Open AccessPasteurella multocida toxin is a potent activator of anti‐apoptotic signalling pathways
Author(s) -
Preuß Inga,
Hildebrand Dagmar,
Orth Joachim H. C.,
Aktories Klaus,
Kubatzky Katharina F.
Publication year - 2010
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/j.1462-5822.2010.01462.x
Subject(s) - biology , staurosporine , protein kinase b , signal transduction , microbiology and biotechnology , pi3k/akt/mtor pathway , wortmannin , activator (genetics) , apoptosis , kinase , heterotrimeric g protein , ly294002 , rhoa , cancer research , g protein , protein kinase c , receptor , biochemistry
Summary 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 Gα q , Gα 13 and Gα i , 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.