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Mol. Cell. Biol., Mar 1995, 1294-1301, Vol 15, No. 3
Copyright © 1995, American Society for Microbiology

In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B

I Alkalay, A Yaron, A Hatzubai, S Jung, A Avraham, O Gerlitz, I Pashut-Lavon and Y Ben-Neriah
Lautenberg Center for General and Tumor Immunology, Hebrew University, Hadassah Medical School, Jerusalem, Israel.

NF-kappa B is a major inducible transcription factor in many immune and inflammatory reactions. Its activation involves the dissociation of the inhibitory subunit I kappa B from cytoplasmic NF-kappa B/Rel complexes, following which the Rel proteins are translocated to the nucleus, where they bind to DNA and activate transcription. Phosphorylation of I kappa B in cell-free experiments results in its inactivation and release from the Rel complex, but in vivo NF-kappa B activation is associated with I kappa B degradation. In vivo phosphorylation of I kappa B alpha was demonstrated in several recent studies, but its role is unknown. Our study shows that the T-cell activation results in rapid phosphorylation of I kappa B alpha and that this event is a physiological one, dependent on appropriate lymphocyte costimulation. Inducible I kappa B alpha phosphorylation was abolished by several distinct NF-kappa B blocking reagents, suggesting that it plays an essential role in the activation process. However, the in vivo induction of I kappa B alpha phosphorylation did not cause the inhibitory subunit to dissociate from the Rel complex. We identified several protease inhibitors which allow phosphorylation of I kappa B alpha but prevent its degradation upon cell stimulation, presumably through inhibition of the cytoplasmic proteasome. In the presence of these inhibitors, phosphorylated I kappa B alpha remained bound to the Rel complex in the cytoplasm for an extended period of time, whereas NF-kappa B activation was abolished.(ABSTRACT TRUNCATED AT 250 WORDS)


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Copyright © 1995 by the American Society for Microbiology. All rights reserved.