Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IkappaB kinase (IKK) in vitro. The S525P mutation reduces IKKalpha- and tumor necrosis factor (TNF)alpha-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFalpha-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL.
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PMID:Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity. 1707 39

Angiotensin II (Ang II) is the major effector peptide of the renin angiotensin system that induces inflammatory gene expression through the nuclear factor-kappaB (NF-kappaB) transcription factor. Activation of latent cytoplasmic NF-kappaB is controlled by distinct pathways, the best known being the canonical pathway controlling IkappaB kinase activation. Interestingly, Ang II only weakly activates the canonical pathway. Although basal nucleocytoplasmic RelA shuttling is required for Ang II stimulation, changes in RelA translocation do not account for its transcriptional effect. Instead, Ang II rapidly induced RelA phosphorylation at Ser residue 536, and complex formation with the Ser(536) kinase known as the NF-kappaB-inducing kinase (NIK)/MEKK14. The requirement of NIK in Ang II-inducible transcription was shown by expressing a dominant-negative NIK or small interfering RNA (siRNA)-mediated knockdown; both inhibited Ang II-induced transcription. Conversely, constitutively active NIK potently induced RelA transactivation activity. Consistent with its actions independent of the canonical pathway, NIK induces the activity of the RelA transactivation domains -1 and -2 in constitutively nuclear GAL4-RelA fusion proteins that do not bind IkappaBalpha. Ang II induces NIK activity, phosphorylation of its endogenous IkappaB kinase alpha substrate, and induction of nuclear NF-kappaB2 (p52) processing. NIK down-regulation prevents Ang II-induced phospho-Ser(536) RelA formation, indicating that it is essential for RelA activation. The Ang II pathway further involves the RhoA small GTP-binding protein because RhoA inhibition blocks Ang II-induced transcriptional activity and formation of phospho-Ser(536) RelA formation. Finally, we demonstrate that Ang II infusion in vivo rapidly induces phospho-Ser(536) RelA formation and activation of the NF-kappaB-dependent IL-6 gene. These data indicate that Ang II induces NF-kappaB-dependent transcription through an alternative pathway, being largely independent of IkappaB proteolysis, but mediated by the small GTPases Rac/RhoA, required for NIK.RelA complex formation and inducible Ser(536) RelA phosphorylation.
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PMID:Involvement of a novel Rac/RhoA guanosine triphosphatase-nuclear factor-kappaB inducing kinase signaling pathway mediating angiotensin II-induced RelA transactivation. 1759 24

Human c-Rel (REL) is a member of the NF-kappa B family of transcription factors, and one of its primary physiological roles is in the regulation of B-cell proliferation and survival. Although REL is primarily regulated by cytoplasmic-nuclear translocation through interaction with I kappa B inhibitors, REL also undergoes several posttranslational modifications that have been proposed to modulate its transcriptional activation activity. For example, phosphorylation of C-terminal sequences of REL has been proposed to increase its transactivation activity. In this report, we have used immune complex kinase assays to identify Ser484 and Ser494 as the primary sites of IKK alpha- and IKK beta-mediated in vitro phosphorylation in the C-terminal transactivation domain of REL. However, in cotransfection studies in A293 cells we have failed to detect IKK beta-mediated phosphorylation of these sites on REL in vivo, nor does IKK beta appear to interact with REL in these cells. Ser-to-Ala mutation of Ser484 and Ser494 does not affect IKK's ability to enhance GAL4-REL transactivation in reporter gene assays in A293 cells. We also show that the previously reported effects of overexpressed IKK and tumor necrosis factor treatment on GAL4-REL transactivation are due to IKK-mediated activation of the endogenous NF-kappa B pathway, which increases transcription from kappa B sites in the promoter of a commonly used GAL4 expression vector. Taken together, these results do not support a role for IKK-mediated phosphorylation as means for regulating the activity of REL in vivo.
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PMID:Ser484 and Ser494 in REL are the major sites of IKK phosphorylation in vitro: evidence that IKK does not directly enhance GAL4-REL transactivation. 1911 Jul 19