CRAF R391W is a melanoma driver oncogene
| Autor: | Charles Ng, Bjoern Titz, Amanda Lassen, Antoni Ribas, Michael C. Friedman, Jennifer Tsoi, Bartosz Chmielowski, Anastasia Lomova, Thomas G. Graeber, Mohammad Atefi, Allison Le, Earl Avramis |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog MAP Kinase Signaling System Biology medicine.disease_cause Article 03 medical and health sciences Mice medicine Genetics Animals Humans 2.1 Biological and endogenous factors Kinase activity Aetiology Vemurafenib neoplasms Melanoma Aged Cancer Mutation Multidisciplinary Oncogene GNA11 Human Genome Oncogenes medicine.disease 3. Good health Proto-Oncogene Proteins c-raf 030104 developmental biology Cancer research NIH 3T3 Cells GNAQ medicine.drug |
| Zdroj: | Scientific reports, vol 6, iss 1 Scientific Reports |
| Popis: | Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas. |
| Databáze: | OpenAIRE |
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