Cooperativity of Cdk4R24C and Ras in melanoma development |
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| Authors: | Rachna Chawla Judith A Procknow Ramana V Tantravahi Jasvir S Khurana Judith Litvin E Premkumar Reddy |
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| Institution: | 1.Temple University School of Medicine; Fels Institute of Cancer Research and Molecular Biology; Philadelphia, PA USA;2.Department of Anatomy and Cell Biology; Philadelphia, PA USA;3.Department of Pathology; Philadelphia, PA USA;4.Department of Oncological Sciences; Mount Sinai School of Medicine; New York, NY USA |
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| Abstract: | The importance of the Cdk4 protein in human cancer 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 argininefirst 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 Cdk4R24C/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 Cdk4R24C background. Treatment of Tyr-HRas:Cdk4R24C/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:Cdk4R24C/R24C mice, we observed that activated Cdk4 cooperates with the oncogenic HRAS(G12V) protein to increase the susceptibility of melanoma development in vivo.Key words: Cdk4R24C, ras, melanoma, skin, carcinogen |
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