Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 50
Filter
Add more filters










Publication year range
1.
Cell Rep ; 33(3): 108296, 2020 10 20.
Article in English | MEDLINE | ID: mdl-33086069

ABSTRACT

CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.


Subject(s)
Data Mining/methods , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/metabolism , Algorithms , Cell Line, Tumor , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Epigenomics/methods , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic/genetics , Genomics/methods , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Pharmacological and Toxicological Phenomena , Reproducibility of Results , Software , Transcription Factors/genetics
2.
iScience ; 10: 247-264, 2018 Dec 21.
Article in English | MEDLINE | ID: mdl-30553813

ABSTRACT

CellMinerCDB provides a web-based resource (https://discover.nci.nih.gov/cellminercdb/) for integrating multiple forms of pharmacological and genomic analyses, and unifying the richest cancer cell line datasets (the NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables data queries for genomics and gene regulatory network analyses, and exploration of pharmacogenomic determinants and drug signatures. It leverages overlaps of cell lines and drugs across databases to examine reproducibility and expand pathway analyses. We illustrate the value of CellMinerCDB for elucidating gene expression determinants, such as DNA methylation and copy number variations, and highlight complexities in assessing mutational burden. We demonstrate the value of CellMinerCDB in selecting drugs with reproducible activity, expand on the dominant role of SLFN11 for drug response, and present novel response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins. We also introduce LIX1L as a gene associated with mesenchymal signature and regulation of cellular migration and invasiveness.

3.
Cancer Res ; 77(3): 601-612, 2017 02 01.
Article in English | MEDLINE | ID: mdl-27923837

ABSTRACT

A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (∼21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and miRNA transcripts, DNA copy number, and protein levels. Here, we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2.0 (https://discover.nci.nih.gov/cellminer). Among new insights, transcript versus DNA methylation correlations revealed the epithelial/mesenchymal gene functional category as being influenced most heavily by methylation. DNA methylation and copy number integration with transcript levels yielded an assessment of their relative influence for 15,798 genes, including tumor suppressor, mitochondrial, and mismatch repair genes. Four forms of molecular data were combined, providing rationale for microsatellite instability for 8 of the 9 cell lines in which it occurred. Individual cell line analyses showed global methylome patterns with overall methylation levels ranging from 17% to 84%. A six-gene model, including PARP1, EP300, KDM5C, SMARCB1, and UHRF1 matched this pattern. In addition, promoter methylation of two translationally relevant genes, Schlafen 11 (SLFN11) and methylguanine methyltransferase (MGMT), served as indicators of therapeutic resistance or susceptibility, respectively. Overall, our database provides a resource of pharmacologic data that can reinforce known therapeutic strategies and identify novel drugs and drug targets across multiple cancer types. Cancer Res; 77(3); 601-12. ©2016 AACR.


Subject(s)
Cell Line, Tumor , DNA Methylation , Databases, Factual , Neoplasms/genetics , Humans , Internet
4.
PLoS Comput Biol ; 11(5): e1004144, 2015 May.
Article in English | MEDLINE | ID: mdl-26020938

ABSTRACT

The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage.


Subject(s)
Circadian Rhythm/physiology , DNA Damage , Models, Biological , NAD/metabolism , ARNTL Transcription Factors/genetics , ARNTL Transcription Factors/metabolism , Animals , Apraxia, Ideomotor , CLOCK Proteins/genetics , CLOCK Proteins/metabolism , Circadian Rhythm/genetics , Circadian Rhythm Signaling Peptides and Proteins/genetics , Circadian Rhythm Signaling Peptides and Proteins/metabolism , Computational Biology , Computer Simulation , Humans , Period Circadian Proteins/genetics , Period Circadian Proteins/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Sirtuin 1/metabolism
5.
Hum Genet ; 134(1): 3-11, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25213708

ABSTRACT

The current convergence of molecular and pharmacological data provides unprecedented opportunities to gain insights into the relationships between the two types of data. Multiple forms of large-scale molecular data, including but not limited to gene and microRNA transcript expression, DNA somatic and germline variations from next-generation DNA and RNA sequencing, and DNA copy number from array comparative genomic hybridization are all potentially informative when one attempts to recognize the panoply of potentially influential events both for cancer progression and therapeutic outcome. Concurrently, there has also been a substantial expansion of the pharmacological data being accrued in a systematic fashion. For cancer cell lines, the National Cancer Institute cell line panel (NCI-60), the Cancer Cell Line Encyclopedia (CCLE), and the collaborative Genomics of Drug Sensitivity in Cancer (GDSC) databases all provide subsets of these forms of data. For the patient-derived data, The Cancer Genome Atlas (TCGA) provides analogous forms of genomic information along with treatment histories. Integration of these data in turn relies on the fields of statistics and statistical learning. Multiple algorithmic approaches may be chosen, depending on the data being considered, and the nature of the question being asked. Combining these algorithms with prior biological knowledge, the results of molecular biological studies, and the consideration of genes as pathways or functional groups provides both the challenge and the potential of the field. The ultimate goal is to provide a paradigm shift in the way that drugs are selected to provide a more targeted and efficacious outcome for the patient.


Subject(s)
Algorithms , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Gene Expression Profiling , Neoplasms/drug therapy , Neoplasms/genetics , Pharmacogenetics , Humans , Precision Medicine
6.
PLoS One ; 9(7): e101670, 2014.
Article in English | MEDLINE | ID: mdl-25032700

ABSTRACT

Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among the richest genomic and pharmacological publicly available cancer cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants that are either enriched or depleted compared to non-cancerous genomes, and thus may be influential in cancer progression and differential drug response were identified for 2,546 genes. Potential gene knockouts are made available. Assessment of cell line response to 19,940 compounds, including 110 FDA-approved drugs, reveals ≈80-fold range in resistance versus sensitivity response across cell lines. 103,422 gene variants were significantly correlated with at least one compound (at p<0.0002). These include genes of known pharmacological importance such as IGF1R, BRAF, RAD52, MTOR, STAT2 and TSC2 as well as a large number of candidate genes such as NOM1, TLL2, and XDH. We introduce two new web-based CellMiner applications that enable exploration of variant-to-compound relationships for a broad range of researchers, especially those without bioinformatics support. The first tool, "Genetic variant versus drug visualization", provides a visualization of significant correlations between drug activity-gene variant combinations. Examples are given for the known vemurafenib-BRAF, and novel ifosfamide-RAD52 pairings. The second, "Genetic variant summation" allows an assessment of cumulative genetic variations for up to 150 combined genes together; and is designed to identify the variant burden for molecular pathways or functional grouping of genes. An example of its use is provided for the EGFR-ERBB2 pathway gene variant data and the identification of correlated EGFR, ERBB2, MTOR, BRAF, MEK and ERK inhibitors. The new tools are implemented as an updated web-based CellMiner version, for which the present publication serves as a compendium.


Subject(s)
Computational Biology/methods , Data Mining/methods , Exome/genetics , Genome/genetics , Neoplasms/genetics , Antineoplastic Agents/pharmacology , Base Sequence , Cell Line, Tumor , Databases, Factual , Genetic Variation/genetics , Genomics/methods , Humans , Neoplasms/drug therapy , Sequence Analysis, DNA
7.
PLoS One ; 9(6): e99269, 2014.
Article in English | MEDLINE | ID: mdl-24940735

ABSTRACT

Using gene expression data to enhance our knowledge of control networks relevant to cancer biology and therapy is a challenging but urgent task. Based on the premise that genes that are expressed together in a variety of cell types are likely to functions together, we derived mutually correlated genes that function together in various processes in epithelial-like tumor cells. Expression-correlated genes were derived from data for the NCI-60 human tumor cell lines, as well as data from the Broad Institute's CCLE cell lines. NCI-60 cell lines that selectively expressed a mutually correlated subset of tight junction genes served as a signature for epithelial-like cancer cells. Those signature cell lines served as a seed to derive other correlated genes, many of which had various other epithelial-related functions. Literature survey yielded molecular interaction and function information about those genes, from which molecular interaction maps were assembled. Many of the genes had epithelial functions unrelated to tight junctions, demonstrating that new function categories were elicited. The most highly correlated genes were implicated in the following epithelial functions: interactions at tight junctions (CLDN7, CLDN4, CLDN3, MARVELD3, MARVELD2, TJP3, CGN, CRB3, LLGL2, EPCAM, LNX1); interactions at adherens junctions (CDH1, ADAP1, CAMSAP3); interactions at desmosomes (PPL, PKP3, JUP); transcription regulation of cell-cell junction complexes (GRHL1 and 2); epithelial RNA splicing regulators (ESRP1 and 2); epithelial vesicle traffic (RAB25, EPN3, GRHL2, EHF, ADAP1, MYO5B); epithelial Ca(+2) signaling (ATP2C2, S100A14, BSPRY); terminal differentiation of epithelial cells (OVOL1 and 2, ST14, PRSS8, SPINT1 and 2); maintenance of apico-basal polarity (RAB25, LLGL2, EPN3). The findings provide a foundation for future studies to elucidate the functions of regulatory networks specific to epithelial-like cancer cells and to probe for anti-cancer drug targets.


Subject(s)
Epithelial Cells/metabolism , Transcriptome , Alternative Splicing , Biological Transport , Calcium Signaling , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cell Differentiation , Cell Line, Tumor , Cell Polarity , Humans , Intercellular Junctions/metabolism , Phenotype , Protein Interaction Maps
8.
Genome Integr ; 4(1): 6, 2013 Dec 20.
Article in English | MEDLINE | ID: mdl-24360018

ABSTRACT

An intricate network regulates the activities of SIRT1 and PARP1 proteins and continues to be uncovered. Both SIRT1 and PARP1 share a common co-factor nicotinamide adenine dinucleotide (NAD+) and several common substrates, including regulators of DNA damage response and circadian rhythms. We review this complex network using an interactive Molecular Interaction Map (MIM) to explore the interplay between these two proteins. Here we discuss how NAD + competition and post-transcriptional/translational feedback mechanisms create a regulatory network sensitive to environmental cues, such as genotoxic stress and metabolic states, and examine the role of those interactions in DNA repair and ultimately, cell fate decisions.

9.
Cancer Res ; 73(15): 4830-9, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23786772

ABSTRACT

Topoisomerase I (Top1) relaxes DNA supercoiling by forming transient cleavage complexes (Top1cc) up- and downstream of transcription complexes. Top1cc can be trapped by carcinogenic and endogenous DNA lesions and by camptothecin, resulting in transcription blocks. Here, we undertook genome-wide analysis of camptothecin-treated cells at exon resolution. RNA samples from HCT116 and MCF7 cells were analyzed with the Affy Exon Array platform, allowing high-resolution mapping along 18,537 genes. Long genes that are highly expressed were the most susceptible to downregulation, whereas short genes were preferentially upregulated. Along the body of genes, downregulation was most important toward the 3'-end and increased with the number of exon-intron junctions. Ubiquitin and RNA degradation-related pathway genes were selectively downregulated. Parallel analysis of microRNA with the Agilent miRNA microarray platform revealed that miR-142-3p was highly induced by camptothecin. More than 10% of the downregulated genes were targets of this p53-dependent microRNA. Our study shows the profound impact of Top1cc on transcription elongation, especially at intron-exon junctions and on transcript stability by microRNA miR-142-3p upregulation.


Subject(s)
DNA Topoisomerases, Type I/genetics , Gene Expression Regulation/genetics , MicroRNAs/genetics , Transcription, Genetic/genetics , Camptothecin/pharmacology , Cell Line, Tumor , HCT116 Cells , Humans , Oligonucleotide Array Sequence Analysis , RNA Splicing/drug effects , RNA Splicing/genetics , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction , Topoisomerase I Inhibitors/pharmacology , Transcription, Genetic/drug effects , Transfection
10.
Bioinformatics ; 29(11): 1465-6, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23547033

ABSTRACT

PURPOSE: The PathVisio-Faceted Search plugin helps users explore and understand complex pathways by overlaying experimental data and data from webservices, such as Ensembl BioMart, onto diagrams drawn using formalized notations in PathVisio. The plugin then provides a filtering mechanism, known as a faceted search, to find and highlight diagram nodes (e.g. genes and proteins) of interest based on imported data. The tool additionally provides a flexible scripting mechanism to handle complex queries. AVAILABILITY: The PathVisio-Faceted Search plugin is compatible with PathVisio 3.0 and above. PathVisio is compatible with Windows, Mac OS X and Linux. The plugin, documentation, example diagrams and Groovy scripts are available at http://PathVisio.org/wiki/PathVisioFacetedSearchHelp. The plugin is free, open-source and licensed by the Apache 2.0 License.


Subject(s)
Models, Biological , Software , Genes , Humans , Lymphoma/genetics , Proteins/metabolism , Systems Biology/methods , User-Computer Interface
11.
PLoS One ; 7(7): e40062, 2012.
Article in English | MEDLINE | ID: mdl-22848369

ABSTRACT

BACKGROUND: The NCI-60 is a panel of 60 diverse human cancer cell lines used by the U.S. National Cancer Institute to screen compounds for anticancer activity. We recently clustered genes based on correlation of expression profiles across the NCI-60. Many of the resulting clusters were characterized by cancer-associated biological functions. The set of curated glioblastoma (GBM) gene expression data from the Cancer Genome Atlas (TCGA) initiative has recently become available. Thus, we are now able to determine which of the processes are robustly shared by both the immortalized cell lines and clinical cancers. RESULTS: Our central observation is that some sets of highly correlated genes in the NCI-60 expression data are also highly correlated in the GBM expression data. Furthermore, a "double fishing" strategy identified many sets of genes that show Pearson correlation ≥0.60 in both the NCI-60 and the GBM data sets relative to a given "bait" gene. The number of such gene sets far exceeds the number expected by chance. CONCLUSION: Many of the gene-gene correlations found in the NCI-60 do not reflect just the conditions of cell lines in culture; rather, they reflect processes and gene networks that also function in vivo. A number of gene network correlations co-occur in the NCI-60 and GBM data sets, but there are others that occur only in NCI-60 or only in GBM. In sum, this analysis provides an additional perspective on both the utility and the limitations of the NCI-60 in furthering our understanding of cancers in vivo.


Subject(s)
Databases, Genetic , Gene Expression Regulation, Neoplastic , Genes, Neoplasm , Genome, Human , Glioblastoma/metabolism , Cell Line, Tumor , Gene Expression Profiling , Glioblastoma/genetics , Humans , National Cancer Institute (U.S.) , United States
12.
Proc Natl Acad Sci U S A ; 109(32): 12866-72, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22753480

ABSTRACT

The "apoptotic ring" is characterized by the phosphorylation of histone H2AX at serine 139 (γ-H2AX) by DNA-dependent protein kinase (DNA-PK). The γ-H2AX apoptotic ring differs from the nuclear foci patterns observed in response to DNA-damaging agents. It contains phosphorylated DNA damage response proteins including activated Chk2, activated ATM, and activated DNA-PK itself but lacks MDC1 and 53BP1, which are required to initiate DNA repair. Because DNA-PK can phosphorylate heat shock protein 90α (HSP90α) in biochemical assays, we investigated whether HSP90α is involved in the apoptotic ring. Here we show that HSP90α is phosphorylated by DNA-PK on threonines 5 and 7 early during apoptosis and that both phosphorylated HSP90α and DNA-PK colocalize in the apoptotic ring. We also show that DNA-PK is a client of HSP90α and that HSP90α is required for full DNA-PK activation, γ-H2AX formation, DNA fragmentation, and apoptotic body formation. In contrast, HSP90 inhibition by geldanamycin markedly enhances TRAIL-induced DNA-PK and H2AX activation. Together, our results reveal that HSP90α is a substrate and chaperone of DNA-PK in the apoptotic response. The response of phosphorylated HSP90α to TRAIL and its localization to the γ-H2AX ring represent epigenetic features of apoptosis that offer insights for studying and monitoring nuclear apoptosis.


Subject(s)
Apoptosis/physiology , DNA-Activated Protein Kinase/metabolism , HSP90 Heat-Shock Proteins/metabolism , Histones/metabolism , Blotting, Western , Cell Line, Tumor , DNA Fragmentation , DNA-Activated Protein Kinase/genetics , Enzyme Activation/physiology , Flow Cytometry , Fluorometry , Humans , In Situ Nick-End Labeling , Microscopy, Fluorescence , Phosphorylation , RNA, Small Interfering/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolism
13.
Cancer Res ; 72(14): 3499-511, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22802077

ABSTRACT

High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, and pharmacology. However, the information usually resides in unwieldy databases, limiting ready data analysis and integration. One resource that offers substantial potential for improvement in this regard is the NCI-60 cell line database compiled by the U.S. National Cancer Institute, which has been extensively characterized across numerous genomic and pharmacologic response platforms. In this report, we introduce a CellMiner (http://discover.nci.nih.gov/cellminer/) web application designed to improve the use of this extensive database. CellMiner tools allowed rapid data retrieval of transcripts for 22,379 genes and 360 microRNAs along with activity reports for 20,503 chemical compounds including 102 drugs approved by the U.S. Food and Drug Administration. Converting these differential levels into quantitative patterns across the NCI-60 clarified data organization and cross-comparisons using a novel pattern match tool. Data queries for potential relationships among parameters can be conducted in an iterative manner specific to user interests and expertise. Examples of the in silico discovery process afforded by CellMiner were provided for multidrug resistance analyses and doxorubicin activity; identification of colon-specific genes, microRNAs, and drugs; microRNAs related to the miR-17-92 cluster; and drug identification patterns matched to erlotinib, gefitinib, afatinib, and lapatinib. CellMiner greatly broadens applications of the extensive NCI-60 database for discovery by creating web-based processes that are rapid, flexible, and readily applied by users without bioinformatics expertise.


Subject(s)
Databases, Factual , Drug Evaluation , Gene Expression , Genomics , Information Storage and Retrieval , Internet , Antineoplastic Agents/therapeutic use , Computational Biology , Humans , MicroRNAs , Microarray Analysis , National Cancer Institute (U.S.) , RNA , United States
14.
PLoS One ; 7(5): e35716, 2012.
Article in English | MEDLINE | ID: mdl-22570691

ABSTRACT

Although there is extensive information on gene expression and molecular interactions in various cell types, integrating those data in a functionally coherent manner remains challenging. This study explores the premise that genes whose expression at the mRNA level is correlated over diverse cell lines are likely to function together in a network of molecular interactions. We previously derived expression-correlated gene clusters from the database of the NCI-60 human tumor cell lines and associated each cluster with function categories of the Gene Ontology (GO) database. From a cluster rich in genes associated with GO categories related to cell migration, we extracted 15 genes that were highly cross-correlated; prominent among them were RRAS, AXL, ADAM9, FN14, and integrin-beta1. We then used those 15 genes as bait to identify other correlated genes in the NCI-60 database. A survey of current literature disclosed, not only that many of the expression-correlated genes engaged in molecular interactions related to migration, invasion, and metastasis, but that highly cross-correlated subsets of those genes engaged in specific cell migration processes. We assembled this information in molecular interaction maps (MIMs) that depict networks governing 3 cell migration processes: degradation of extracellular matrix, production of transient focal complexes at the leading edge of the cell, and retraction of the rear part of the cell. Also depicted are interactions controlling the release and effects of calcium ions, which may regulate migration in a spaciotemporal manner in the cell. The MIMs and associated text comprise a detailed and integrated summary of what is currently known or surmised about the role of the expression cross-correlated genes in molecular networks governing those processes.


Subject(s)
Cell Movement/genetics , Gene Regulatory Networks , Transcriptome , Actins/genetics , Actins/metabolism , Calcium/metabolism , Calpain/genetics , Calpain/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Membrane/metabolism , Cluster Analysis , Epithelial-Mesenchymal Transition/genetics , Extracellular Matrix/genetics , Extracellular Matrix/metabolism , Gene Expression Regulation, Neoplastic , Humans , Integrins/genetics , Integrins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Protein Interaction Maps , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , ras Proteins/genetics , ras Proteins/metabolism , Axl Receptor Tyrosine Kinase
15.
PLoS One ; 7(1): e30317, 2012.
Article in English | MEDLINE | ID: mdl-22291933

ABSTRACT

BACKGROUND: The NCI-60 is a panel of 60 diverse human cancer cell lines used by the U.S. National Cancer Institute to screen compounds for anticancer activity. In the current study, gene expression levels from five platforms were integrated to yield a single composite transcriptome profile. The comprehensive and reliable nature of that dataset allows us to study gene co-expression across cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Hierarchical clustering revealed numerous clusters of genes in which the genes co-vary across the NCI-60. To determine functional categorization associated with each cluster, we used the Gene Ontology (GO) Consortium database and the GoMiner tool. GO maps genes to hierarchically-organized biological process categories. GoMiner can leverage GO to perform ontological analyses of gene expression studies, generating a list of significant functional categories. CONCLUSIONS/SIGNIFICANCE: GoMiner analysis revealed many clusters of coregulated genes that are associated with functional groupings of GO biological process categories. Notably, those categories arising from coherent co-expression groupings reflect cancer-related themes such as adhesion, cell migration, RNA splicing, immune response and signal transduction. Thus, these clusters demonstrate transcriptional coregulation of functionally-related genes.


Subject(s)
Gene Expression Regulation, Neoplastic , Gene Regulatory Networks/physiology , Multigene Family/genetics , Multigene Family/physiology , Neoplasms/genetics , Algorithms , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cluster Analysis , Drug Evaluation, Preclinical/methods , Gene Expression Profiling , Genetic Association Studies , High-Throughput Screening Assays/methods , Humans , Neoplasms/pathology
16.
Bioinformatics ; 28(6): 889-90, 2012 Mar 15.
Article in English | MEDLINE | ID: mdl-22199389

ABSTRACT

PURPOSE: The PathVisio-Validator plugin aims to simplify the task of producing biological pathway diagrams that follow graphical standardized notations, such as Molecular Interaction Maps or the Systems Biology Graphical Notation. This plugin assists in the creation of pathway diagrams by ensuring correct usage of a notation, and thereby reducing ambiguity when diagrams are shared among biologists. Rulesets, needed in the validation process, can be generated for any graphical notation that a developer desires, using either Schematron or Groovy. The plugin also provides support for filtering validation results, validating on a subset of rules, and distinguishing errors and warnings.


Subject(s)
Computer Graphics , Software , Systems Biology/methods
17.
Bioinformatics ; 27(15): 2165-6, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21636591

ABSTRACT

MOTIVATION: A plugin for the Java-based PathVisio pathway editor has been developed to help users draw diagrams of bioregulatory networks according to the Molecular Interaction Map (MIM) notation. Together with the core PathVisio application, this plugin presents a simple to use and cross-platform application for the construction of complex MIM diagrams with the ability to annotate diagram elements with comments, literature references and links to external databases. This tool extends the capabilities of the PathVisio pathway editor by providing both MIM-specific glyphs and support for a MIM-specific markup language file format for exchange with other MIM-compatible tools and diagram validation. AVAILABILITY: The PathVisio-MIM plugin is freely available and works with versions of PathVisio 2.0.11 and later on Windows, Mac OS X and Linux. Information about MIM notation and the MIMML format is available at http://discover.nci.nih.gov/mim. The plugin, along with diagram examples, instructions and Java source code, may be downloaded at http://discover.nci.nih.gov/mim/mim_pathvisio.html.


Subject(s)
Computational Biology/methods , Metabolic Networks and Pathways , Software , Computer Graphics , Molecular Sequence Annotation/methods , Programming Languages , User-Computer Interface
18.
BMC Bioinformatics ; 12: 167, 2011 May 17.
Article in English | MEDLINE | ID: mdl-21586134

ABSTRACT

BACKGROUND: The Molecular Interaction Map (MIM) notation offers a standard set of symbols and rules on their usage for the depiction of cellular signaling network diagrams. Such diagrams are essential for disseminating biological information in a concise manner. A lack of software tools for the notation restricts wider usage of the notation. Development of software is facilitated by a more detailed specification regarding software requirements than has previously existed for the MIM notation. RESULTS: A formal implementation of the MIM notation was developed based on a core set of previously defined glyphs. This implementation provides a detailed specification of the properties of the elements of the MIM notation. Building upon this specification, a machine-readable format is provided as a standardized mechanism for the storage and exchange of MIM diagrams. This new format is accompanied by a Java-based application programming interface to help software developers to integrate MIM support into software projects. A validation mechanism is also provided to determine whether MIM datasets are in accordance with syntax rules provided by the new specification. CONCLUSIONS: The work presented here provides key foundational components to promote software development for the MIM notation. These components will speed up the development of interoperable tools supporting the MIM notation and will aid in the translation of data stored in MIM diagrams to other standardized formats. Several projects utilizing this implementation of the notation are outlined herein. The MIM specification is available as an additional file to this publication. Source code, libraries, documentation, and examples are available at http://discover.nci.nih.gov/mim.


Subject(s)
Models, Biological , Signal Transduction , Software , Animals , Information Storage and Retrieval , Metabolic Networks and Pathways , Programming Languages
19.
Cancer Res ; 70(20): 8055-65, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20817775

ABSTRACT

RNA splicing is required to remove introns from pre-mRNA, and alternative splicing generates protein diversity. Topoisomerase I (Top1) has been shown to be coupled with splicing by regulating serine/arginine-rich splicing proteins. Prior studies on isolated genes also showed that Top1 poisoning by camptothecin (CPT), which traps Top1 cleavage complexes (Top1cc), can alter RNA splicing. Here, we tested the effect of Top1 inhibition on splicing at the genome-wide level in human colon carcinoma HCT116 and breast carcinoma MCF7 cells. The RNA of HCT116 cells treated with CPT for various times was analyzed with ExonHit Human Splice Array. Unlike other exon array platforms, the ExonHit arrays include junction probes that allow the detection of splice variants with high sensitivity and specificity. We report that CPT treatment preferentially affects the splicing of splicing-related factors, such as RBM8A, and generates transcripts coding for inactive proteins lacking key functional domains. The splicing alterations induced by CPT are not observed with cisplatin or vinblastine and are not simply due to reduced Top1 activity, as Top1 downregulation by short interfering RNA did not alter splicing like CPT treatment. Inhibition of RNA polymerase II (Pol II) hyperphosphorylation by 5,6-dichloro-1-ß-d-ribofuranosylbenzimidazole (DRB) blocked the splicing alteration induced by CPT, which suggests that the rapid Pol II hyperphosphorylation induced by CPT interferes with normal splicing. The preferential effect of CPT on genes encoding splicing factors may explain the abnormal splicing of a large number of genes in response to Top1cc.


Subject(s)
DNA Topoisomerases, Type I/poisoning , Genome-Wide Association Study/methods , Alternative Splicing/drug effects , Alternative Splicing/genetics , Antineoplastic Agents, Phytogenic/pharmacology , Camptothecin/pharmacology , Cisplatin/pharmacology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , DNA Topoisomerases, Type I/genetics , DNA-Binding Proteins/drug effects , DNA-Binding Proteins/genetics , Down-Regulation/drug effects , Exons/drug effects , Exons/genetics , Genetic Variation , Humans , Models, Statistical , Phosphorylation , RNA Polymerase II/drug effects , RNA Polymerase II/metabolism , RNA Splicing/genetics , RNA, Small Interfering/drug effects , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction , Vinblastine/pharmacology
20.
Mol Cancer Ther ; 9(5): 1080-91, 2010 May.
Article in English | MEDLINE | ID: mdl-20442302

ABSTRACT

As part of the Spotlight on Molecular Profiling series, we present here new profiling studies of mRNA and microRNA expression for the 60 cell lines of the National Cancer Institute (NCI) Developmental Therapeutics program (DTP) drug screen (NCI-60) using the 41,000-probe Agilent Whole Human Genome Oligo Microarray and the 15,000-feature Agilent Human microRNA Microarray V2. The expression levels of approximately 21,000 genes and 723 human microRNAs were measured. These profiling studies include quadruplicate technical replicates for six and eight cell lines for mRNA and microRNA, respectively, and duplicates for the remaining cell lines. The resulting data sets are freely available and searchable online in our CellMiner database. The result indicates high reproducibility for both platforms and an essential biological similarity across the various cell types. The mRNA and microRNA expression levels were integrated with our previously published 1,429-compound database of anticancer activity obtained from the NCI DTP drug screen. Large blocks of both mRNAs and microRNAs were identified with predominately unidirectional correlations to approximately 1,300 drugs, including 121 drugs with known mechanisms of action. The data sets presented here will facilitate the identification of groups of mRNAs, microRNAs, and drugs that potentially affect and interact with one another.


Subject(s)
Antineoplastic Agents/pharmacology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , MicroRNAs/genetics , RNA, Messenger/genetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Databases, Factual , Drug Interactions , Drug Resistance, Neoplasm/genetics , Drug Screening Assays, Antitumor , HCT116 Cells , HT29 Cells , Humans , MicroRNAs/metabolism , National Cancer Institute (U.S.) , Oligonucleotide Array Sequence Analysis , RNA, Messenger/metabolism , RNA, Neoplasm/analysis , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Tissue Banks , Treatment Outcome , United States
SELECTION OF CITATIONS
SEARCH DETAIL
...