The Brn-2 transcription factor links activated BRAF to melanoma proliferation.

Abstract	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.
Authors	Jane Goodall, Claudia Wellbrock, Timothy J Dexter, Karen Roberts, Richard Marais, Colin R Goding
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 24 Issue 7 Pg. 2923-31 (Apr 2004) ISSN: 0270-7306 [Print] United States
PMID	15024080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Homeodomain Proteins POU Domain Factors RNA, Small Interfering Recombinant Fusion Proteins Transcription Factors transcription factor Brn-2 BRAF protein, human Braf protein, mouse Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-raf
Topics	Animals Cell Line, Tumor Down-Regulation Gene Expression Regulation, Neoplastic Homeodomain Proteins Humans MAP Kinase Signaling System (physiology) Melanocytes (cytology, metabolism) Melanoma (genetics, metabolism, pathology) Mice POU Domain Factors Promoter Regions, Genetic Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-raf (genetics, metabolism) RNA, Small Interfering (metabolism) Recombinant Fusion Proteins (metabolism) Transcription Factors (genetics, metabolism)

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