Cell type-specific expression of the I kappa B kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation

Gustin, JA; Ozes, ON; Akca, H; Pincheira, R; Mayo, LD; Li, QT; Guzman, JR; Korgaonkar, CK; Donner, DB


Phosphatidylinositol (PI) 3-kinase/Akt signaling activates NF-kappaB through pleiotropic, cell type-specific mechanisms. This study investigated the significance of PI 3-kinase/Akt signaling to tumor necrosis factor (TNF)-induced NF-kappaB activation in transformed, immortalized, and primary cells. Pharmacological inhibition of PI 3-kinase blocked TNF-induced NF-kappaB DNA binding in the 293 line of embryonic kidney cells, partially affected binding in MCF-7 breast cancer cells, HeLa and ME-180 cervical carcinoma cells, and NIH 3T3 cells but was without significant effect in H1299 and human umbilical vein endothelial cells, cell types in which TNF activated Akt. NF-kappaB is retained in the cytoplasm by inhibitory proteins, IkappaBs, which are phosphorylated and targeted for degradation by IkappaB kinases (IKKalpha and IKKbeta). Expression and the ratios of IKKalpha and IKKbeta, which homo- and heterodimerize, varied among cell types. Cells with a high proportion of IKKalpha ( the IKK kinase activated by Akt) to IKKbeta were most sensitive to PI 3-kinase inhibitors. Consequently, transient expression of IKKbeta diminished the capacity of the inhibitors to block NF-kappaB DNA binding in 293 cells. Also, inhibitors of PI 3-kinase blocked NF-kappaB DNA binding in Ikkbeta-/- but not Ikkalpha-/- or wild-type cells in which the ratio of IKKalpha to IKKbeta is low. Thus, noncoordinate expression of IkappaB kinases plays a role in determining the cell type-specific role of Akt in NF-kappaB activation.

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Título según WOS: ID WOS:000188005700008 Not found in local WOS DB
Volumen: 279
Número: 3
Editorial: Elsevier
Fecha de publicación: 2004
Página de inicio: 1615
Página final: 1620


Notas: ISI