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A cytokine-responsive IκB kinase that activates the transcription factor NF-κB


Nuclear transcription factors of the NF-κB/Rel family are inhibited by IκB proteins, which inactivate NF-κB by trapping it in the cell cytoplasm. Phosphorylation of IκBs marks them out for destruction, thereby relieving their inhibitory effect on NF-κB. A cytokine-activated protein kinase complex, IKK (for IκB kinase), has now been purified that phosphorylates IκBs on the sites that trigger their degradation. A component of IKK was molecularly cloned and identified as a serine kinase. IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-κB activation.

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Figure 1: Identification of a TNF-stimulated IκBα kinase activity.
Figure 2: Purification and substrate specificity of IκBα kinase (IKK).
Figure 3: The predicted amino-acid sequence of IKKα: the two peptides whose sequence was determined are overlined.
Figure 4: Cell-free translation of IKKα generates IκB kinase activity.
Figure 5: Expression and cytokine activation of IKK in mammalian cells.
Figure 6: Mapping of IKK phosphorylation sites on IκBα.
Figure 7: Expression of IKKα accelerates IκBα degradation.
Figure 8: IKKα and NF-κB activation.
Figure 9: IKK is sensitive to PP2A.

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We thank T. Thannhauser for help with peptide sequencing; C. Hoeger for the gift of γ-ATP–Sepharose; F. Mercurio and S. Ghosh for IκBβ plasmids; T. Haystead and L. Graves for discussion and for affinity resin; G. Walter for PP2A; M. Pasillas for oligonucleotide synthesis; G. Cadwell for technical assistance; and P. Alford for manuscript preparation. This work was supported by a Program Project grant from the National Cancer Institute and grants from the National Institutes of Environmental Health Sciences and the Human Frontier Science Project (HFSP). M.H., D.R. and E.Z. were supported by postdoctoral fellowships from HFSP, American Cancer Society (ACS) and ACS-California Division.

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Correspondence to Michael Karin.

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DiDonato, J., Hayakawa, M., Rothwarf, D. et al. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388, 548–554 (1997).

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