Focal adhesion kinase mediates the interferon-gamma-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-kappaB activation.
Cell Microbiol
; 10(9): 1787-800, 2008 Sep.
Article
em En
| MEDLINE
| ID: mdl-18452580
ABSTRACT
Interferon-gamma-inducible GTPase (IGTP) expression is upregulated in coxsackievirus B3 (CVB3)-infected murine heart and inhibits CVB3-induced apoptosis through activation of the PI3 kinase/Akt pathway. However, the mechanism of this pathway activation is unknown. In this study, using doxcycycline-inducible Tet-On HeLa cells that overexpress IGTP, we have demonstrated that focal adhesion kinase (FAK) is phosphorylated in response to IGTP expression and that transfection of the Tet-On HeLa cells with a dominant negative FAK (FRNK) blocks Akt activation. Furthermore, induction of IGTP also promoted the NF-kappaB activation as evidenced by its enhanced nuclear translocation, binding to transcriptional promoters and increased transcriptional activity. However, FRNK transfection and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 both blocked the IGTP-induced translocation and NF-kappaB activation. Furthermore, silencing NF-kappaB with siRNAs significantly inhibited the phosphorylation of FAK and Akt, but not their total expression levels, indicating that NF-kappaB activation is required for the IGTP-induced activation of FAK and PI3K/Akt. Finally, blocking this survival pathway by transfection of FRNK or silencing of NF-kappaB reduced CVB3 replication and enhanced cell death during CVB3 infection. Taken together, these results suggest that FAK is a mediator upstream of PI3K/Akt and NF-kappaB functions as a downstream effector and also positively regulates the activity of upstream kinases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
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Enterovirus Humano B
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Fosfatidilinositol 3-Quinases
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Infecções por Coxsackievirus
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Proteínas Proto-Oncogênicas c-akt
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Proteína-Tirosina Quinases de Adesão Focal
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GTP Fosfo-Hidrolases
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article