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Molecular and Cellular Biology, April 2004, p. 2915-2922, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2915-2922.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Brn-2 Expression Controls Melanoma Proliferation and Is Directly Regulated by ß-Catenin

Jane Goodall,1 Silvia Martinozzi,2 Timothy J. Dexter,1,{dagger} Delphine Champeval,2 Suzanne Carreira,1 Lionel Larue,2 and Colin R. Goding1*

Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom,1 UMR146 CNRS, Institut Curie, Centre Universitaire, 91405 Orsay Cedex, France2

Received 4 December 2003/ Accepted 2 January 2004

Constitutive activation of the Wnt/ß-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/ß-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 ß-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.

* Corresponding author. Mailing address: Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom. Phone: (44) 1883 722306. Fax: (44) 1883 714375. E-mail: c.goding{at}mcri.ac.uk.

{dagger} Present address: The Institute of Cancer Research, London, SW3 6JB, United Kingdom.

Molecular and Cellular Biology, April 2004, p. 2915-2922, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2915-2922.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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