期刊
ONCOGENE
卷 26, 期 13, 页码 1954-1958出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209994
关键词
BRAF; melanoma; beta-Trcp; NF-kappa B; I kappa B kinase
资金
- NCI NIH HHS [P01 CA025874, CA108972, P50 CA093372, R01 CA092900, CA092900, CA102709, R01 CA108972, R01 CA102709, CA93372, CA25874] Funding Source: Medline
Mutational activation of BRAF is a frequent event in human malignant melanomas suggesting that BRAF-dependent signaling is conducive to melanoma cell growth and survival. Previously published work reported that melanoma cells exhibit constitutive anti-apoptotic nuclear factor kappa B (NF-kappa B) transcription factor activation triggered by proteolysis of its inhibitor I kappa B. I kappa B degradation is dependent upon its phosphorylation by the I kappa B kinase (IKK) complex and subsequent ubiquitination facilitated by beta-Trcp E3 ubiquitin ligase. Here, we report that melanocytes expressing a conditionally oncogenic form of BRAF(V600E) exhibit enhanced beta-Trcp expression, increased IKK activity and a concomitant increase in the rate of I kappa B alpha degradation. Conversely, inhibition of BRAF signaling using either a broad-spectrum Raf inhibitor (BAY 43-9006) or by selective knock-down of BRAF(V600E) expression by RNA interference in human melanoma cells leads to decreased IKK activity and beta-Trcp expression, stabilization of I kappa B, inhibition of NF-kappa B transcriptional activity and sensitization of these cells to apoptosis. Taken together, these data support a model in which mutational activation of BRAF in human melanomas contributes to constitutive induction of NF-kappa B activity and to increased survival of melanoma cells.
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