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A JNK-Independent Signaling Pathway Regulates TNF-Stimulated, c-Jun-Driven FRA-1 Protooncogene Transcription in Pulmonary Epithelial Cells¹

Pavan Adiseshaiah^*, Dhananjaya V. Kalvakolanu and Sekhar P. Reddy^2,*

^* Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205; and Greenbaum Cancer Center and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201

Among the several effectors that mediate TNF- action is AP-1, which consists of transcription factors belonging to the JUN and FOS families. Although the effects of TNF- in immune cells, such as the induction of NF-B, 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- 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- 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--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--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- in pulmonary epithelial cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grants ES11863 and HL66109 and (to S.P.R.) and by National Cancer Institute Grants CA782282 and CA105005 (to D.V.K.).

² Address correspondence and reprint requests to Dr. Sekhar P. Reddy, Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Room E7610, Baltimore, MD 21205. E-mail address: sreddy{at}jhsph.edu

³ Abbreviations used in this paper: TPA, 12-O-tetradecanoylphorbol-13-acetate; TRE, TPA response element; MMP, matrix metalloproteinases; WT, wild type; MEF, mouse embryonic fibroblast; rRNA, rRNA-encoding DNA; ChIP, chromatin immunoprecipitation; siRNA, small interfering RNA; SRE, serum response element.