title: 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 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 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 -327 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 findings 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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas-M.D. Anderson Cancer Centre, Houston 77030, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Chaudhary
authors.forename: G L
authors.initials: GL
authors.lastname: Walsh
authors.forename: W K
authors.initials: WK
authors.lastname: Hong
authors.forename: J M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D001980:Bronchi / Q000473:pathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins; D004847:Epithelial Cells; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases