Oncogenic B-Raf(V600E) induces spindle abnormalities, supernumerary centrosomes, and aneuploidy in human melanocytic cells.
Cancer Res
; 70(2): 675-84, 2010 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-20068179
ABSTRACT
Activating B-Raf mutations arise in 60% to 70% of human melanomas and are thought to play a vital role in tumorigenesis, although how this occurs remains poorly understood. Wild-type B-Raf is critical for normal mitosis of human somatic cells, suggesting that mutational activation of B-Raf might compromise mitosis. We examined this hypothesis by introducing oncogenic mutant B-Raf(V600E) into established human melanoma cells, assessing the effects on mitosis and their possible relationship to extracellular signal-regulated kinase (ERK) pathway activation. Exogenous expression of this activated B-Raf mutant led to a high incidence of aberrant spindles and supernumerary centrosomes. These mitotic abnormalities were suppressed by expression of a B-Raf(V600E) mutant-specific shRNA or by the addition of the mitogen-activated protein/ERK kinase-specific inhibitor U0126. Mitotic abnormalities generated by B-Raf(V600E) also caused missegregation of chromosomes leading to aneuploidy. Because activating B-Raf mutations are detected frequently in benign nevi, we extended our studies to primary human melanocytes. Remarkably, short-term expression of B-Raf(V600E) was sufficient to induce aneuploidy in human melanocytes or in immortalized human mammary epithelial cells. Collectively, our studies identify a novel role for the B-Raf oncogene in driving aneuploidy in melanocytic cells. We propose that disruption of mitotic controls by oncogenic B-Raf has important implications for understanding melanoma tumor development.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Centrosoma
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Proteínas Proto-Oncogénicas B-raf
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Aneuploidia
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Melanocitos
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Melanoma
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Huso Acromático
Límite:
Female
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Humans
Idioma:
En
Revista:
Cancer Res
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos