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J. Biol. Chem., Vol. 278, Issue 48, 47423-47433, November 28, 2003

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Multiple cis-Elements Mediate the Transcriptional Activation of Human fra-1 by 12-O-Tetradecanoylphorbol-13-acetate in Bronchial Epithelial Cells^*

Pavan Adiseshaiah, Srinivas R. Papaiahgari, Hue Vuong, Dhananjaya V. Kalvakolanu, and Sekhar P. Reddy¶||

From the Department of Environmental Health Sciences, Bloomberg School of Public Health and ^¶Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21205 and Greenbaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

Recent studies indicate a potential role for Fra-1, a heterodimeric partner of activator protein 1 (AP1), in toxicant-induced epithelial injury, repair, and cellular transformation. Here, we have investigated the transcriptional regulation of fra-1 by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human bronchial epithelial (HBE) cells, which are the direct targets of inhaled toxins/carcinogens. In contrast to a transient induction by H₂O₂, TPA persistently activated fra-1 transcription, principally at the transcriptional level. A deletion analysis of the fra-1 promoter revealed that several cis-elements located between –105/+32 and –283/–105 bp mediate minimal and basal promoter activities, respectively. A region between –379 and –283 bp, which harbors a putative TPA response element, a GC box, and an Ets-like binding site, was required for high level TPA-inducible expression. Mutations in any of these cis-elements markedly reduced both basal and TPA-inducible expression. Thus, cooperative interactions between factors binding to multiple cis-elements of the –379/–283 promoter region appear to regulate TPA-induced fra-1 transcription in HBE cells. Consistent with this finding, electrophoretic mobility shift assays indicated the formation of multiple complexes consisting of the AP1-, Sp-, and ETS-specific family of transcription factors with the –379/–283 fragment. Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. Chromatin immunoprecipitation assays revealed an enhanced recruitment of c-Jun, Jun-D, and Fra-2 to the endogenous fra-1 promoter upon TPA stimulation. These results underscore the regulatory role of c-Jun, Jun-D, and Fra-2 in TPA-inducible fra-1 expression in HBE cells in vivo.

Received for publication, April 4, 2003 , and in revised form, September 11, 2003.

^* This work was supported by National Institutes of Health (NIH) Grants ES011863, HL58122, and HL66109 (to S. P. R.) and CA78282 (to D. V. K.). The Johns Hopkins Urban Environmental Health Center core facilities were supported by NIH Grant ES30819. 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.

^|| To whom all correspondence should be addressed: The Johns Hopkins University, Dept. of Environmental Health Sciences, Division of Physiology, Rm. W7006, 615 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-614-5442; Fax: 410-955-0299; E-mail: sreddy{at}jhsph.edu.

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