title: BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma.
abstract: Melanoma is the most lethal form of skin cancer, and the incidence and mortality rates are rapidly rising. Epidemiologically, high numbers of nevi (moles) are associated with higher risk of melanoma . The majority of melanomas exhibit activating mutations in the serine/threonine kinase BRAF . BRAF mutations may be critical for the initiation of melanoma ; however, the direct role of BRAF in nevi and melanoma has not been tested in an animal model. To directly test the role of activated BRAF in nevus and melanoma development, we have generated transgenic zebrafish expressing the most common BRAF mutant form (V600E) under the control of the melanocyte mitfa promoter. Expression of mutant, but not wild-type, BRAF led to dramatic patches of ectopic melanocytes, which we have termed fish (f)-nevi. Remarkably, in p53-deficient fish, activated BRAF induced formation of melanocyte lesions that rapidly developed into invasive melanomas, which resembled human melanomas and could be serially transplanted. These data provide direct evidence that BRAF activation is sufficient for f-nevus formation, that BRAF activation is among the primary events in melanoma development, and that the p53 and BRAF pathways interact genetically to produce melanoma.
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: E Elizabeth
authors.initials: EE
authors.lastname: Patton
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Kamden R
authors.initials: KR
authors.lastname: Kopani
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Murphey
authors.forename: Stephane
authors.initials: S
authors.lastname: Berghmans
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mayhall
authors.forename: David
authors.initials: D
authors.lastname: Traver
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Scott R
authors.initials: SR
authors.lastname: Granter
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure; D008545:Melanoma / Q000235:genetics*; D008854:Microscopy, Electron; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009506:Nevus / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D016159:Tumor Suppressor Protein p53; D048493:Proto-Oncogene Proteins B-raf