TY - JOUR
T1 - Nuclear Role of IκB Kinase-γ/NF-κB Essential Modulator (IKKγ/NEMO) in NF-κB-dependent Gene Expression
AU - Verma, Udit N.
AU - Yamamoto, Yumi
AU - Prajapati, Shashi
AU - Gaynor, Richard B.
PY - 2004/1/30
Y1 - 2004/1/30
N2 - The IκB kinase (IKK) complex, which is composed of the two kinases IKKα and IKKβ and the regulatory subunit IKKγ/nuclear factor-κB (NF-κB) essential modulator (NEMO), is important in the cytokine-induced activation of the NF-κB pathway. In addition to modulation of IKK activity, the NF-κB pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-κB-dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-κB pathway. IKKγ/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and to interact with the nuclear coactivator cAMP-responsive element-binding protein-binding protein (CBP). Using both in vitro and in vivo analysis, we demonstrated that IKKγ/NEMO competed with p65 and IKKα for binding to the N terminus of CBP, inhibiting CBP-dependent transcriptional activation. These results indicate that, in addition to the key role of IKKγ/NEMO in regulating cytokine-induced IKK activity, its ability to shuttle between the cytoplasm and the nucleus and to bind to CBP can lead to transcriptional repression of the NF-κB pathway.
AB - The IκB kinase (IKK) complex, which is composed of the two kinases IKKα and IKKβ and the regulatory subunit IKKγ/nuclear factor-κB (NF-κB) essential modulator (NEMO), is important in the cytokine-induced activation of the NF-κB pathway. In addition to modulation of IKK activity, the NF-κB pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-κB-dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-κB pathway. IKKγ/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and to interact with the nuclear coactivator cAMP-responsive element-binding protein-binding protein (CBP). Using both in vitro and in vivo analysis, we demonstrated that IKKγ/NEMO competed with p65 and IKKα for binding to the N terminus of CBP, inhibiting CBP-dependent transcriptional activation. These results indicate that, in addition to the key role of IKKγ/NEMO in regulating cytokine-induced IKK activity, its ability to shuttle between the cytoplasm and the nucleus and to bind to CBP can lead to transcriptional repression of the NF-κB pathway.
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U2 - 10.1074/jbc.M309300200
DO - 10.1074/jbc.M309300200
M3 - Article
C2 - 14597638
AN - SCOPUS:0942298113
SN - 0021-9258
VL - 279
SP - 3509
EP - 3515
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
ER -