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Malignant melanoma, an aggressive and increasingly common cancer, is characterized by a strikingly high rate (70%) of mutations in BRAF, a key component of the mitogen-activated protein (MAP) kinase signaling pathway. How signaling events downstream from BRAF affect the underlying program of gene expression is poorly understood. We show that the Brn-2 POU domain transcription factor is highly expressed in melanoma cell lines but not in melanocytes or melanoblasts and that overexpression of Brn-2 in melanocytes results in increased proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference-mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased proliferation. The results suggest that the high levels of Brn-2 expression observed in melanomas link BRAF signaling to increased proliferation.

Type

Journal article

Journal

Mol Cell Biol

Publication Date

04/2004

Volume

24

Pages

2923 - 2931

Keywords

Animals, Cell Line, Tumor, Down-Regulation, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, MAP Kinase Signaling System, Melanocytes, Melanoma, Mice, POU Domain Factors, Promoter Regions, Genetic, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, RNA, Small Interfering, Recombinant Fusion Proteins, Transcription Factors