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The Brn-2 Transcription Factor Links Activated BRAF to Melanoma Proliferation

Jane Goodall,^1, Claudia Wellbrock,^2, Timothy J. Dexter,^1, Karen Roberts,¹ Richard Marais,² and Colin R. Goding^1*

Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL,¹ Institute of Cancer Research, London SW3 6JB, United Kingdom²

Received 4 December 2003/ Accepted 2 January 2004

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.

J.G. and C.W. made an equal contribution to this work.

Present address: Institute of Cancer Research, London SW3 6JB, United Kingdom.

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