title: A conditional zebrafish MITF mutation reveals MITF levels are critical for melanoma promotion vs. regression in vivo.
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.
authors.affiliation: Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. Electronic address: jalister@vcu.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Lister
authors.affiliation: 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.
authors.forename: Amy
authors.initials: A
authors.lastname: Capper
authors.affiliation: 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.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Pathology, Western General Hospital, Edinburgh, UK.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Mathers
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richardson
authors.affiliation: 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.
authors.forename: Karthika
authors.initials: K
authors.lastname: Paranthaman
authors.affiliation: MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Elizabeth Patton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D029961:Zebrafish Proteins; C497237:mitfa protein, zebrafish; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf