Ikappa Balpha is a target for the mitogen-activated 90kDa ribosomal S6 kinase

Schouten, Govert J.; Vertegaal, Alfred C.O.; Whiteside, Simon T.; Israël, Alain; Toebes, Mireille; Dorsman, Josephine C.; Eb, A. J. Van Der; Zantema, A.

doi:10.1093/emboj/16.11.3133

Cited by 216 publications

(170 citation statements)

References 108 publications

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“…The latter would not seem to include PKC, however, as inhibition of PKC did not decrease EGF activation of NF-kB. Other growth factor activated signaling components, Raf (Bertrand et al, 1995), p90 rsk1 (Schouten et al, 1997), and MEKK-1 (Lee et al, 1997), have been implicated in NF-kB activation. Also, EGF is reported to generate H 2 O 2 in A-431 cells (Bae et al, 1997) and peroxide and oxidative stress are, in some cells, activators of NFkB (Schmidt et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor activation of NF-κB is mediated through IκBα degradation and intracellular free calcium

1998

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The transcription factor NF-kB is normally sequestered in the cytoplasm by its inhibitory subunit IkB. Most extracellular signals activate NF-kB through a mechanism involving the phosphorylation and proteasomedependent degradation of IkB. EGF activates NF-kB in A-431 carcinoma cells, which overexpress EGF receptors and in mouse embryo ®broblasts, which have a normal complement of receptors. Supershift experiments indicate that the NF-kB complexes induced by EGF are composed of p50/p50 homodimers and p65/p50 heterodimers, but not c-rel. EGF stimulation enhances the degradation of IkBa, but not IkBb nor an N-terminal deletion mutant of IkBa. Treatment of cells with a proteasome inhibitor, such as ALLN or MG132, blocks EGF-mediated NF-kB activation, indicating that EGFinduced NF-kB activation requires proteasome-dependent IkB degradation. Also, Bapta A/M (a cell-permeable chelator of intracellular calcium) blocks EGF-induced NF-kB activation and IkBa degradation, suggesting a requirement of intracellular free Ca 2+ for this growth factor response. Protein kinase C inhibition, in contrast, did not in¯uence EGF activation of NF-kB.

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Section: Discussionmentioning

confidence: 99%

Epidermal growth factor activation of NF-κB is mediated through IκBα degradation and intracellular free calcium

1998

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“…Thus, distinct adapter molecules of TLR-4 are likely to engage alternative signaling pathways and alternative kinases involved in I B␣ phosphorylation. In addition to IKK-1 and IKK-2, other kinases have been shown to phosphorylate I B␣, including IKK /IKKi, p90 rsk , PKR (doublestranded RNA-dependent kinase), casein kinase II, and the catalytic subunit of DNA-dependent kinase (68)(69)(70)(71)(72)(73), although it remains to be determined whether these kinases specifically phosphorylate both Ser 32 and Ser 36 of I B␣. The importance and involvement of these kinases in IKK-2-independent pathways of LPS signaling need to be addressed.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapy

Andreakos¹,

Smith²,

Kiriakidis³

et al. 2003

Arthritis & Rheumatism

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Objective. To investigate the potential role of I B kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor B (NF-B) activation and the expression of tumor necrosis factor ␣ (TNF␣), as well as interleukin-1␤ (IL-1␤), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA).Methods. Recombinant adenoviruses expressing ␤-galactosidase, dominant-negative IKK-1 and IKK-2, or I B␣ were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelialcells(HUVECs),andmonocyte-derivedmacrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined.Results. IKK-2 was not required for lipopolysaccharide (LPS)-induced NF-B activation or TNF␣, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand,

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“…The IKKs are part of a larger multiprotein complex called the IKK signalsome, which contains the IKK complex-associated protein (IKAP) and IKKg (also called NEMO), which is also crucial for NFkB activation (Cohen et al, 1998;Yamaoka et al, 1998;Bowie and O'Neill, 2000). Many upstream activators and regulators of IKK activity have been identified, including the NF-kB-inducing kinase (NIK) (Nakano et al, 1998), protein kinase Cz (PKCz) (Lallena et al, 1999), transforming growth factor b-activated kinase (TAK-1) (Ninomiya-Tsuji et al, 1999), MEK kinase (MEKK) 1, 2 and 3 (Zhao and Lee, 1999), and S6 kinase (Schouten et al, 1997). NF-kB can induce the expression of numerous target genes, including COX-2.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

et al. 2003

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Cyclooxygenase-2 (COX-2) is selectively overexpressed in colorectal tumours. The mechanism of COX-2 induction is not fully understood, but requires de novo messenger RNA and protein synthesis, indicating regulation at the transcriptional level. Sequence analysis of the 5 0 -flanking region of the COX-2 gene shows two nuclear factor-kB (NF-kB) sites. Inhibition of this protein in model cell culture systems attenuates COX-2 expression and implies that NF-kB plays an important role in COX-2 induction. We measured COX-2, NF-kB and IkB kinase a (IKKa) protein expression in matched colonic biopsy samples comprising both nontumour and adjacent tumour tissue from 32 colorectal cancer patients using immunohistochemistry. There was none or very little expression of COX-2, NF-kB and IKKa in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (Po0.05, Wilcoxon's signed rank test) in adjacent cancerous cells. Moreover, all three proteins were found to be coexpressed in the neoplastic epithelium, with the expression of COX-2 and NF-kB highly correlated (Pearson's correlation, Po0.005). There was no apparent correlation between enhanced COX-2, NF-kB or IKKa expression and tumour Dukes' stages. Our results are compatible with the hypothesis that IKKa and NF-kB are involved in COX-2 induction in these tumours and the lack of association between COX-2 expression and severity of disease as measured by Dukes' stage is consistent with the proposal that COX-2 expression is an early postinitiation event.

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Ikappa Balpha is a target for the mitogen-activated 90kDa ribosomal S6 kinase

Cited by 216 publications

References 108 publications

Epidermal growth factor activation of NF-κB is mediated through IκBα degradation and intracellular free calcium

Epidermal growth factor activation of NF-κB is mediated through IκBα degradation and intracellular free calcium

Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapy

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

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