[PMID]: | 28454577 |
[Au] Autor: | Marranci A; Jiang Z; Vitiello M; Guzzolino E; Comelli L; Sarti S; Lubrano S; Franchin C; Echevarría-Vargas I; Tuccoli A; Mercatanti A; Evangelista M; Sportoletti P; Cozza G; Luzi E; Capobianco E; Villanueva J; Arrigoni G; Signore G; Rocchiccioli S; Pitto L; Tsinoremas N; Poliseno L |
[Ad] Endereço: | Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori (ITT), AOUP, CNR-IFC, Via Moruzzi 1, 56124, Pisa, Italy. |
[Ti] Título: | The landscape of BRAF transcript and protein variants in human cancer. |
[So] Source: | Mol Cancer;16(1):85, 2017 04 28. |
[Is] ISSN: | 1476-4598 |
[Cp] País de publicação: | England |
[La] Idioma: | eng |
[Ab] Resumo: | BACKGROUND: The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. RESULTS: Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3-10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3-10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. CONCLUSIONS: By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies. |
[Mh] Termos MeSH primário: |
Melanoma/genética Neoplasias/genética Isoformas de Proteínas/genética Proteínas Proto-Oncogênicas B-raf/genética
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[Mh] Termos MeSH secundário: |
Processamento Alternativo/genética Linhagem Celular Tumoral Resistência a Medicamentos Antineoplásicos/genética Éxons/genética Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Indóis/administração & dosagem Melanoma/tratamento farmacológico Melanoma/patologia Neoplasias/tratamento farmacológico Neoplasias/patologia RNA Mensageiro/genética Sulfonamidas/administração & dosagem
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Indoles); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (Sulfonamides); 207SMY3FQT (vemurafenib); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) |
[Em] Mês de entrada: | 1802 |
[Cu] Atualização por classe: | 180227 |
[Lr] Data última revisão:
| 180227 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170430 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1186/s12943-017-0645-4 |
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