The incidence of malignant melanoma is increasing at a rate greater than that of any other human cancer. The etiologic factors contributing to the development of malanoma are multiple; genetic factors may be considered to be of primary importance with secondary contributions from carcinogenic stimuli. Several oncogenes and tumor suppressor genes have been implicated in melanoma progression, however, no particular amplification, mutation, or rearrangement of these genes has been found to contribute to transformation. To implicate an oncogene in the onset of malanoma development, a gain of function, most likely through mutation of an existing gene, is required. Conversely, inactivation of a tumor suppressor gene can be achieved through a number of different mechanisms, including mutation, deletion, or rearrangement. Transgenic mice provide model systems that can be used to broaden the understanding of human diseases. Currently, very few experimental animal models exist for melanoma formation and all mouse models require a combination of carcinogen and UV treatments. In contrast, a lone of transgenic mice was generated in the laboratory that displays a phenotype similar to melanoma without exposure to any known stimuli. The animals showed areas of pigmented spots on the ear at 10 to 14 days after birth followed by appearance of raised pigmented lesions by about 2 to 3 months of age. The majority of the animals died before one year of age. They propose a set of experiments to study the host gene(s) which was interrupted by the insertion of the transgene. This interruption may have activated an """"""""off"""""""" oncogene to the """"""""on"""""""" state, thus activating its expression and resulting in the transformation of cells. Alternatively, their transgene may have interrupted a tumor suppressor gene, thus leading to unrestricted expansion of targeted cells. A third possibility is specific interaction(s) transpired between the transgene and the interrupted host sequences, such interaction(s) resulted in tumor development. To distinguish among these possibilities, they propose a set of experiments to isolate and characterize the gene product of the disrupted host sequences. Analysis of the DNA sequences from cDNA clones will be done first to see if the sequences is known or novel. If the DNA sequences are of a known """"""""oncogene"""""""" or """"""""tumor suppressor gene"""""""", regulation of its expression will be examined in the system. If the DNA sequences have not been described, in vitro biological assays will be done to see if it is a general or specific """"""""oncogene"""""""" or """"""""tumor suppressor gene"""""""". Regulation of expression of this putative gene in normal and tumor cells will be done. Involvement of this putative gene in human melanoma tumors will be studied. The long term goal is to use this line of transgenic mice as a model system for the molecular, and genetic characterization of the development of melanoma.
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