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Nature ; 417(6892): 949-54, 2002 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-12068308

RESUMEN

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.


Asunto(s)
Melanoma/genética , Mutación Missense/genética , Neoplasias/genética , Proteínas Proto-Oncogénicas c-raf/genética , Células 3T3 , Secuencia de Aminoácidos , Animales , Secuencia de Bases , División Celular , Transformación Celular Neoplásica/genética , Análisis Mutacional de ADN , Activación Enzimática , Humanos , Sistema de Señalización de MAP Quinasas , Melanoma/enzimología , Melanoma/metabolismo , Melanoma/patología , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , Neoplasias/enzimología , Neoplasias/metabolismo , Neoplasias/patología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas c-raf/química , Proteínas Proto-Oncogénicas c-raf/metabolismo , Células Tumorales Cultivadas , Proteínas ras/inmunología , Proteínas ras/metabolismo
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