The Role of VILIP-1 in Development of Skin Tumors

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DESCRIPTION (provided by applicant): Using differential display and other molecular techniques we identified the absence of expression of a gene homologous to the human Visinin-like Protein 1 (VILIP-1) in selected high grade murine squamous cell carcinoma (SCC) and in tumor cell lines. Ectopic expression of VILIP-1 in SCC cell lines resulted in a less aggressive phenotype associated with increased levels of cAMP, decreased cell proliferation and decreased RhoA activation. The central hypothesis to be tested in vivo is that the loss of VILIP-1 expression enhances the malignant phenotype of SCC cells by down-regulating cyclic nucleotide-dependent pathways that include specific tumor-progression-related targets, such as small GTPases, thus constituting an important element in the chain of events leading to the malignant phenotype. Conversely, VILIP-1 expression should increase resistance to skin carcinogenesis by decreasing tumor cell growth and/or inhibiting tumor progression. For this purpose we have designed three specific aims: 1) Examine biological and biochemical mechanisms whereby loss of VILIP-1 expression may lead to increased malignancy. In this experiment, we will study cell proliferation, differentiation, adhesiveness, migration and invasiveness of VILIP-1 transfectants and knocked-down SCC cells in the context of cyclic nucleotide regulation. We will focus on the relative hierarchical role played by cAMP and cGMP, both known to be regulated by VILIP-1, and their participation as possible effectors of small GTPases. 2) We will evaluate the in vivo susceptibility to carcinogenesis in K5-VILIP-1 transgenic mice. These mice should be less susceptible to skin chemical carcinogenesis and will be utilized to evaluate in vivo the mechanism of action of VILIP-1. 3) Investigate the in vivo susceptibility to skin carcinogenesis using a protocol of ultraviolet carcinogenesis in K5-VILEP-1 transgenic mice backcrossed to a SHK-1 background.