We have constructed a cDNA library from CHP9CJ cells, a v-Ki-ras revertant cell line, in a eukaryotic expression vector. Using an expression cloning strategy that includes transfection into Ki-ras transformed cells and selection for drug resistance and phenotypic change, we have isolated two candidate cDNA molecules which alter the transformed phenotype. One cDNA encodes a mouse 4.5S gene, a small nuclear RNA that is highly overexpressed in ras-revertant cell lines. The other is a novel gene, referred to as rsp-1 which contains, as part of its long open reading frame a leucine repeat array homologous to the leucine arrays in the regulatory region of yeast adenylylcyclase. Our current efforts are aimed at determining the functions of these genes in normal and transformed cells.