Document Detail

INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis.
MedLine Citation:
PMID:  20865015     Owner:  NLM     Status:  MEDLINE    
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.
S K Niture; A K Jaiswal
Related Documents :
7646485 - Bcl-2, a novel regulator of cell death.
9659295 - Leydig cell apoptosis in the rat testes after administration of the cytotoxin ethane di...
25190685 - Timing is everything: dendritic cell subsets in murine leishmania infection.
9719055 - Overexpression of bax protein and enhanced apoptosis in the left ventricle of spontaneo...
12390445 - Hypoproteinemia in severe childhood atopic dermatitis: a serious complication.
19101205 - Immune barriers to successful gene therapy.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Retracted Publication     Date:  2010-09-24
Journal Detail:
Title:  Cell death and differentiation     Volume:  18     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-14     Completed Date:  2011-05-31     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  439-51     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adaptor Proteins, Signal Transducing / metabolism*
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
Hydroquinones / pharmacology
Intracellular Signaling Peptides and Proteins / metabolism*
Lung Neoplasms / metabolism,  pathology
Lysine / metabolism
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
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Antioxidants; 0/Carrier Proteins; 0/Cullin Proteins; 0/Cytoskeletal Proteins; 0/Hydroquinones; 0/Intracellular Signaling Peptides and Proteins; 0/KEAP1 protein, human; 0/Keap1 protein, mouse; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 17885-08-4/Phosphoserine; 6PLQ3CP4P3/Etoposide; C12674942B/2-tert-butylhydroquinone; K3Z4F929H6/Lysine
Retraction In:
Cell Death Differ. 2014 Mar;21(3):503   [PMID:  24336049 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Coordinated waves of gene expression during neuronal differentiation of embryonic stem cells as basi...
Next Document:  Mechanisms of force generation and force transmission during interstitial leukocyte migration.