Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin

Jane Goodall; Silvia Martinozzi; Timothy J Dexter; Delphine Champeval; Suzanne Carreira; Lionel Larue; Colin R Goding

doi:10.1128/MCB.24.7.2915-2922.2004

Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin

Mol Cell Biol. 2004 Apr;24(7):2915-22. doi: 10.1128/MCB.24.7.2915-2922.2004.

Authors

Jane Goodall¹, Silvia Martinozzi, Timothy J Dexter, Delphine Champeval, Suzanne Carreira, Lionel Larue, Colin R Goding

Affiliation

¹ Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CTNNB1 protein, human
CTNNB1 protein, mouse
Cytoskeletal Proteins
Homeodomain Proteins
POU Domain Factors
Proto-Oncogene Proteins
RNA, Small Interfering
Recombinant Fusion Proteins
Trans-Activators
Transcription Factors
Wnt Proteins
Zebrafish Proteins
beta Catenin
transcription factor Brn-2
BRAF protein, human
Braf protein, mouse
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf