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Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila.

Wandler AM, Guillemin K - PLoS Pathog. (2012)

Bottom Line: This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells.We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis.In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.

ABSTRACT
Gastric cancer development is strongly correlated with infection by Helicobacter pylori possessing the effector protein CagA. Using a transgenic Drosophila melanogaster model, we show that CagA expression in the simple model epithelium of the larval wing imaginal disc causes dramatic tissue perturbations and apoptosis when CagA-expressing and non-expressing cells are juxtaposed. This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells. We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis. In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner. These data suggest a potential role for CagA-mediated JNK pathway activation in promoting gastric cancer progression.

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Models illustrating short-term effects of CagA on an epithelium and long-term effects resulting from a change in host genetic background.(A) Once inside the host epithelial cell, CagA effector protein downregulates the neoplastic tumor suppressors (nTSGs) which induces endocytic activation of the TNF homolog Eiger (Egr) leading to activation of JNK (Bsk). CagA also triggers Egr-dependent JNK pathway activation in neighboring wild type cells. In the absence of this pathway, CagA activates JNK signaling through other upstream pathway components including the small GTPase Rho1. In a wild type host genetic background, CagA-mediated JNK pathway activation causes apoptosis and subsequent extrusion from the epithelium, or engulfment by neighboring cells. (B) Introduction of CagA into host cells causes upregulation of JNK signaling which triggers apoptosis and compensatory proliferation within the epithelium as part of the cell editing process. When the host genetic background is perturbed by expression of an oncogenic mutation which blocks apoptosis, CagA-mediated JNK pathway activation drives tumor progression.
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ppat-1002939-g006: Models illustrating short-term effects of CagA on an epithelium and long-term effects resulting from a change in host genetic background.(A) Once inside the host epithelial cell, CagA effector protein downregulates the neoplastic tumor suppressors (nTSGs) which induces endocytic activation of the TNF homolog Eiger (Egr) leading to activation of JNK (Bsk). CagA also triggers Egr-dependent JNK pathway activation in neighboring wild type cells. In the absence of this pathway, CagA activates JNK signaling through other upstream pathway components including the small GTPase Rho1. In a wild type host genetic background, CagA-mediated JNK pathway activation causes apoptosis and subsequent extrusion from the epithelium, or engulfment by neighboring cells. (B) Introduction of CagA into host cells causes upregulation of JNK signaling which triggers apoptosis and compensatory proliferation within the epithelium as part of the cell editing process. When the host genetic background is perturbed by expression of an oncogenic mutation which blocks apoptosis, CagA-mediated JNK pathway activation drives tumor progression.

Mentions: In the current study, we used transgenic expression of the CagA virulence factor in Drosophila to demonstrate a role for JNK pathway activation in H. pylori pathogenesis. When CagA was expressed in a subset of wing imaginal disc cells juxtaposed to non-expressing cells, the epithelium underwent apoptosis and proper formation of the adult wing structure was disrupted. We showed that the apoptosis phenotype occurs through activation of the JNK signaling pathway. CagA-induced apoptosis was enhanced by loss of nTSGs or ectopic expression of the small GTPase Rho1 in the CagA-expressing cells and loss of the TNF homolog Egr in non-expressing cells (Figure 6A). We next showed that CagA-mediated JNK pathway activation can enhance the growth and invasion of tumors generated by expression of oncogenic Ras. Our data uncover a novel genetic interaction between CagA and JNK signaling and demonstrate its potential importance in promoting tumor progression.


Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila.

Wandler AM, Guillemin K - PLoS Pathog. (2012)

Models illustrating short-term effects of CagA on an epithelium and long-term effects resulting from a change in host genetic background.(A) Once inside the host epithelial cell, CagA effector protein downregulates the neoplastic tumor suppressors (nTSGs) which induces endocytic activation of the TNF homolog Eiger (Egr) leading to activation of JNK (Bsk). CagA also triggers Egr-dependent JNK pathway activation in neighboring wild type cells. In the absence of this pathway, CagA activates JNK signaling through other upstream pathway components including the small GTPase Rho1. In a wild type host genetic background, CagA-mediated JNK pathway activation causes apoptosis and subsequent extrusion from the epithelium, or engulfment by neighboring cells. (B) Introduction of CagA into host cells causes upregulation of JNK signaling which triggers apoptosis and compensatory proliferation within the epithelium as part of the cell editing process. When the host genetic background is perturbed by expression of an oncogenic mutation which blocks apoptosis, CagA-mediated JNK pathway activation drives tumor progression.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475654&req=5

ppat-1002939-g006: Models illustrating short-term effects of CagA on an epithelium and long-term effects resulting from a change in host genetic background.(A) Once inside the host epithelial cell, CagA effector protein downregulates the neoplastic tumor suppressors (nTSGs) which induces endocytic activation of the TNF homolog Eiger (Egr) leading to activation of JNK (Bsk). CagA also triggers Egr-dependent JNK pathway activation in neighboring wild type cells. In the absence of this pathway, CagA activates JNK signaling through other upstream pathway components including the small GTPase Rho1. In a wild type host genetic background, CagA-mediated JNK pathway activation causes apoptosis and subsequent extrusion from the epithelium, or engulfment by neighboring cells. (B) Introduction of CagA into host cells causes upregulation of JNK signaling which triggers apoptosis and compensatory proliferation within the epithelium as part of the cell editing process. When the host genetic background is perturbed by expression of an oncogenic mutation which blocks apoptosis, CagA-mediated JNK pathway activation drives tumor progression.
Mentions: In the current study, we used transgenic expression of the CagA virulence factor in Drosophila to demonstrate a role for JNK pathway activation in H. pylori pathogenesis. When CagA was expressed in a subset of wing imaginal disc cells juxtaposed to non-expressing cells, the epithelium underwent apoptosis and proper formation of the adult wing structure was disrupted. We showed that the apoptosis phenotype occurs through activation of the JNK signaling pathway. CagA-induced apoptosis was enhanced by loss of nTSGs or ectopic expression of the small GTPase Rho1 in the CagA-expressing cells and loss of the TNF homolog Egr in non-expressing cells (Figure 6A). We next showed that CagA-mediated JNK pathway activation can enhance the growth and invasion of tumors generated by expression of oncogenic Ras. Our data uncover a novel genetic interaction between CagA and JNK signaling and demonstrate its potential importance in promoting tumor progression.

Bottom Line: This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells.We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis.In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.

ABSTRACT
Gastric cancer development is strongly correlated with infection by Helicobacter pylori possessing the effector protein CagA. Using a transgenic Drosophila melanogaster model, we show that CagA expression in the simple model epithelium of the larval wing imaginal disc causes dramatic tissue perturbations and apoptosis when CagA-expressing and non-expressing cells are juxtaposed. This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells. We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis. In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner. These data suggest a potential role for CagA-mediated JNK pathway activation in promoting gastric cancer progression.

Show MeSH
Related in: MedlinePlus