title: Modulation of host cell gene expression through activation of STAT transcription factors by Pasteurella multocida toxin.
abstract: The Pasteurella multocida toxin (PMT) is highly mitogenic and has potential carcinogenic properties. PMT causes porcine atrophic rhinitis that is characterized by bone resorption and loss of nasal turbinates, but experimental nasal infection also leads to excess proliferation of bladder epithelial cells. PMT acts intracellularly and activates phospholipase C-linked signals and MAPK pathways via the heterotrimeric Galpha(q) and Galpha(12/13) proteins. We found that PMT induces activation of STAT proteins, and we identified STAT1, STAT3, and STAT5 as new targets of PMT-induced Galpha(q) signaling. Inhibition of Janus kinases completely abolished STAT activation. PMT-dependent STAT phosphorylation remained constitutive for at least 18 h. PMT caused down-regulation of the expression of the suppressor of cytokine signaling-3, indicating a novel mechanism to maintain activation of STATs. Moreover, stimulation of Swiss 3T3 cells with PMT increased transcription of the cancer-associated STAT-dependent gene cyclooxygenase-2. Because constitutive activation of STATs has been found in a number of cancers, our findings offer a new mechanism for a carcinogenic role of PMT.
authors.affiliation: Institut für Experimentelle and Klinische Pharmakologie and Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, D-79104 Freiburg, Germany.
authors.forename: Joachim H C
authors.initials: JH
authors.lastname: Orth
authors.forename: Klaus
authors.initials: K
authors.lastname: Aktories
authors.forename: Katharina F
authors.initials: KF
authors.lastname: Kubatzky
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002467:Cell Nucleus / Q000502:physiology; D003600:Cytosol / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D016979:Pasteurella multocida / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C062258:Pasteurella multocida toxin; D050791:STAT Transcription Factors; D019204:GTP-Binding Proteins