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J Invest Dermatol. 2014 Jan;134(1):133-140. doi: 10.1038/jid.2013.293. Epub 2013 Jul 5.

A conditional zebrafish MITF mutation reveals MITF levels are critical for melanoma promotion vs. regression in vivo.

Author information

1
Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. Electronic address: jalister@vcu.edu.
2
MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK; University of Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
3
Department of Pathology, Western General Hospital, Edinburgh, UK.
4
MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
5
MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK; University of Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: e.patton@igmm.ed.ac.uk.

Abstract

The microphthalmia-associated transcription factor (MITF) is the "master melanocyte transcription factor" with a complex role in melanoma. MITF protein levels vary between and within clinical specimens, and amplifications and gain- and loss-of-function mutations have been identified in melanoma. How MITF functions in melanoma development and the effects of targeting MITF in vivo are unknown because MITF levels have not been directly tested in a genetic animal model. Here, we use a temperature-sensitive mitf zebrafish mutant to conditionally control endogenous MITF activity. We show that low levels of endogenous MITF activity are oncogenic with BRAF(V600E) to promote melanoma that reflects the pathology of the human disease. Remarkably, abrogating MITF activity in BRAF(V600E)mitf melanoma leads to dramatic tumor regression marked by melanophage infiltration and increased apoptosis. These studies are significant because they show that targeting MITF activity is a potent antitumor mechanism, but also show that caution is required because low levels of wild-type MITF activity are oncogenic.

PMID:
23831555
PMCID:
PMC3898314
DOI:
10.1038/jid.2013.293
[Indexed for MEDLINE]
Free PMC Article

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