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1.
Oncogene ; 30(22): 2587-94, 2011 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-21297663

RESUMO

Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn't target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf-Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target.


Assuntos
Apoptose/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/metabolismo , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteína Supressora de Tumor p53/antagonistas & inibidores , Fatores de Ribosilação do ADP/metabolismo , Antineoplásicos/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular Tumoral , Humanos , MicroRNAs/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirazinas/farmacologia
2.
Nat Biotechnol ; 19(4): 342-7, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11283592

RESUMO

We describe a flexible system for gene expression profiling using arrays of tens of thousands of oligonucleotides synthesized in situ by an ink-jet printing method employing standard phosphoramidite chemistry. We have characterized the dependence of hybridization specificity and sensitivity on parameters including oligonucleotide length, hybridization stringency, sequence identity, sample abundance, and sample preparation method. We find that 60-mer oligonucleotides reliably detect transcript ratios at one copy per cell in complex biological samples, and that ink-jet arrays are compatible with several different sample amplification and labeling techniques. Furthermore, results using only a single carefully selected oligonucleotide per gene correlate closely with those obtained using complementary DNA (cDNA) arrays. Most of the genes for which measurements differ are members of gene families that can only be distinguished by oligonucleotides. Because different oligonucleotide sequences can be specified for each array, we anticipate that ink-jet oligonucleotide array technology will be useful in a wide variety of DNA microarray applications.


Assuntos
Expressão Gênica , Hibridização In Situ/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Oligonucleotídeos/química , Células Cultivadas , Cromatografia Líquida de Alta Pressão , DNA Complementar/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Células Jurkat , Células K562 , Oligonucleotídeos/síntese química , Fases de Leitura Aberta , Reação em Cadeia da Polimerase , RNA Complementar/metabolismo , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saccharomyces cerevisiae , Sensibilidade e Especificidade , Fatores de Tempo , Transcrição Gênica , Tretinoína/química , Células Tumorais Cultivadas
3.
Nature ; 409(6822): 922-7, 2001 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11237012

RESUMO

The most important product of the sequencing of a genome is a complete, accurate catalogue of genes and their products, primarily messenger RNA transcripts and their cognate proteins. Such a catalogue cannot be constructed by computational annotation alone; it requires experimental validation on a genome scale. Using 'exon' and 'tiling' arrays fabricated by ink-jet oligonucleotide synthesis, we devised an experimental approach to validate and refine computational gene predictions and define full-length transcripts on the basis of co-regulated expression of their exons. These methods can provide more accurate gene numbers and allow the detection of mRNA splice variants and identification of the tissue- and disease-specific conditions under which genes are expressed. We apply our technique to chromosome 22q under 69 experimental condition pairs, and to the entire human genome under two experimental conditions. We discuss implications for more comprehensive, consistent and reliable genome annotation, more efficient, full-length complementary DNA cloning strategies and application to complex diseases.


Assuntos
Cromossomos Humanos Par 22 , Biologia Computacional , Genoma Humano , Análise de Sequência com Séries de Oligonucleotídeos , Algoritmos , Processamento Alternativo , Linhagem Celular , DNA Complementar , Éxons , Projeto Genoma Humano , Humanos , Sondas de Oligonucleotídeos
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