Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway.

Alkalay, Irit; Yaron, Avraham; Hatzubai, Ada; Orian, Amir; Ciechanover, Aaron; Ben‐Neriah, Yinon

doi:10.1073/pnas.92.23.10599

Cited by 414 publications

(291 citation statements)

References 45 publications

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“…The arrow indicates the position of the speci®c NF-kB complex commonly a prerequisite for its ubiquitination and degradation (May and Ghosh, 1998). We used the protease inhibitor ALLN (N-Acetyl-Leucyl-LeucylNorleucinal) and phosphatase inhibitors (see Materials and methods) in an attempt to detect a phosphorylation-induced shift of IkBa (Alkalay et al, 1995) after treatment with CPT. Cells were treated with ALLN as indicated (Figure 6b), then with TNF-a or CPT, and the cytoplasmic proteins were extracted in the presence of phosphatase inhibitors for analysis by Western blotting.…”

Section: Ikba Degradation In Normal and At ®Broblastsmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kB. It is activated by various stress situations, including oxidative stress, and by DNAdamaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NFkB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.

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Section: Ikba Degradation In Normal and At ®Broblastsmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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“…Given the fact that several transcription factors, such as HIF1a and NF-kB, are under the control of the UPP (Alkalay et al, 1995;Cho et al, 2001), we hypothesized that impairment of the UPP in RPE could result in altered gene expression that promotes the development of AMD-like phenotypes. To test this hypothesis, we inhibited proteasome activity in cultured RPE and assessed the effects on the expression and secretion of growth factors and chemokines that may be involved in the development of AMD.…”

Section: Introductionmentioning

confidence: 99%

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

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As in many other types of cells, retinal pigment epithelial (RPE) cells have an active ubiquitineproteasome pathway (UPP). However, the function of the UPP in RPE remains to be elucidated. The objective of this study is to determine the role of the UPP in controlling the levels and activities of transcription factors hypoxia-inducible factor (HIF) and NF-kB. We inhibited the UPP with proteasome-specific inhibitors and determined the activation of HIF and NF-kB as well as the expression and secretion of pro-angiogenic factors. HIF-1a was not detectable in ARPE-19 cells under normal culture conditions. However, when proteasome activity was inhibited, HIF-1a accumulated in RPE in a time-dependent manner. Consistent with accumulation of HIF-1a in the cells, levels of mRNA for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in RPE were up to 7-fold higher upon inhibition of the proteasome. Proteasome inhibition was also associated with a 2-fold increase in levels of mRNA for angiopoietin-1 (Ang-1). ARPE-19 cells secrete significant levels of VEGF under normal culture conditions. Inhibition of proteasome activity increased the secretion of VEGF by 2-fold. In contrast to the increase in HIF activity, NF-kB activation was reduced by proteasome inhibition. In addition, the expression and secretion of monocyte chemoattractant protein-1 (MCP-1) by RPE were substantially attenuated by the inhibition of proteasome activity. These data demonstrate that the UPP plays an important role in modulating the activities of HIF and NF-kB in the RPE. Consequences of an impairment of the UPP include accumulation of HIF-1a and diminished NF-kB activation, which lead to enhanced expression and secretion of pro-angiogenic factors and attenuated expression of MCP-1. Taken together, these data predict that the impairment of the UPP could lead to the development of AMD-related phenotypes.

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“…The proteasome, a large multi-subunit protease complex, has been shown to be involved in these processes [32][33][34] and it has been suggested that additional proteases, such as calpains, may play a further role [35]. In addition to these mechanisms, the existence of proteolysisindependent pathways for NF-B activation has been postulated, although their involvement in cytokine gene expression is not known [36,37].…”

Section: Introductionmentioning

confidence: 99%

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

Haas

Page

et al. 1998

Journal of Leukocyte Biology

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Abstract:We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-B (NF-B). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of I B-␣ and -␤, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-B binding activity and NF-B transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1␤ (IL-1␤), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of I B-␣ and -␤, efficiently blocked the production of TNF and, to a lesser extent, IL-1␤, whereas that of IL-8 was not inhibited. The expression of NF-B-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

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Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway.

Cited by 414 publications

References 45 publications

The ATM protein is required for sustained activation of NF-κB following DNA damage

The ATM protein is required for sustained activation of NF-κB following DNA damage

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

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