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J. Biol. Chem., Vol. 282, Issue 5, 3050-3057, February 2, 2007

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Modulation of Host Cell Gene Expression through Activation of STAT Transcription Factors by Pasteurella multocida Toxin^*

From the Institut für Experimentelle and Klinische Pharmakologie and Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, D-79104 Freiburg, Germany

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 G_q and G_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 G_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.

Received for publication, September 22, 2006 , and in revised form, November 21, 2006.

^* This work was supported by a grant from the Deutsche Forschungsgemeinschaft (to K. F. K.). 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 To whom correspondence should be addressed. Tel.: 49-761-203-5299; Fax: 49-761-203-5311; E-mail: kubatzky{at}pharmakol.uni-freiburg.de.

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