title: A JNK-independent signaling pathway regulates TNF alpha-stimulated, c-Jun-driven FRA-1 protooncogene transcription in pulmonary epithelial cells.
abstract: Among the several effectors that mediate TNF-alpha action is AP-1, which consists of transcription factors belonging to the JUN and FOS families. Although the effects of TNF-alpha in immune cells, such as the induction of NF-kappaBeta, are well known, the mechanisms by which it induces transcriptional activation of AP-1 in pulmonary epithelial cells are not well defined. In this study, we report that TNF-alpha stimulates the expression of the FRA-1 protooncogene in human pulmonary epithelial cells using c-Jun, acting via a 12-O-tetradecanoylphorbol-13 acetate response element located at -318. Although TNF-alpha stimulates phosphorylation of c-Jun, the inhibition of JNK activity had no significant effect on FRA-1 induction. Consistent with this result, ectopic expression of a c-Jun mutant lacking JNK phosphorylation sites had no effect on the TNF-alpha-induced expression of the promoter. In contrast, inhibition of the ERK pathway or ectopic expression of an ERK1 mutant strikingly reduced FRA-1 transcription. ERK inhibition not only blocked phosphorylation of Elk1, CREB, and ATF1, which constitutively bind to the FRA-1 promoter, but also suppressed the recruitment of c-Jun to the promoter. We found that short interfering RNA-mediated silencing of FRA-1 enhances TNF-alpha-induced IL-8 expression, whereas overexpression causes an opposite effect. Our findings collectively indicate that ERK signaling plays key roles in both Elk1, CREB, and ATF-1 activation and the subsequent recruitment of c-Jun to the FRA-1 promoter in response to TNF-alpha in pulmonary epithelial cells.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Adiseshaiah
authors.forename: Dhananjaya V
authors.initials: DV
authors.lastname: Kalvakolanu
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002999:Clone Cells; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D011401:Promoter Regions, Genetic; D021381:Protein Transport / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000099169:Fos-Related Antigen 1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D000099169:Fos-Related Antigen 1