Loss of heterozygosity (LOH) and cytogenetic aberrations on the short arm of chromosome 1 have been observed in histologically diverse human cancers. At least three separate regions on chromosome 1p have been implicated as sites for tumor suppressor genes associated with the initiation and/or progression of neuroblastoma, and breast and colon carcinoma. We have identified a gene, CAR-1 (Cancer Associated RING-1), that maps exactly into one of these regions on chromosome 1. We hypothesize that this gene is one of the tumor suppressor genes on chromosome 1 p and that its disruption results in tumorigenesis.
The specific aims of this research proposal are to: 1) Obtain the tools necessary to study CAR-1, including the full-length cDNA sequence and antibodies, 2) Screen for mutations in CAR-1 in primary tumor samples as well as cancer cell lines, 3) Determine the role of CAR-1 in in vitro and in vivo growth regulation and dissect the roles of the gene's specific protein domains in growth regulation by mutational analysis, and 4) Elucidate cellular targets or co-factors of the CAR-1 gene product by protein-protein interaction studies. Because CAR-1 shares interesting structural motifs with an important class of genes, many of which play roles in oncogenesis, molecular analysis of the gene as described in this proposal will lead to a better understanding of the functions of 7b5 and other related genes associated with cancer progression.
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