| Knock-in reconstitution studies reveal an unexpected role of Cys-65 in regulating APE1/Ref-1 subcellular trafficking and function. | |
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MedLine Citation:
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PMID: 21865600 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-08-24 |
Journal Detail:
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Title: Molecular biology of the cell Volume: 22 ISSN: 1939-4586 ISO Abbreviation: Mol. Biol. Cell Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-14 Completed Date: 2012-02-14 Revised Date: 2013-05-23 |
Medline Journal Info:
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Nlm Unique ID: 9201390 Medline TA: Mol Biol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 3887-901 Citation Subset: IM |
Affiliation:
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Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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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 Humans Mitochondria / genetics, metabolism* Mitochondrial Membrane Transport Proteins / metabolism Mitochondrial Membranes / metabolism* Mutation Oxidation-Reduction Oxidative Stress / drug effects Propionates / pharmacology Protein Binding Protein Folding Protein Transport / drug effects Signal Transduction* |
| Grant Support | |
ID/Acronym/Agency:
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CA106298/CA/NCI NIH HHS; CA121168/CA/NCI NIH HHS; CA94025/CA/NCI NIH HHS; R01 CA114571/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzoquinones; 0/MIA40 protein, human; 0/Mitochondrial Membrane Transport Proteins; 0/Propionates; 136164-66-4/E 3330; 52-90-4/Cysteine; EC 4.2.99.18/APEX1 protein, human; EC 4.2.99.18/DNA-(Apurinic or Apyrimidinic Site) Lyase |
| Comments/Corrections | |
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