Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells.
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 kappaB (NF-kappaB) transcription factor activation triggered by proteolysis of its inhibitor IkappaB. IkappaB degradation is dependent upon its phosphorylation by the IkappaB 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 IkappaBalpha 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 IkappaB, inhibition of NF-kappaB 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-kappaB activity and to increased survival of melanoma cells.Oncogene (2007) 26, 1954-1958. doi:10.1038/sj.onc.1209994; published online 25 September 2006.[1]References
- Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. Liu, J., Suresh Kumar, K.G., Yu, D., Molton, S.A., McMahon, M., Herlyn, M., Thomas-Tikhonenko, A., Fuchs, S.Y. Oncogene (2007) [Pubmed]
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