Involvement of overexpressed wild-type BRAF in the growth of malignant melanoma cell lines

Hideaki Tanami, Issei Imoto, Akira Hirasawa, Yasuhiro Yuki, Itaru Sonoda, Jim Inoue, Kohichiro Yasui, Akiko Misawa-Furihata, Yutaka Kawakami, Johji Inazawa

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72 Citations (Scopus)

Abstract

Comparative genomic hybridization (CGH) using 40 cell lines derived from malignant melanomas (MMs) revealed frequent amplification at 7q33-q34 containing BRAF gene, which often is mutated in MM. We found this gene to be amplified to a remarkable degree in the MM cell lines that exhibited high-level gains at 7q33-q34 in CGH. Among 40 cell lines, the eight lines that revealed neither BRAF nor NRAS mutations showed even higher levels of BRAF mRNA expression than the 32 mutated lines, although DNA amplification at 7q33-q34 was not detected in every lines overexpressing BRAF. MM cells that carried wild-type BRAF and NRAS showed constitutive over-expression of B-Raf protein and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), even after serum starvation. Not only downregulation of the endogenously overexpressed wild-type B-Raf by antisense oligonucleotide but also a treatment with an inhibitor of mitogen-activated protein kinase kinase (MAPKK, MEK) reduced phosphorylated ERK1/2 and cell growth, whereas the exogenously expressed wild-type B-Raf promoted cell growth in MM cells. Our results provide the evidence that overexpression of wild-type B-Raf, in part but not always as a result of gene amplification, is one of the mechanisms underlying constitutive activation of the MAPK pathway that stimulates growth of MM cells.

Original languageEnglish
Pages (from-to)8796-8804
Number of pages9
JournalOncogene
Volume23
Issue number54
DOIs
Publication statusPublished - Nov 18 2004
Externally publishedYes

Keywords

  • BRAF
  • Comparative genomic hybridization
  • Gene amplification
  • Malignant melanoma
  • Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Tanami, H., Imoto, I., Hirasawa, A., Yuki, Y., Sonoda, I., Inoue, J., Yasui, K., Misawa-Furihata, A., Kawakami, Y., & Inazawa, J. (2004). Involvement of overexpressed wild-type BRAF in the growth of malignant melanoma cell lines. Oncogene, 23(54), 8796-8804. https://doi.org/10.1038/sj.onc.1208152