SUPPRESSION OF C-FOS GENE-TRANSCRIPTION WITH MALIGNANT TRANSFORMATIONOF HUMAN BRONCHIAL EPITHELIAL-CELLS

The Activator Protein-1 (AP-1) complex is a dimeric transcription fact or composed of fos and jun proteins that regulates cellular growth and differentiation. We previously demonstrated a reduction in basal AP-1 transcriptional activity associated with the malignant transformation of human bronchial epithelial (HBE) cells that was, in part, a conseq uence of decreased c-fos expression. In this study, we investigated th e mechanisms underlying the reduction in c-fos expression associated w ith the malignant transformation of HBE cells. c-Fos gene transcriptio n was lower in tumorigenic HBE cells than in normal HBE cells, and the reduction in transcription involved c-fos gene promoter elements from -327 to +40. DNasel footprinting and band shift analyses of motifs wi thin this c-fos promoter region, including a cyclic AMP response eleme nt (CRE), serum response element (SRE), sis-inducible element (SIE), a nd a YY1 site, revealed that binding to these motifs was greater in tu morigenic HBE cells than in normal HBE cells. Site-directed mutagenesi s of the CRE partially relieved the repression of c-fas promoter activ ity in tumorigenic HBE cells. Further, the activity of the Jun N-termi nal Kinase (JNK)-dependent pathway, which was a positive regulator of the c-fos promoter, was greater in normal HBE cells than in tumorigeni c HBE cells. These findings demonstrate a transcriptionally-mediated s uppression of c-fos gene expression associated with the malignant tran sformation of HBE cells. The decreased activity of the c-fos promoter in tumorigenic 1170I cells appeared to involve suppression through a C RE site and reduced activation by JNK-dependent pathways.