Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Cell ; 173(1): 260-274.e25, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29551266

RESUMO

Protein degradation plays important roles in biological processes and is tightly regulated. Further, targeted proteolysis is an emerging research tool and therapeutic strategy. However, proteome-wide technologies to investigate the causes and consequences of protein degradation in biological systems are lacking. We developed "multiplexed proteome dynamics profiling" (mPDP), a mass-spectrometry-based approach combining dynamic-SILAC labeling with isobaric mass tagging for multiplexed analysis of protein degradation and synthesis. In three proof-of-concept studies, we uncover different responses induced by the bromodomain inhibitor JQ1 versus a JQ1 proteolysis targeting chimera; we elucidate distinct modes of action of estrogen receptor modulators; and we comprehensively classify HSP90 clients based on their requirement for HSP90 constitutively or during synthesis, demonstrating that constitutive HSP90 clients have lower thermal stability than non-clients, have higher affinity for the chaperone, vary between cell types, and change upon external stimuli. These findings highlight the potential of mPDP to identify dynamically controlled degradation mechanisms in cellular systems.


Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Proteoma/análise , Proteômica/métodos , Azepinas/química , Azepinas/metabolismo , Azepinas/farmacologia , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Estradiol/farmacologia , Humanos , Marcação por Isótopo , Células Jurkat , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Proteólise/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Espectrometria de Massas em Tandem , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologia
2.
Genes Chromosomes Cancer ; 49(8): 733-45, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20544847

RESUMO

We performed DNA microarray-based comparative genomic hybridization to identify somatic alterations specific to melanoma genome in 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells. Our data showed gross but nonrandom somatic changes specific to the tumor genome. Although the CDKN2A (78%) and PTEN (70%) loci were the major targets of mono-allelic and bi-allelic deletions, amplifications affected loci with BRAF (53%) and NRAS (12%) as well as EGFR (52%), MITF (40%), NOTCH2 (35%), CCND1 (18%), MDM2 (18%), CCNE1 (10%), and CDK4 (8%). The amplified loci carried additional genes, many of which could potentially play a role in melanoma. Distinct patterns of copy number changes showed that alterations in CDKN2A tended to be more clustered in cell lines with mutations in the BRAF and NRAS genes; the PTEN locus was targeted mainly in conjunction with BRAF mutations. Amplification of CCND1, CDK4, and other loci was significantly increased in cell lines without BRAF-NRAS mutations and so was the loss of chromosome arms 13q and 16q. Our data suggest involvement of distinct genetic pathways that are driven either through oncogenic BRAF and NRAS mutations complemented by aberrations in the CDKN2A and PTEN genes or involve amplification of oncogenic genomic loci and loss of 13q and 16q. It also emerges that each tumor besides being affected by major and most common somatic genetic alterations also acquires additional genetic alterations that could be crucial in determining response to small molecular inhibitors that are being currently pursued.


Assuntos
Biomarcadores Tumorais/genética , Hibridização Genômica Comparativa , Genoma Humano , Melanoma/genética , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Perda de Heterozigosidade , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA