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1.
Drug Discov Today ; 28(7): 103628, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37230284

RESUMO

Fatty acid binding protein 5 (FABP5, or epidermal FABP) is an intracellular chaperone of fatty acid molecules that regulates lipid metabolism and cell growth. In patient-derived tumours, FABP5 expression is increased up to tenfold, often co-expressed with other cancer-related proteins. High tumoral FABP5 expression is associated with poor prognosis. FABP5 activates transcription factors (TFs) leading to increased expression of proteins involved in tumorigenesis. Genetic and pharmacological preclinical studies show that inhibiting FABP5 reduces protumoral markers, whereas elevation of FABP5 promotes tumour growth and spread. Thus, FABP5 might be a valid target for novel therapeutics. The evidence base is currently strongest for liver, prostate, breast, and brain cancers, and squamous cell carcinoma (SCC), which could represent relevant patient populations for any drug discovery programme.


Assuntos
Neoplasias , Masculino , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ácidos Graxos/metabolismo , Proliferação de Células , Fígado/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo
2.
Nucleic Acids Res ; 48(D1): D613-D620, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31733065

RESUMO

The pathogen-host interactions database (PHI-base) is available at www.phi-base.org. PHI-base contains expertly curated molecular and biological information on genes proven to affect the outcome of pathogen-host interactions reported in peer reviewed research articles. PHI-base also curates literature describing specific gene alterations that did not affect the disease interaction phenotype, in order to provide complete datasets for comparative purposes. Viruses are not included, due to their extensive coverage in other databases. In this article, we describe the increased data content of PHI-base, plus new database features and further integration with complementary databases. The release of PHI-base version 4.8 (September 2019) contains 3454 manually curated references, and provides information on 6780 genes from 268 pathogens, tested on 210 hosts in 13,801 interactions. Prokaryotic and eukaryotic pathogens are represented in almost equal numbers. Host species consist of approximately 60% plants (split 50:50 between cereal and non-cereal plants), and 40% other species of medical and/or environmental importance. The information available on pathogen effectors has risen by more than a third, and the entries for pathogens that infect crop species of global importance has dramatically increased in this release. We also briefly describe the future direction of the PHI-base project, and some existing problems with the PHI-base curation process.


Assuntos
Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/parasitologia , Biologia Computacional/métodos , Bases de Dados Factuais , Interações Hospedeiro-Patógeno/genética , Algoritmos , Animais , Antifúngicos , Bioensaio , Produtos Agrícolas , Gerenciamento de Dados , Genoma de Planta , Humanos , Internet , Fenótipo , Plantas , Ferramenta de Busca
3.
Nucleic Acids Res ; 43(Database issue): D662-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25352552

RESUMO

Ensembl (http://www.ensembl.org) is a genomic interpretation system providing the most up-to-date annotations, querying tools and access methods for chordates and key model organisms. This year we released updated annotation (gene models, comparative genomics, regulatory regions and variation) on the new human assembly, GRCh38, although we continue to support researchers using the GRCh37.p13 assembly through a dedicated site (http://grch37.ensembl.org). Our Regulatory Build has been revamped to identify regulatory regions of interest and to efficiently highlight their activity across disparate epigenetic data sets. A number of new interfaces allow users to perform large-scale comparisons of their data against our annotations. The REST server (http://rest.ensembl.org), which allows programs written in any language to query our databases, has moved to a full service alongside our upgraded website tools. Our online Variant Effect Predictor tool has been updated to process more variants and calculate summary statistics. Lastly, the WiggleTools package enables users to summarize large collections of data sets and view them as single tracks in Ensembl. The Ensembl code base itself is more accessible: it is now hosted on our GitHub organization page (https://github.com/Ensembl) under an Apache 2.0 open source license.


Assuntos
Bases de Dados de Ácidos Nucleicos , Genômica , Animais , Epigênese Genética , Variação Genética , Genoma Humano , Humanos , Internet , Camundongos , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico , Software
4.
Nucleic Acids Res ; 42(Database issue): D749-55, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24316576

RESUMO

Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.


Assuntos
Bases de Dados Genéticas , Genômica , Animais , Cordados/genética , Variação Genética , Humanos , Internet , Camundongos , Anotação de Sequência Molecular , Fenótipo , Ratos
5.
Nature ; 446(7132): 153-8, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17344846

RESUMO

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.


Assuntos
Genes Neoplásicos/genética , Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias/genética , Sequência de Aminoácidos , Análise Mutacional de DNA , Humanos , Dados de Sequência Molecular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas Quinases/química , Proteínas Quinases/genética
6.
Am J Hum Genet ; 79(6): 1119-24, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17186471

RESUMO

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.


Assuntos
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Subunidades sigma do Complexo de Proteínas Adaptadoras/metabolismo , Adulto , Criança , Endossomos/metabolismo , Feminino , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/etiologia , Deficiência Intelectual Ligada ao Cromossomo X/psicologia , Linhagem
7.
Mol Cancer Ther ; 5(11): 2606-12, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17088437

RESUMO

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.


Assuntos
Linhagem Celular Tumoral , Genes Neoplásicos , Mutação , Análise Mutacional de DNA , Éxons , Deleção de Genes , Perfilação da Expressão Gênica , Homozigoto , Humanos , Sítios de Splice de RNA
8.
Cancer Res ; 66(8): 3987-91, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16618716

RESUMO

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Dacarbazina/análogos & derivados , Glioma/genética , Mutação , Recidiva Local de Neoplasia/genética , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Dacarbazina/uso terapêutico , Feminino , Glioma/tratamento farmacológico , Glioma/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enzimologia , Proteínas Quinases/genética , Temozolomida
9.
Genes Chromosomes Cancer ; 45(1): 42-6, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16175573

RESUMO

The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas. Our results show a remarkably low mutation frequency, with only a single somatic point mutation, a K277E mutation in the STK10 gene, being identified in a total of more than 15 megabases of sequence analyzed. Sequencing of STK10 in an additional 40 TGCTs revealed no further mutations. Comparative genomic hybridization and LOH analysis using SNP arrays demonstrated that the 13 TGCTs mutationally screened through the 518 protein kinase genes were uniformly aneuploid with consistent chromosomal gains on 12p, 8q, 7, and X and losses on 13q, 18q, 11q, and 4q. Our results do not provide evidence for a mutated protein kinase implicated in the development of TGCT other than KIT. Moreover, they demonstrate that the general prevalence of point mutations in TGCT is low, in contrast to the high frequency of copy number changes.


Assuntos
Neoplasias Embrionárias de Células Germinativas/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Seminoma/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Aberrações Cromossômicas , Éxons , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual
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