Cytotoxic necrotizing factor from Escherichia coli induces RhoA-dependent expression of the cyclooxygenase-2 Gene.
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.
Thomas
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W
Oral Microbiology Unit, King's College London, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom.
Ascott
Z K
ZK
Harmey
D
D
Slice
L W
LW
Rozengurt
E
E
Lax
A J
AJ
D016475:3T3 Cells; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D015638:Cytochalasin D / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology*; D004926:Escherichia coli / Q000737:chemistry; D029968:Escherichia coli Proteins; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics*; D051379:Mice; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D001427:Bacterial Toxins; D003603:Cytotoxins; D029968:Escherichia coli Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C060296:cytotoxic necrotizing factor type 1; D015638:Cytochalasin D; D014443:Tyrosine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein