Oncology Medical News about oncogenic BRAF;metastatic melanoma;NFAT signalling

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NFAT signalling is a novel target of oncogenic BRAF in metastatic melanoma
British Journal of Cancer, 09/04/09

Flockhart RJ et al. – NFAT2 and 4 are expressed in human metastatic melanoma cell lines and are activated by oncogenic BRAFV600E via MEK/ERK signalling. NFAT is an important upstream regulator of COX-2 in metastatic melanoma.

Methods

Nuclear factor of activated T-cells transcriptional activity and protein expression were determined in three human metastatic melanoma cell lines with differing B-RAF mutational status
NFAT activation by oncogenic BRAFV600E was explored by BRAFV600E overexpression and application of the specific MEK inhibitor PD98059
Regulation of COX-2 expression by NFAT was investigated using NFAT-targeted siRNA, calcineurin inhibitors cyclosporin A and FK506, in addition to COX-2 luciferase reporter vectors that selectively lacked NFAT binding sites

Results

NFAT transcriptional activity was increased in BRAF-mutated melanoma cells compared with wild-type cells
In wild-type cells, overexpression of BRAFV600E increased NFAT activity, which was blocked by the MEK inhibitor PD98059
Using calcineurin inhibitors and siRNA-mediated knockdown of NFAT2 and 4, we show NFAT is required for COX-2 promoter activation and protein induction in metastatic melanoma cells

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