OVEREXPRESSION OF MEMBERS OF THE AP-1 TRANSCRIPTIONAL FACTOR FAMILY FROM AN EARLY-STAGE OF RENAL CARCINOGENESIS AND INHIBITION OF CELL-GROWTH BY AP-1 GENE ANTISENSE OLIGONUCLEOTIDES IN THE TSC2 GENE MUTANT (EKER) RAT MODEL

We previously isolated subtracted cDNA clones for genes having increas ed expression in Tsc2 gene mutant (Eker) rat renal carcinomas (RCs). A mong them, fra-1 encoding a transcriptional factor activator protein 1 (AP-1) was identified. We have therefore investigated whether other m embers of the AP-1 transcription factor family might also be involved in renal carcinogenesis in the Eker rat model. In the present study, o verexpression of fra-1, fra-2, c-jun, junB, and junD mRNAs was demonst rated in RCs by Northern blot analysis. Interestingly, AP-1 proteins w ere highly expressed even in the earliest preneoplastic lesions (e.g., phenotypically altered tubules) as suggested by immunohistochemistry. Moreover, 12-O-tetradecanoylphorbol-13-acetate-responsive element (TR E)-binding activity of AP-1 proteins was observed in RC cell extracts by electrophoretic mobility shift assay. As a next step, we transfecte d antisense oligonucleotides targeting AP-1 genes into RC cells and de monstrated that their growth was strongly inhibited. Thus, the data su ggest that overexpression of AP-1 genes might play a crucial role in r enal carcinogenesis in the Eker rat model. (C) 1997 Academic Press.