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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Disease Models, Animal
  • Genotype
  • Humans
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Point Mutation
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Signal Transduction / physiology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology*
  • Zebrafish
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism


  • Microphthalmia-Associated Transcription Factor
  • Zebrafish Proteins
  • mitfa protein, zebrafish
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf