Document Detail

Selective targeting of c-Abl via a cryptic mitochondrial targeting signal activated by cellular redox status in leukemic and breast cancer cells.
MedLine Citation:
PMID:  22549737     Owner:  NLM     Status:  MEDLINE    
PURPOSE: The tyrosine kinase c-Abl localizes to the mitochondria under cell stress conditions and promotes apoptosis. However, c-Abl has not been directly targeted to the mitochondria. Fusing c-Abl to a mitochondrial translocation signal (MTS) that is activated by reactive oxygen species (ROS) will selectively target the mitochondria of cancer cells exhibiting an elevated ROS phenotype. Mitochondrially targeted c-Abl will thereby induce malignant cell death.
METHODS: Confocal microscopy was used to determine mitochondrial colocalization of ectopically expressed c-Abl-EGFP/cMTS fusion across three cell lines (K562, Cos-7, and 1471.1) with varying levels of basal (and pharmacologically modulated) ROS. ROS were quantified by indicator dye assay. The functional consequences of mitochondrial c-Abl were assessed by DNA accessibility to 7-AAD using flow cytometry.
RESULTS: The cMTS and cMTS/c-Abl fusions colocalized to the mitochondria in leukemic (K562) and breast (1471.1) cancer phenotypes (but not Cos-7 fibroblasts) in a ROS and PKC dependent manner.
CONCLUSIONS: We confirm and extend oxidative stress activated translocation of the cMTS by demonstrating that the cMTS and Abl/cMTS fusion selectively target the mitochondria of K562 leukemia and mammary adenocarcinoma 1471.1 cells. c-Abl induced K562 leukemia cell death when targeted to the matrix but not the outer membrane of the mitochondria.
Jonathan E Constance; Samuel D Despres; Akemi Nishida; Carol S Lim
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-02
Journal Detail:
Title:  Pharmaceutical research     Volume:  29     ISSN:  1573-904X     ISO Abbreviation:  Pharm. Res.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-18     Completed Date:  2012-11-23     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2317-28     Citation Subset:  IM    
Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah 84108, USA.
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MeSH Terms
Amino Acid Sequence
COS Cells
Cell Death
Cell Line, Tumor
Cercopithecus aethiops
Gene Expression
Leukemia / genetics,  metabolism*,  pathology
Mammary Neoplasms, Animal / genetics,  metabolism*,  pathology
Mitochondria / genetics,  metabolism*,  pathology
Molecular Sequence Data
Oxidative Stress
Protein Transport
Proto-Oncogene Proteins c-abl / analysis,  genetics,  metabolism*
Reactive Oxygen Species / metabolism*
Recombinant Fusion Proteins / analysis,  genetics,  metabolism
Grant Support
P30CA042014/CA/NCI NIH HHS; R01 CA129528/CA/NCI NIH HHS; R01-CA129528/CA/NCI NIH HHS
Reg. No./Substance:
0/Reactive Oxygen Species; 0/Recombinant Fusion Proteins; EC Proteins c-abl

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