Suppression of c-Fos gene transcription with malignant transformation of human bronchial epithelial cells

Abstract

The Activator Protein-1 (AP-1) complex is a dimeric transcription factor composed of fos and jun proteins that regulates cellular growth and di erentiation. 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 consequence of decreased c-fos expression. In this study, we investigated the mechanisms underlying the reduction in c-fos expression associated with the malignant transformation of HBE cells. c-Fos gene transcription was lower in tumorigenic HBE cells than in normal HBE cells, and the reduction in transcription involved c-fos gene promoter elements from 7327 to +40. DNaseI footprinting and band shift analyses of motifs within this c-fos promoter region, including a cyclic AMP response element (CRE), serum response element (SRE), sis-inducible element (SIE), and a YY1 site, revealed that binding to these motifs was greater in tumorigenic HBE cells than in normal HBE cells. Site-directed mutagenesis of the CRE partially relieved the repression of c-fos promoter activity in tumorigenic HBE cells. Further, the activity of the Jun N-terminal Kinase (JNK)-dependent pathway, which was a positive regulator of the c-fos promoter, was greater in normal HBE cells than in tumorigenic HBE cells. These ®ndings demonstrate a transcriptionally-mediated suppression of c-fos gene expression associated with the malignant transformation of HBE cells. The decreased activity of the c-fos promoter in tumorigenic 1170I cells appeared to involve suppression through a CRE site and reduced activation by JNK-dependent pathways.

Fra-1 Induces Morphological Transformation and Increases In Vitro Invasiveness and Motility of Epithelioid Adenocarcinoma Cells

“…5). This is consistent with the recently described suppression of c-fos transcription with the malignant transformation of human bronchial epithelial cells (52). In human bronchial epithelial cells, the suppression of c-fos transcription occurs through a CRE site located in a promoter of the gene.…”

Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors

“…This implies that an alteration of the AP-1 composition might contribute to the dysregulation of dierentiation-speci®c gene expression in malignant BE cells. Consistent with this, a reduction in the basal level AP-1 transcriptional activity, in part due to a decrease in c-fos expression, was demonstrated in malignant BE cells (Lee et al, 1998). Thus, dierential expression and/or activation of AP-1 family members might contribute to epithelial cell carcinogenesis.…”

Mitogen-Activated Protein Kinase Phosphatase-1 Is Overexpressed in Non-Small Cell Lung Cancer and Is an Independent Predictor of Outcome in Patients

“…MAPK activation had been previously studied in lung tumor cells in vitro (41)(42)(43)(44)(45)(46), but only basal ERK activation was analyzed in detail in a large panel of lung cancer cell lines (47). Thus far, simultaneous evaluation of ERK, JNK, and p38 activation has not been performed in lung cancer either in a relevant number of cell lines or in clinical specimens.…”