Cooperativity of Cdk4R24C and Ras in melanoma development.
The importance of the CDK4 protein in human cancer first became evident following the identification of a germ line mutation in the Cdk4 locus that predisposes humans to melanoma. This mutation results in substitution of arginine with cysteine at position 24 (R24C). In an earlier study, we introduced the R24C mutation into the Cdk4 locus of mice using Cre-loxP-mediated "knock-in" technology and observed a very low incidence of spontaneous melanomas in Cdk4(R24C/R24C) mice. This suggested that additional oncogenic mutations might be required for development of melanomas. Here we report an increased incidence of spontaneous cutaneous melanoma in mice expressing the oncogene HRAS(G12V) in melanocytes on a Cdk4(R24C) background. Treatment of Tyr-HRas:Cdk4(R24C/R24C) mice with the carcinogen, DMBA/TPA resulted in a further increase in the number of nevi and melanomas developed when compared with Tyr-HRas:Cdk4(+/+) mice. In summary, in Tyr-HRas:Cdk4(R24C/R24C) mice, we observed that activated CDK4 cooperates with the oncogenic HRAS(G12V) protein to increase the susceptibility of melanoma development in vivo.
Chawla
Rachna
R
Temple University School of Medicine, Fels Institute of Cancer Research and Molecular Biology, Philadelphia, Pennsylvania, USA.
Procknow
Judith A
JA
Tantravahi
Ramana V
RV
Khurana
Jasvir S
JS
Litvin
Judith
J
Reddy
E Premkumar
EP
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility; D018095:Germ-Line Mutation; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D051358:Cyclin-Dependent Kinase 4; D015689:Oncogene Protein p21(ras)