CODELETION OF THE JUN PROTOONCOGENE AND THE CDKN2A TUMOR-SUPPRESSOR GENE IN HRAS-TRANSFORMED RAT EMBRYO FIBROBLAST CELL-LINES

The cyclin kinase inhibitor p16, encoded by the CDKN2A gene, suppresse s the transformation of mouse embryonic fibroblasts by oncogenic RAS. In contrast, the c-JUN transcription factor (a major component of AP-I ) has been suggested to be required for RAS transformation of rodent f ibroblasts. The CDKN2A gene and the JUN proto-oncogene have both been mapped to rat chromosome band 5q31 -33. We here show that both copies of the CDKN2A gene are deleted in four of eight transformed cell lines derived from the transfection of rat embryo fibroblasts (REF) with HR AS(VAL12). I, two cell lines, the homozygous deletions involved a larg er area on 5q31-33, which included the JUN proto-oncogene. JUN-defecti ve cells showed high AP-I binding activity. Both AP-I binding activity and stromelysin (transin) mRNA expression were found to be RAS-depend ent in one of the JUN-defective cell lines. The finding of deletions o f the CDKN2A gene in RAS-transformed REF cell lines is consistent with the concept that CDKN2A suppresses transformation by RAS. The occasio nal concomitant loss of the adjacent JUN proto-oncogene does not preve nt establishment of transformed and tumorigenic cell lines. (C) 1997 W iley-Liss, Inc.