Cell Type-specific Expression of the IκB Kinases Determines the Significance of Phosphatidylinositol 3-Kinase/Akt Signaling to NF-κB Activation
Phosphatidylinositol (PI) 3-kinase/Akt signaling activates NF-κB through pleiotropic, cell type-specific mechanisms. This study investigated the significance of PI 3-kinase/Akt signaling to tumor necrosis factor (TNF)-induced NF-κB activation in transformed, immortalized, and primary cells. Pharma...
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Published in | The Journal of biological chemistry Vol. 279; no. 3; p. 1615 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
16.01.2004
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Online Access | Get full text |
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Summary: | Phosphatidylinositol (PI) 3-kinase/Akt signaling activates NF-κB through pleiotropic, cell type-specific mechanisms. This
study investigated the significance of PI 3-kinase/Akt signaling to tumor necrosis factor (TNF)-induced NF-κB activation in
transformed, immortalized, and primary cells. Pharmacological inhibition of PI 3-kinase blocked TNF-induced NF-κB 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-κB is retained in the cytoplasm by inhibitory proteins, IκBs, which are phosphorylated
and targeted for degradation by IκB kinases (IKKα and IKKβ). Expression and the ratios of IKKα and IKKβ, which homo- and heterodimerize,
varied among cell types. Cells with a high proportion of IKKα (the IKK kinase activated by Akt) to IKKβ were most sensitive
to PI 3-kinase inhibitors. Consequently, transient expression of IKKβ diminished the capacity of the inhibitors to block NF-κB
DNA binding in 293 cells. Also, inhibitors of PI 3-kinase blocked NF-κB DNA binding in Ikk βâ/â but not Ikk αâ/â or wild-type cells in which the ratio of IKKα to IKKβ is low. Thus, noncoordinate expression of IκB kinases plays a role
in determining the cell type-specific role of Akt in NF-κB activation. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M306976200 |