期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 134, 期 1, 页码 133-140出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2013.293
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资金
- Concern Foundation for Cancer Research CONCERN (CONquer canCER Now) Award
- Wellcome Trust
- Medical Research Scotland
- Medical Research Council
- FP7-Framework ZF-Cancer grant
- MRC [MC_PC_U127527200, G120/875, MC_U127585840, MC_U127527200, MC_PC_U127585840] Funding Source: UKRI
- Medical Research Council [MC_PC_U127585840, G120/875, MC_PC_U127527200, MC_U127585840, MC_U127527200] Funding Source: researchfish
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.
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