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.
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29 August 2005
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August 29 2005
Elevated expression of MITF counteracts B-RAF–stimulated melanocyte and melanoma cell proliferation
Claudia Wellbrock,
Claudia Wellbrock
Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK
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Richard Marais
Richard Marais
Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK
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Claudia Wellbrock
Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK
Richard Marais
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: [email protected]
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.
Received:
May 10 2005
Accepted:
July 15 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 170 (5): 703–708.
Article history
Received:
May 10 2005
Accepted:
July 15 2005
Citation
Claudia Wellbrock, Richard Marais; Elevated expression of MITF counteracts B-RAF–stimulated melanocyte and melanoma cell proliferation . J Cell Biol 29 August 2005; 170 (5): 703–708. doi: https://doi.org/10.1083/jcb.200505059
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