Document Detail

SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex.
MedLine Citation:
PMID:  23319048     Owner:  NLM     Status:  MEDLINE    
p53 prevents cancer via cell cycle arrest, apoptosis, and the maintenance of genome stability. p53 also regulates energy-generating metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis via transcriptional regulation of SCO2 and TIGAR. SCO2, a cytochrome c oxidase assembly factor, is a metallochaperone which is involved in the biogenesis of cytochrome c oxidase subunit II. Here we have shown that SCO2 functions as an apoptotic protein in tumor xenografts, thus providing an alternative pathway for p53-mediated apoptosis. SCO2 increases the generation of reactive oxygen species (ROS) and induces dissociation of the protein complex between apoptosis signal-regulating kinase 1 (ASK-1) (mitogen-activated protein kinase kinase kinase [MAPKKK]) and its cellular inhibitor, the redox-active protein thioredoxin (Trx). Furthermore, SCO2 induces phosphorylation of ASK-1 at the Thr(845) residue, resulting in the activation of the ASK-1 kinase pathway. The phosphorylation of ASK-1 induces the activation of mitogen-activated protein kinase kinases 4 and 7 (MAP2K4/7) and MAP2K3/6, which switches the c-Jun N-terminal protein kinase (JNK)/p38-dependent apoptotic cascades in cancer cells. Exogenous addition of the SCO2 gene to hypoxic cancer cells and hypoxic tumors induces apoptosis and causes significant regression of tumor xenografts. We have thus discovered a novel apoptotic function of SCO2, which activates the ASK-1 kinase pathway in switching "on" an alternate mode of p53-mediated apoptosis. We propose that SCO2 might possess a novel tumor suppressor function via the ROS-ASK-1 kinase pathway and thus could be an important candidate for anticancer gene therapy.
Esha Madan; Rajan Gogna; Periannan Kuppusamy; Madan Bhatt; Abbas Ali Mahdi; Uttam Pati
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-14
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-11     Completed Date:  2013-07-30     Revised Date:  2013-10-08    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1285-302     Citation Subset:  IM    
Department of Biochemistry, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India.
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MeSH Terms
Apoptosis / physiology*
Carrier Proteins / genetics*,  metabolism
Cell Line, Tumor
JNK Mitogen-Activated Protein Kinases / genetics,  metabolism
MAP Kinase Kinase Kinase 5 / genetics*,  metabolism
MCF-7 Cells
Membrane Proteins / genetics*,  metabolism
Mitochondrial Proteins / genetics*,  metabolism
Mitogen-Activated Protein Kinase Kinases / genetics,  metabolism
Reactive Oxygen Species / metabolism
Signal Transduction / genetics
Tumor Suppressor Protein p53 / genetics*,  metabolism
p38 Mitogen-Activated Protein Kinases / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Carrier Proteins; 0/Membrane Proteins; 0/Mitochondrial Proteins; 0/Reactive Oxygen Species; 0/SCO2 protein, human; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/VAC14 protein, human; EC Mitogen-Activated Protein Kinases; EC Mitogen-Activated Protein Kinases; EC Kinase Kinase Kinase 5; EC protein, human; EC Protein Kinase Kinases

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