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Constitutive activation of the Wnt/beta-catenin signaling pathway is a notable feature of a large minority of cases of malignant melanoma, an aggressive and increasingly common cancer. The identification of target genes downstream from this pathway is therefore crucial to our understanding of the disease. The POU domain transcription factor Brn-2 has been implicated in control of proliferation and melanoma survival, and its expression is strongly upregulated in melanoma. We show here that in vivo Brn-2 is expressed in melanocytes but not in embryonic day 11.5 melanoblasts and that its expression is directly controlled by the Wnt/beta-catenin signaling pathway in melanoma cell lines and in transgenic mice. Moreover, silent interfering RNA-mediated inhibition of Brn-2 expression in melanoma cells overexpressing beta-catenin results in significantly decreased proliferation. These results, together with the observation that BRAF signaling also induces Brn-2 expression, reveal that Brn-2 is a focus for the convergence of two key melanoma-associated signaling pathways that are linked to cell proliferation.

Type

Journal article

Journal

Mol Cell Biol

Publication Date

04/2004

Volume

24

Pages

2915 - 2922

Keywords

Animals, Cell Line, Tumor, Cytoskeletal Proteins, Embryo, Mammalian, Homeodomain Proteins, Humans, In Situ Hybridization, Melanocytes, Melanoma, Mice, Mice, Transgenic, POU Domain Factors, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, RNA, Small Interfering, Recombinant Fusion Proteins, Signal Transduction, Trans-Activators, Transcription Factors, Wnt Proteins, Zebrafish Proteins, beta Catenin