Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice.
Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4(R24C/R24C) mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4(R24C/R24C)/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4(R24C/+)/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4(R24C/R24C)/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4(R24C/R24C)/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4(R24C/R24C)/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors.
Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Elke
E
Hacker
H Konrad
HK
Muller
Nicole
N
Irwin
Brian
B
Gabrielli
Douglas
D
Lincoln
Sandra
S
Pavey
Marianne Broome
MB
Powell
Marcos
M
Malumbres
Mariano
M
Barbacid
Nicholas
N
Hayward
Graeme
G
Walker
D000818:Animals; D003043:Cocarcinogenesis; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D008546:Melanoma, Experimental / Q000209:etiology* / Q000235:genetics* / Q000556:secondary; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D014466:Ultraviolet Rays
C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4