Using the technique of differential display of mRNAs, we isolated 42 differentially expressed cDNAs from squamous papillomas induced in the skin of SENCAR mice by a standard 7,12-dimethylbenz(a)anthracene initiation and 12-O-tetradecanoylphorbol-13-acetate promotion protocol. Thirty-one of the cDNAs were cloned and sequenced and the sequences compared with the catalogued sequences in the GenBank/EMBL DNA databases. Two of the cDNA clones-pJTM-4 and pJTM-12-showed insignificant homology with the known murine DNA and protein sequences and thus are novel gene transcripts. Putative protein product of the cDNA clone pJTM-15 showed homology to a stretch of amino acids (with a difference of two amino acids out of 16 compared) within the coding region of the previously reported murine platelet derived growth factor inducible KC protein cDNA (KC/Gro, a member of small cytokine family). By Northern blot analysis, transcripts of pJTM-4 and pJTM-12 cDNAs were found to be expressed in mRNA samples prepared from similarly induced skin tumors in other mice but were not expressed in the epidermis of either untreated mice or in uninvolved epidermis of the tumor bearing mice. Expression of pJTM-4 and pJTM-12 was also detected in mouse sarcoma and lymphosarcoma cell lines but not in a melanoma cell line. These results suggest possible involvement of these novel genes in non-melanoma skin cancer. Full length sequences of these novel transcripts and characterization of their protein products may provide useful information regarding the molecular events which occur during multistage skin carcinogenesis.