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Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK

Correspondence to Richard Marais: richard.marais{at}icr.ac.uk

Abstract
The protein kinase B-RAF is a human oncogene that is mutated in 70% of human melanomas and transforms mouse melanocytes. Microphthalmia-associated transcription factor (MITF) is an important melanocyte differentiation and survival factor, but its role in melanoma is unclear. In this study, we show that MITF expression is suppressed by oncogenic B-RAF in immortalized mouse and primary human melanocytes. However, low levels of MITF persist in human melanoma cells harboring oncogenic B-RAF, suggesting that additional mechanisms regulate its expression. MITF reexpression in B-RAF–transformed melanocytes inhibits their proliferation. Furthermore, differentiation-inducing factors that elevate MITF expression in melanoma cells inhibit their proliferation, but when MITF up-regulation is prevented by RNA interference, proliferation is not inhibited. These data suggest that MITF is an antiproliferation factor that is down-regulated by B-RAF signaling and that this is a crucial event for the progression of melanomas that harbor oncogenic B-RAF.

Abbreviations used in this paper: 4-OHT, 4-hydroxy-tamoxifen; CREB, cAMP response element binding protein; ER, estrogen receptor; ERK, extracellular regulated protein kinase; MEK, MAPK and ERK kinase; MITF, microphthalmia-associated transcription factor; NHM, normal human melanocyte; ppERK, phosphorylated ERK; RNAi, RNA interference; VE, V600E.

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