Document Detail

Knock-in reconstitution studies reveal an unexpected role of Cys-65 in regulating APE1/Ref-1 subcellular trafficking and function.
MedLine Citation:
PMID:  21865600     Owner:  NLM     Status:  MEDLINE    
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1) protects cells from oxidative stress via the base excision repair pathway and as a redox transcriptional coactivator. It is required for tumor progression/metastasis, and its up-regulation is associated with cancer resistance. Loss of APE1 expression causes cell growth arrest, mitochondrial impairment, apoptosis, and alterations of the intracellular redox state and cytoskeletal structure. A detailed knowledge of the molecular mechanisms regulating its different activities is required to understand the APE1 function associated with cancer development and for targeting this protein in cancer therapy. To dissect these activities, we performed reconstitution experiments by using wild-type and various APE1 mutants. Our results suggest that the redox function is responsible for cell proliferation through the involvement of Cys-65 in mediating APE1 localization within mitochondria. C65S behaves as a loss-of-function mutation by affecting the in vivo folding of the protein and by causing a reduced accumulation in the intermembrane space of mitochondria, where the import protein Mia40 specifically interacts with APE1. Treatment of cells with (E)-3-(2-[5,6-dimethoxy-3-methyl-1,4-benzoquinonyl])-2-nonyl propenoic acid, a specific inhibitor of APE1 redox function through increased Cys-65 oxidation, confirm that Cys-65 controls APE1 subcellular trafficking and provides the basis for a new role for this residue.
Carlo Vascotto; Elena Bisetto; Mengxia Li; Leo A H Zeef; Chiara D'Ambrosio; Rossana Domenis; Marina Comelli; Daniela Delneri; Andrea Scaloni; Fabio Altieri; Irene Mavelli; Franco Quadrifoglio; Mark R Kelley; Gianluca Tell
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-24
Journal Detail:
Title:  Molecular biology of the cell     Volume:  22     ISSN:  1939-4586     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-14     Completed Date:  2012-02-14     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3887-901     Citation Subset:  IM    
Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
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MeSH Terms
Apoptosis / drug effects
Benzoquinones / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Transformation, Neoplastic / genetics,  metabolism
Cysteine / chemistry,  genetics,  metabolism*
Cytoplasm / metabolism
DNA Repair / drug effects
DNA-(Apurinic or Apyrimidinic Site) Lyase / antagonists & inhibitors,  chemistry,  genetics,  metabolism*
Gene Knock-In Techniques
Mitochondria / genetics,  metabolism*
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Membranes / metabolism*
Oxidative Stress / drug effects
Propionates / pharmacology
Protein Binding
Protein Folding
Protein Transport / drug effects
Signal Transduction*
Grant Support
Reg. No./Substance:
0/Benzoquinones; 0/MIA40 protein, human; 0/Mitochondrial Membrane Transport Proteins; 0/Propionates; 136164-66-4/E 3330; 52-90-4/Cysteine; EC protein, human; EC or Apyrimidinic Site) Lyase

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