Nuclear Role of IκB Kinase-γ/NF-κB Essential Modulator (IKKγ/NEMO) in NF-κB-dependent Gene Expression

Verma, Udit; Yamamoto, Yumi; Prajapati, Shashi; Gaynor, Richard B.

doi:10.1074/jbc.m309300200

Cited by 75 publications

(62 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is confusion about whether or not nuclear abundance of IKKa is stimulated by TNFa and how much nuclear IKKa is present in unstimulated cells (Anest et al, 2003;Yamamoto et al, 2003;Verma et al, 2004). Inconsistent effects were seen with leptomycin B under the different conditions used, indicating nuclear shuttling of IKKa (Birbach et al, 2002) or of NEMO, but not of IKKa .…”

Section: Nuclear Functions For Ikksmentioning

confidence: 96%

IκB kinase complexes: gateways to NF-κB activation and transcription

2006

View full text Add to dashboard Cite

Section: Nuclear Functions For Ikksmentioning

confidence: 96%

IκB kinase complexes: gateways to NF-κB activation and transcription

2006

View full text Add to dashboard Cite

“…IKK␤ is a core component of the oligomeric IKK complex, which consists of two catalytic subunits, IKK␣ and IKK␤, and a regulatory subunit IKK␥, or NEMO (16,18,30,31). The two catalytic subunits share ϳ50% amino acid sequence homology, whereas the regulatory subunit does not contain a recognizable catalytic domain (21).…”

Section: Discussionmentioning

confidence: 99%

“…The TNFR1 receptor subtype transduces TNF-␣ signaling to the transcription factor nuclear factor-B (NF-B) (14). TNF-␣-induced activation of NF-B is mediated by inhibitor of nuclear factor-B kinase (IKK)␤, a serine kinase involved in the phosphorylation and subsequent degradation of inhibitor of nuclear factor-B (IB), which leads to the activation of the transcription factor NF-B (15)(16)(17)(18). IKK␤ has been implicated in the development of insulin resistance (19).…”

mentioning

confidence: 99%

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-Proinflammatory cytokines contribute to systemic low-grade inflammation and insulin resistance. Tumor necrosis factor (TNF)-␣ impedes insulin signaling in insulin target tissues. We determined the role of inhibitor of nuclear factor-B kinase (IKK)␤ in TNF-␣-induced impairments in insulin signaling and glucose metabolism in skeletal muscle.RESEARCH DESIGN AND METHODS-Small interfering RNA (siRNA) was used to silence IKK␤ gene expression in primary human skeletal muscle myotubes from nondiabetic subjects. siRNA gene silencing reduced IKK␤ protein expression 73% (P Ͻ 0.05). Myotubes were incubated in the absence or presence of insulin and/or TNF-␣, and effects of IKK␤ silencing on insulin signaling and glucose metabolism were determined.RESULTS-Insulin increased glucose uptake 1.7-fold (P Ͻ 0.05) and glucose incorporation into glycogen 3.8-fold (P Ͻ 0.05) in myotubes from nondiabetic subjects. TNF-␣ exposure fully impaired insulin-mediated glucose uptake and metabolism. IKK␤ siRNA protected against TNF-␣-induced impairments in glucose metabolism, since insulin-induced increases in glucose uptake (1.5-fold; P Ͻ 0.05) and glycogen synthesis (3.5-fold; P Ͻ 0.05) were restored. Conversely, TNF-␣-induced increases in insulin receptor substrate-1 serine phosphorylation (Ser 312 ), Jun NH 2 -terminal kinase phosphorylation, and extracellular signal-related kinase-1/2 mitogen-activated protein kinase (MAPK) phosphorylation were unaltered by siRNA-mediated IKK␤ reduction. siRNA-mediated IKK␤ reduction prevented TNF-␣-induced insulin resistance on Akt Ser 473 and Thr 308 phosphorylation and phosphorylation of the 160-kDa Akt substrate AS160. IKK␤ silencing had no effect on cell differentiation. Finally, mRNA expression of GLUT1 or GLUT4 and protein expression of MAPK kinase kinase kinase isoform 4 (MAP4K4) was unaltered by IKK␤ siRNA.CONCLUSIONS-IKK␤ silencing prevents TNF-␣-induced impairments in insulin action on Akt phosphorylation and glucose uptake and metabolism in human skeletal muscle.

show abstract

“…In contrast to IKK-b, IKK-a accumulated in cell nucleus in response to cytokine exposure and was directly recruited onto the promoter of NF-kB-regulated genes in association with histone H3 phosphorylation (Anest et al, 2003;Yamamoto et al, 2003). Additionally, Verma et al (2004) described that IKK-g shuttles between cytoplasm and nucleus, and interacts with nuclear co-activator CBP. Wu et al (2006) demonstrated that, upon DNA damage, IKK-g is phosphorylated by ATM, which encodes a PI3 K family of nuclear Ser/Thr kinase (Kastan and Lim, 2000), and thereby promotes its nuclear export.…”

mentioning

confidence: 99%

ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin

et al. 2007

View full text Add to dashboard Cite

I kappa B kinase (IKK) complex plays an important role in the regulation of signaling pathway that activates nuclear factor-kappa-B (NF-jB). Recently, we reported that cisplatin (CDDP) treatment causes a remarkable nuclear accumulation of IKK-a in association with stabilization and activation of p73. However, underlying mechanisms of CDDP-induced nuclear accumulation of IKK-a are elusive. Here, we found that ataxia-telangiectasia mutated (ATM) is one of upstream mediators of IKK-a during CDDP-induced apoptosis. In response to CDDP, ATM was phosphorylated at Ser-1981, which was accompanied with nuclear accumulation of IKK-a in HepG2 cells, whereas CDDP treatment had undetectable effects on IKK-a in ATM-deficient cells. Indirect immunofluorescence experiments demonstrated that phosphorylated form of ATM colocalizes with nuclear IKK-a in response to CDDP. In vitro kinase assay indicated that ATM phosphorylates IKK-a at Ser-473. Moreover, IKKa-deficient MEFs displayed CDDP-resistant phenotype as compared with wild-type MEFs. Taken together, our present results suggest that ATM-mediated phosphorylation of nuclear IKK-a, which stabilizes p73, is one of the main apoptotic pathways in response to CDDP.

show abstract

Nuclear Role of IκB Kinase-γ/NF-κB Essential Modulator (IKKγ/NEMO) in NF-κB-dependent Gene Expression

Cited by 75 publications

References 56 publications

IκB kinase complexes: gateways to NF-κB activation and transcription

IκB kinase complexes: gateways to NF-κB activation and transcription

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin

Contact Info

Product

Resources

About