Actins, CDC2 Protein Kinase, Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Phosphorylation, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
In , cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring (CR). A single essential formin, Cdc12, localizes to the cell middle upon mitotic onset and nucleates the F-actin of the CR. Cdc12 medial recruitment is mediated in part by its direct binding to the F-BAR scaffold Cdc15. Given that Cdc12 is hyperphosphorylated in M phase, we explored whether Cdc12 phosphoregulation impacts its association with Cdc15 during mitosis. We found that Cdk1, a major mitotic kinase, phosphorylates Cdc12 on six N-terminal residues near the Cdc15-binding site, and phosphorylation on these sites inhibits its interaction with the Cdc15 F-BAR domain. Consistent with this finding, a mutant with all six Cdk1 sites changed to phosphomimetic residues () displays phenotypes similar to , in which the Cdc15-binding motif is disrupted; both show reduced Cdc12 at the CR and delayed CR formation. Together, these results indicate that Cdk1 phosphorylation of formin Cdc12 antagonizes its interaction with Cdc15 and thereby opposes Cdc12's CR localization. These results are consistent with a general role for Cdk1 in inhibiting cytokinesis until chromosome segregation is complete.
© 2018 Willet et al. 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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11 MeSH Terms
Set2 methyltransferase facilitates cell cycle progression by maintaining transcriptional fidelity.
Dronamraju R, Jha DK, Eser U, Adams AT, Dominguez D, Choudhury R, Chiang YC, Rathmell WK, Emanuele MJ, Churchman LS, Strahl BD
(2018) Nucleic Acids Res 46: 1331-1344
MeSH Terms: Anaphase-Promoting Complex-Cyclosome, Biological Evolution, Cdc20 Proteins, Cell Cycle, Gene Expression Regulation, Fungal, Histone-Lysine N-Methyltransferase, Histones, Humans, Lysine, Methylation, Methyltransferases, Nocodazole, Protein Processing, Post-Translational, Proteolysis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription, Genetic, Tubulin Modulators
Show Abstract · Added October 30, 2019
Methylation of histone H3 lysine 36 (H3K36me) by yeast Set2 is critical for the maintenance of chromatin structure and transcriptional fidelity. However, we do not know the full range of Set2/H3K36me functions or the scope of mechanisms that regulate Set2-dependent H3K36 methylation. Here, we show that the APC/CCDC20 complex regulates Set2 protein abundance during the cell cycle. Significantly, absence of Set2-mediated H3K36me causes a loss of cell cycle control and pronounced defects in the transcriptional fidelity of cell cycle regulatory genes, a class of genes that are generally long, hence highly dependent on Set2/H3K36me for their transcriptional fidelity. Because APC/C also controls human SETD2, and SETD2 likewise regulates cell cycle progression, our data imply an evolutionarily conserved cell cycle function for Set2/SETD2 that may explain why recurrent mutations of SETD2 contribute to human disease.
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Nanoscale architecture of the contractile ring.
McDonald NA, Lind AL, Smith SE, Li R, Gould KL
(2017) Elife 6:
MeSH Terms: Cell Cycle Proteins, Cell Division, Cell Membrane, Cytoplasm, Fluorescence Resonance Energy Transfer, Macromolecular Substances, Microscopy, Fluorescence, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
The contractile ring is a complex molecular apparatus which physically divides many eukaryotic cells. Despite knowledge of its protein composition, the molecular architecture of the ring is not known. Here we have applied super-resolution microscopy and FRET to determine the nanoscale spatial organization of contractile ring components relative to the plasma membrane. Similar to other membrane-tethered actin structures, we find proteins localize in specific layers relative to the membrane. The most membrane-proximal layer (0-80 nm) is composed of membrane-binding scaffolds, formin, and the tail of the essential myosin-II. An intermediate layer (80-160 nm) consists of a network of cytokinesis accessory proteins as well as multiple signaling components which influence cell division. Farthest from the membrane (160-350 nm) we find F-actin, the motor domains of myosins, and a major F-actin crosslinker. Circumferentially within the ring, multiple proteins proximal to the membrane form clusters of different sizes, while components farther from the membrane are uniformly distributed. This comprehensive organizational map provides a framework for understanding contractile ring function.
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9 MeSH Terms
HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas.
Sun M, Tong P, Kong W, Dong B, Huang Y, Park IY, Zhou L, Liu XD, Ding Z, Zhang X, Bai S, German P, Powell R, Wang Q, Tong X, Tannir NM, Matin SF, Rathmell WK, Fuller GN, McCutcheon IE, Walker CL, Wang J, Jonasch E
(2017) Cancer Res 77: 5313-5326
MeSH Terms: Aneuploidy, Animals, Apoptosis, Carcinoma, Renal Cell, Cell Cycle, Cell Cycle Proteins, Cell Proliferation, Cells, Cultured, Chromosomal Instability, Embryo, Mammalian, Fibroblasts, Hepatocyte Nuclear Factor 1-beta, Humans, Kidney Neoplasms, Mad2 Proteins, Mice, Protein-Serine-Threonine Kinases
Show Abstract · Added October 30, 2019
Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of loss is unique to ChRCC. We also observed a strong correlation between reduced expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of , , and genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed mutations in 33% of ChRCC where expression was repressed. In clinical specimens, combining loss with mutation produced an association with poor patient prognosis. In cells, combining loss and mutation increased cell proliferation and aneuploidy. Our results show how loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of and may enhance cellular survival and confer an aggressive phenotype in ChRCC. .
©2017 American Association for Cancer Research.
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Phosphoinositide-mediated ring anchoring resists perpendicular forces to promote medial cytokinesis.
Snider CE, Willet AH, Chen JS, Arpağ G, Zanic M, Gould KL
(2017) J Cell Biol 216: 3041-3050
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Cell Cycle Proteins, Cytokinesis, GTP-Binding Proteins, Glycosylphosphatidylinositols, Myosin Type V, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
Many eukaryotic cells divide by assembling and constricting an actin- and myosin-based contractile ring (CR) that is physically linked to the plasma membrane (PM). In this study, we report that cells lacking , which encodes a conserved PM scaffold for the phosphatidylinositol-4 kinase Stt4, build CRs that can slide away from the cell middle during anaphase in a myosin V-dependent manner. The Efr3-dependent CR-anchoring mechanism is distinct from previously reported pathways dependent on the Fes/CIP4 homology Bin-Amphiphysin-Rvs167 (F-BAR) protein Cdc15 and paxillin Pxl1. In , the concentrations of several membrane-binding proteins were reduced in the CR and/or on the PM. Our results suggest that proper PM lipid composition is important to stabilize the central position of the CR and resist myosin V-based forces to promote the fidelity of cell division.
© 2017 Snider et al.
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8 MeSH Terms
FUCCI tracking shows cell-cycle-dependent Neurog3 variation in pancreatic progenitors.
Bechard ME, Bankaitis ED, Ustione A, Piston DW, Magnuson MA, Wright CVE
(2017) Genesis 55:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cells, Cultured, Embryonic Stem Cells, Green Fluorescent Proteins, Islets of Langerhans, Mice, Nerve Tissue Proteins
Show Abstract · Added September 5, 2017
During pancreas organogenesis, Neurog3 endocrine-committing cells are generated from a population of Sox9 mitotic progenitors with only a low level of Neurog3 transcriptional activity (Neurog3 ). Low-level Neurog3 protein, in Neurog3 cells, is required to maintain their mitotic endocrine-lineage-primed status. Herein, we describe a Neurog3-driven FUCCI cell-cycle reporter (Neurog3 ) derived from a Neurog3 BAC transgenic reporter that functions as a loxed cassette acceptor (LCA). In cycling Sox9 Neurog3 progenitors, the majority of cells in S-G -M phases have undetectable levels of Neurog3 with increased expression of endocrine progenitor markers, while those in G have low Neurog3 levels with increased expression of endocrine differentiation markers. These findings support a model in which variations in Neurog3 protein levels are coordinated with cell-cycle phase progression in Neurog3 progenitors with entrance into G triggering a concerted effort, beyond increasing Neurog3 levels, to maintain an endocrine-lineage-primed state by initiating expression of the downstream endocrine differentiation program prior to endocrine-commitment.
© 2017 Wiley Periodicals, Inc.
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9 MeSH Terms
ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
Rellinger EJ, Padmanabhan C, Qiao J, Appert A, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH
(2017) Biochem Biophys Res Commun 491: 463-468
MeSH Terms: Antigens, CD, Antineoplastic Agents, Apoptosis, Cadherins, Caspase 3, Cell Cycle, Cell Line, Tumor, Drug Synergism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Humans, Isoxazoles, Mesenchymal Stem Cells, Niacinamide, Poly(ADP-ribose) Polymerases, Sarcoma, Ewing, Signal Transduction, Small Molecule Libraries, TNF-Related Apoptosis-Inducing Ligand, Vimentin
Show Abstract · Added March 14, 2018
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms