Abstract
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 κB (NF-κB) transcription factor activation triggered by proteolysis of its inhibitor IκB. IκB degradation is dependent upon its phosphorylation by the IκB kinase (IKK) complex and subsequent ubiquitination facilitated by β-Trcp E3 ubiquitin ligase. Here, we report that melanocytes expressing a conditionally oncogenic form of BRAFV600E exhibit enhanced β-Trcp expression, increased IKK activity and a concomitant increase in the rate of IκBα degradation. Conversely, inhibition of BRAF signaling using either a broad-spectrum Raf inhibitor (BAY 43-9006) or by selective knock-down of BRAFV600E expression by RNA interference in human melanoma cells leads to decreased IKK activity and β-Trcp expression, stabilization of IκB, inhibition of NF-κB 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-κB activity and to increased survival of melanoma cells.
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Acknowledgements
We are indebted to Michael May and Dave Tuveson for the discussion, reagents and critical comments. We thank D Ballard, DC Bennett M Karin and C Smith for the reagents. This work was supported in part by NIH Grants CA092900 (to SYF), CA108972 (to MM), CA 102709 (to ATT) and CA25874 and CA93372 (to MH).
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Liu, J., Suresh Kumar, K., Yu, D. et al. Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells. Oncogene 26, 1954–1958 (2007). https://doi.org/10.1038/sj.onc.1209994
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DOI: https://doi.org/10.1038/sj.onc.1209994
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