Pasteurella multocida toxin is a potent activator of anti-apoptotic signalling pathways

• Verfasst von: Preuß, Inga [VerfasserIn]
• Verfasst von: Hildebrand, Dagmar [VerfasserIn]
• Verfasst von: Orth, Joachim H. C. [VerfasserIn]
• Verfasst von: Aktories, Klaus [VerfasserIn]
• Verfasst von: Hieke-Kubatzky, Katharina [VerfasserIn]
• Titel: Pasteurella multocida toxin is a potent activator of anti-apoptotic signalling pathways
• Verf.angabe: Inga Preuß, Dagmar Hildebrand, Joachim H.C. Orth, Klaus Aktories and Katharina F. Kubatzky
• E-Jahr: 2010
• Jahr: 09 July 2010
• Umfang: 7 S.
• Fussnoten: Gesehen am 08.05.2023
• Titel Quelle: Enthalten in: Cellular microbiology
• Ort Quelle: London : Hindawi Limited, 1999
• Jahr Quelle: 2010
• Band/Heft Quelle: 12(2010), 8 vom: Juli, Seite 1174-1185
• ISSN Quelle: 1462-5822
• DOI: doi:10.1111/j.1462-5822.2010.01462.x
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 184475586X

Abstract

Toxigenic Pasteurella multocida strains produce a 146 kDa protein toxin (PMT) that due to its high mitogenic activity is thought to possess carcinogenic properties. PMT affects several signal transduction pathways related to cancer by constitutively stimulating heterotrimeric G proteins. Downstream of Gαq, Gα13 and Gαi, the toxin activates the small GTPase RhoA, MAP kinases and signal transducer and activator of transcription (STAT) proteins. PMT also stimulates Gβγ signalling and activates phosphoinositide 3-kinase (PI3K)-related pathways, which play a crucial role in proliferation and apoptosis. We show that treatment of HEK293 cells with PMT inhibits staurosporine-mediated apoptosis through PI3K-dependent phosphorylation of Akt and constitutive expression of Pim-1 kinase. Simultaneous activation of these survival kinases allows the activation of pro-survival pathways, such as GSK3β, Mcl-1, Bcl-xL and Bcl-2, as well as the downregulation of apoptotic signals by Bax or Puma. Only the combined inhibition of Akt and Pim reverses the PMT-induced protection from staurosporine-induced apoptosis. In addition, we show that apoptosis induced by tumour chemotherapeutic agents is blocked by PMT in human cancer cell lines. Our data indicate that PMT is a highly potent anti-apoptotic agent, which supports the view of a carcinogenic potential of the toxin.