TY - JOUR
T1 - Suppression of c-Fos gene transcription with malignant transformation of human bronchial epithelial cells
AU - Lee, Ho Young
AU - Chaudhary, Jaideep
AU - Walsh, Garrett L.
AU - Hong, Waun Ki
AU - Kurie, Jonathan M.
N1 - Funding Information:
This work was supported in part by NIH grants R29-CA67353 and P50-CA70907 (Lung Cancer SPORE) Cavigelli M, Dolfi F, Clare FX and Karin M. (1995). EMBO J., 14, 5957 – 5964. Chiu R, Boyle WJ, Meek J, Smeal T, Hunter T and Karin M. (1988). Cell, 54, 541 – 552. Cohen DR and Curran T. (1989). Critical Rev. Oncogenesis, 1, 65 – 68. Curran T, Bravo R and Muller R. (1985). Cancer Surv., 4, 655 – 681. Fan Z, Baselga J, Masui H, Mendelsohn J. (1993). Cancer Res., 53, 4637 – 4642.
PY - 1998/6/11
Y1 - 1998/6/11
N2 - 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 tumorgenic 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.
AB - 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 tumorgenic 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.
KW - Extra-cellular signal-related kinase
KW - Jun N-terminal kinase
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U2 - 10.1038/sj.onc.1201843
DO - 10.1038/sj.onc.1201843
M3 - Article
C2 - 9662337
AN - SCOPUS:0032507965
SN - 0950-9232
VL - 16
SP - 3039
EP - 3046
JO - Oncogene
JF - Oncogene
IS - 23
ER -