A proteasome inhibitor prevents activation of NF‐kappa B and stabilizes a newly phosphorylated form of I kappa B‐alpha that is still bound to NF‐kappa B.

doi:10.1002/j.1460-2075.1994.tb06878.x

Paper

A proteasome inhibitor prevents activation of NF‐kappa B and stabilizes a newly phosphorylated form of I kappa B‐alpha that is still bound to NF‐kappa B.

Published Nov 1, 1994 · E. Traenckner, S. Wilk, P. Baeuerle

The EMBO Journal

Q1 SJR score

709

Citations

24

Influential Citations

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Abstract

Activation of the inducible transcription factor NF‐kappa B involves removal of the inhibitory subunit I kappa B‐alpha from a latent cytoplasmic complex. It has been reported that I kappa B‐alpha is subject to both phosphorylation and proteolysis in the process of NF‐kappa B activation. In this study, we present evidence that the multicatalytic cytosolic protease (proteasome) is involved in the degradation of I kappa B‐alpha. Micromolar amounts of the peptide Cbz‐Ile‐Glu(O‐t‐Bu)‐Ala‐leucinal (PSI), a specific inhibitor of the chymotrypsin‐like activity of the proteasome, prevented activation of NF‐kappa B in response to tumor necrosis factor‐alpha (TNF) and okadaic acid (OA) through inhibition of I kappa B‐alpha degradation. The m‐calpain inhibitor Cbz‐Leu‐leucinal was ineffective. In the presence of PSI, a newly phosphorylated form of I kappa B‐alpha accumulated in TNF‐ and OA‐stimulated cells. However, the covalent modification of I kappa B‐alpha was not sufficient for activation of NF‐kappa B: no substantial NF‐kappa B DNA binding activity appeared in cells because the newly phosphorylated form of I kappa B‐alpha was still tightly bound to p65 NF‐kappa B. Pyrrolidinedithiocarbamate, an antioxidant inhibitor of NF‐kappa B activation which did not interfere with proteasome activities, prevented de novo phosphorylation of I kappa B‐alpha as well as its subsequent degradation. This suggests that phosphorylation of I kappa B‐alpha is equally necessary for the activation of NF‐kappa B.(ABSTRACT TRUNCATED AT 250 WORDS)

In Vitro Study

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Study Snapshot

A proteasome inhibitor prevents NF-kappa B activation by inhibiting its degradation, suggesting that both phosphorylation and proteasome activity are necessary for NF-kappa B activation.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

A proteasome inhibitor prevents activation of NF‐kappa B and stabilizes a newly phosphorylated form of I kappa B‐alpha that is still bound to NF‐kappa B.

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References

Citations

Proteasomes and Ubiquitin C-Terminal Hydrolase L1 as Biomarkers of Tissue Damage and Inflammatory Response to Different Types of Injury—A Short Review

Proteasomes and UCHL1 serve as biomarkers for identifying tissue damage and inflammation in various injuries, aiding in diagnosis and prognosis.

Ketorolac disturbs proteasome functions and induces mitochondrial abnormality-associated apoptosis.

Ketorolac disrupts proteasome functions and induces apoptosis in cancer cells by disrupting cell membrane potential and releasing cytochrome c.

Fibroblasts activation by embryonic signal switching: A novel mechanism of placental growth factor-induced cardiac remodeling.

High circulating levels of placental growth factor can potentially regulate cardiac remodeling by stimulating fibroblast activation and inflammatory response.

Effect of proteasome inhibitors on canine lymphoma cell response to CHOP chemotherapy in vitro.

Proteasome inhibitors, such as bortezomib and ixazomib, can improve canine lymphoma cell responsiveness to CHOP chemotherapy, potentially improving treatment outcomes for dogs.

A longitudinal single-cell atlas of treatment response in pediatric AML.

Pediatric acute myeloid leukemia patients show subtype-specific plasticity in cellular composition and treatment response, suggesting potential targets for targeted therapies.