Somatic p16(INK4a) loss accelerates melanomagenesis.
Loss of p16(INK4a)-RB and ARF-p53 tumor suppressor pathways, as well as activation of RAS-RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16(INK4a) are associated with familial melanoma, most melanomas result from somatic genetic events: often p16(INK4a) loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16(INK4a)-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16(INK4a) and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16(INK4a) and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.
Monahan
K B
KB
Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The Center for Environmental Health and Susceptibility, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA.
Rozenberg
G I
GI
Krishnamurthy
J
J
Johnson
S M
SM
Liu
W
W
Bradford
M K
MK
Horner
J
J
Depinho
R A
RA
Sharpless
N E
NE
D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D019942:Genes, p16; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53