Redox-regulated pathway of tyrosine phosphorylation underlies NF-κB induction by an atypical pathway independent of the 26S proteasome.

Abstract

Alternative redox stimuli such as pervanadate or hypoxia/reoxygenation, induce transcription factor NF-κB by phospho-tyrosine-dependent and proteasome-independent mechanisms. While considerable attention has been paid to the absence of proteasomal regulation of tyrosine phosphorylated IκBα, there is a paucity of information regarding proteasomal regulation of signaling events distinct from tyrosine phosphorylation of IκBα. To delineate roles for the ubiquitin-proteasome pathway in the phospho-tyrosine dependent mechanism of NF-κB induction, we employed the proteasome inhibitor, Aclacinomycin, and the phosphotyrosine phosphatase inhibitor, pervanadate (PV). Results from these studies demonstrate that phospho-IκBα (Tyr-42) is not subject to proteasomal degradation in a murine stromal epithelial cell line, confirming results previously reported. Correspondingly, proteasome inhibition had no discernable effect on the key signaling intermediaries, Src and ERK1/2, involved in the phospho-tyrosine mechanisms regulating PV-mediated activation of NF-κB. Consistent with previous reports, a significant redox imbalance leading to the activation of tyrosine kinases, as occurs with pervanadate, is required for the induction of NF-κB. Strikingly, our studies demonstrate that proteasome inhibition can potentiate oxidative stress associated with PV-stimulation without impacting kinase activation, however, other cellular implications for this increase in intracellular oxidation remain to be fully delineated.

• Authors: Sarah Cullen, Subramaniam Ponnappan, Usha Ponnappan
• Journal: Biomolecules (Biomolecules) Vol. 5 Issue 1 Pg. 95-112 (Feb 09 2015) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 25671697 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NF-kappa B
• Proteasome Inhibitors
• Protein Kinase Inhibitors
• aclacinomycins
• pervanadate
• Vanadates
• Tyrosine
• Aclarubicin
• src-Family Kinases
• I-kappa B Kinase
• Mitogen-Activated Protein Kinase Kinases
• Protein Tyrosine Phosphatases
• Proteasome Endopeptidase Complex
• ATP dependent 26S protease

Topics

• Aclarubicin (analogs & derivatives, pharmacology)
• Animals
• Cell Line
• Enzyme Activation (drug effects)
• Humans
• I-kappa B Kinase (chemistry, metabolism)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• NF-kappa B (metabolism)
• Oxidation-Reduction (drug effects)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Tyrosine Phosphatases (metabolism)
• Signal Transduction (drug effects)
• Tyrosine (metabolism)
• Vanadates (pharmacology)
• src-Family Kinases (antagonists & inhibitors)