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Infection and Immunity, November 2001, p. 6839-6845, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.6839-6845.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cytotoxic Necrotizing Factor from Escherichia coli Induces RhoA-Dependent Expression of the Cyclooxygenase-2 Gene

Warren Thomas,¹ Zoe K. Ascott,¹ Dympna Harmey,¹ Lee W. Slice,² Enrique Rozengurt,² and Alistair J. Lax^1,*

Oral Microbiology Unit, King's College London, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom,¹ and Department of Medicine, School of Medicine and Molecular Biology Institute, University of CaliforniaLos Angeles, Los Angeles, California 90095²

Received 8 May 2001/Returned for modification 27 July 2001/Accepted 14 August 2001

Cytotoxic necrotizing factor 1 (CNF) is a toxin produced by some isolates of Escherichia coli that cause extraintestinal infections. CNF can initiate signaling pathways that are mediated by the Rho family of small GTPases through a covalent modification that results in constitutive activation. In addition to regulating the assembly of actin stress fibers and focal adhesion complexes, RhoA can also regulate gene expression at the level of transcription. Here we demonstrate for the first time, by using a luciferase-based reporter system, that the transcription of cyclooxygenase-2 (COX-2) is strongly upregulated in NIH 3T3 fibroblasts treated with CNF and that this effect is dependent upon the activation of RhoA by the toxin. Subsequent protein tyrosine phosphorylation events modulate the induction, but the transcription signal is not mediated by Rho-associated kinase (p160/ROCK) and so must rely upon another effector that is activated by RhoA. CNF therefore induces COX-2 expression via a RhoA-dependent signaling pathway that diverges from the pathway that regulates cytoskeletal rearrangements in response to RhoA activation.

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^* Corresponding author. Mailing address: Oral Microbiology Unit, King's College London, Floor 28, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom. Phone: 44 (0)20-7955-2848. Fax: 44 (0)20-7955-2847. E-mail: alistair.lax{at}kcl.ac.uk.

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Infection and Immunity, November 2001, p. 6839-6845, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.6839-6845.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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