Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells (original) (raw)

• Short Communication
• Published: 25 September 2006
• K G Suresh Kumar1,
• D Yu2,
• S A Molton3,
• M McMahon3,
• M Herlyn4,
• A Thomas-Tikhonenko2 &
• …
• S Y Fuchs1

Oncogene volume 26, pages 1954–1958 (2007)Cite this article

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 _κ_B (NF-_κ_B) transcription factor activation triggered by proteolysis of its inhibitor I_κ_B. I_κ_B degradation is dependent upon its phosphorylation by the I_κ_B 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 I_κ_B_α 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 I_κ_B, inhibition of NF-_κ_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-_κ_B 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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Authors and Affiliations

1. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
   J Liu, K G Suresh Kumar & S Y Fuchs
2. Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA
   D Yu & A Thomas-Tikhonenko
3. Cancer Research Institute and Department of Cellular and Molecular Pharmacology, San Francisco Comprehensive Cancer Center, University of California, CA, USA
   S A Molton & M McMahon
4. Wistar Institute, Philadelphia, PA, USA
   M Herlyn

Authors

1. J Liu
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2. K G Suresh Kumar
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3. D Yu
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4. S A Molton
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5. M McMahon
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6. M Herlyn
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7. A Thomas-Tikhonenko
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8. S Y Fuchs
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Corresponding author

Correspondence toS Y Fuchs.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Liu, J., Suresh Kumar, K., Yu, D. et al. Oncogenic BRAF regulates _β_-Trcp expression and NF-_κ_B activity in human melanoma cells.Oncogene 26, 1954–1958 (2007). https://doi.org/10.1038/sj.onc.1209994

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• Received: 22 May 2006
• Revised: 14 August 2006
• Accepted: 14 August 2006
• Published: 25 September 2006
• Issue Date: 22 March 2007
• DOI: https://doi.org/10.1038/sj.onc.1209994

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