BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma.
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.
Patton
E Elizabeth
EE
Howard Hughes Medical Institute, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Widlund
Hans R
HR
Kutok
Jeffery L
JL
Kopani
Kamden R
KR
Amatruda
James F
JF
Murphey
Ryan D
RD
Berghmans
Stephane
S
Mayhall
Elizabeth A
EA
Traver
David
D
Fletcher
Christopher D M
CD
Aster
Jon C
JC
Granter
Scott R
SR
Look
A Thomas
AT
Lee
Charles
C
Fisher
David E
DE
Zon
Leonard I
LI
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
D016159:Tumor Suppressor Protein p53; D048493:Proto-Oncogene Proteins B-raf