|INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis.|
|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|
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|Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-09-24|
|Title: Cell death and differentiation Volume: 18 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2011 Mar|
|Created Date: 2011-02-14 Completed Date: 2011-05-31 Revised Date: 2012-09-18|
Medline Journal Info:
|Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England|
|Languages: eng Pagination: 439-51 Citation Subset: IM|
|Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.|
|APA/MLA Format Download EndNote Download BibTex|
Adaptor Proteins, Signal Transducing
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
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
Up-Regulation / drug effects, radiation effects
bcl-2-Associated X Protein / metabolism
|R01 ES012265/ES/NIEHS NIH HHS; R01 ES012265-07/ES/NIEHS NIH HHS; R01 ES012265-08/ES/NIEHS NIH HHS; R01 ES012265-09/ES/NIEHS NIH HHS|
|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; 1948-33-0/2-tert-butylhydroquinone; 33419-42-0/Etoposide; 56-87-1/Lysine|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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