Document Detail

A JNK-independent signaling pathway regulates TNF alpha-stimulated, c-Jun-driven FRA-1 protooncogene transcription in pulmonary epithelial cells.
MedLine Citation:
PMID:  17082637     Owner:  NLM     Status:  MEDLINE    
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.
Pavan Adiseshaiah; Dhananjaya V Kalvakolanu; Sekhar P Reddy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  177     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-03     Completed Date:  2007-01-05     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7193-202     Citation Subset:  AIM; IM    
Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
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MeSH Terms
Cell Line
Cell Line, Tumor
Clone Cells
Extracellular Signal-Regulated MAP Kinases / physiology
JNK Mitogen-Activated Protein Kinases* / antagonists & inhibitors,  physiology
Lung / cytology,  enzymology,  immunology*
MAP Kinase Signaling System* / genetics,  immunology
Promoter Regions, Genetic
Protein Transport / genetics
Proto-Oncogene Proteins c-fos / biosynthesis,  genetics*,  metabolism*
Proto-Oncogene Proteins c-jun / biosynthesis,  genetics,  physiology*
Respiratory Mucosa / cytology,  enzymology,  immunology*,  metabolism
Transcription, Genetic
Tumor Necrosis Factor-alpha / physiology*
Grant Support
Reg. No./Substance:
0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/Tumor Necrosis Factor-alpha; 0/fos-related antigen 1; EC Signal-Regulated MAP Kinases; EC Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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