INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis.

Abstract

Cytosolic inhibitor of Nrf2 (INrf2) is an adaptor protein that mediates ubiquitination/degradation of NF-E2-related factor 2 (Nrf2), a master regulator of cytoprotective gene expression. In this paper, we demonstrate that INrf2 degrades endogenous antiapoptotic B-cell CLL/lymphoma 2 (Bcl-2) protein and controls cellular apoptosis. The DGR domain of INrf2 interacts with the BH2 domain of Bcl-2 and facilitates INrf2:Cul3-Rbx1-mediated ubiquitination of Bcl-2 by the conjugation of ubiquitin molecules to lysine17 of Bcl-2. Further studies showed that INrf2 enhanced etoposide-mediated accumulation of Bax, increased release of cytochrome c from mitochondria, activated caspase-3/7, and enhanced DNA fragmentation and apoptosis. Antioxidants antagonized Bcl-2:INrf2 interaction, led to the release and stabilization of Bcl-2, increased Bcl-2:Bax heterodimers and reduced apoptosis. Moreover, dysfunctional/mutant INrf2 in human lung cancer cells failed to degrade Bcl-2, resulting in decreased etoposide and UV/γ radiation-mediated DNA fragmentation. These data provide the first evidence of INrf2 control of Bcl-2 and apoptotic cell death, with implications in antioxidant protection, survival of cancer cells containing dysfunctional INrf2, and drug resistance.

• Authors: S K Niture, A K Jaiswal
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 18 Issue 3 Pg. 439-51 (Mar 2011) ISSN: 1476-5403 [Electronic] England
• PMID: 20865015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Retracted Publication)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antioxidants
• Carrier Proteins
• Cullin Proteins
• Cytoskeletal Proteins
• Hydroquinones
• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Phosphoserine
• Etoposide
• 2-tert-butylhydroquinone
• Lysine

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Antioxidants (metabolism)
• Apoptosis (drug effects, radiation effects)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects, radiation effects)
• Cullin Proteins (metabolism)
• Cytoskeletal Proteins (metabolism)
• DNA Fragmentation (drug effects, radiation effects)
• Etoposide (pharmacology)
• Gamma Rays
• Humans
• Hydroquinones (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Kelch-Like ECH-Associated Protein 1
• Lung Neoplasms (metabolism, pathology)
• Lysine (metabolism)
• Mice
• Phosphorylation (drug effects, radiation effects)
• Phosphoserine (metabolism)
• Protein Binding (drug effects, radiation effects)
• Protein Processing, Post-Translational (drug effects, radiation effects)
• Protein Stability (drug effects, radiation effects)
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-bcl-2 (chemistry, metabolism)
• Ubiquitination (drug effects, radiation effects)
• Ultraviolet Rays
• Up-Regulation (drug effects, radiation effects)
• bcl-2-Associated X Protein (metabolism)