Document Detail

Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53.
MedLine Citation:
PMID:  19706414     Owner:  NLM     Status:  MEDLINE    
Osteopontin (OPN) is highly expressed in cancer patients and plays important roles in many stages of tumor progression, such as anti-apoptosis, proliferation, and metastasis. From functional screening of human cDNA library, we isolated OPN as a caspase-8 substrate that regulates cell death during hypoxia/reoxygenation (Hyp/RO). In vitro cleavage assays demonstrate that OPN is cleaved at Asp-135 and Asp-157 by caspase-8. Cellular cleavage of OPN is observed in apoptotic cells exposed to Hyp/RO among various apoptotic stimuli and its cleavage is blocked by zVAD or IETD caspase inhibitor. Further, over-expression of OPN, the form with secretion signal, inhibits Hyp/RO-induced cell death. Caspase cleavage-defective OPN mutant (OPN D135A/D157A) is more efficient to suppress Hyp/RO-induced cell death than wild-type OPN. OPN D135A/D157A sustains AKT activity to increase cell viability through inhibition of caspase-9 during Hyp/RO. In addition, OPN is highly induced in some tumor cells during Hyp/RO, such as HeLa and Huh-7 cells, which is associated with their resistance to Hyp/RO by sustaining AKT activity. Notably, OPN C-terminal cleavage fragment produced by caspase-8 is detected in the nucleus. Plasmid-encoded expression of OPN C-terminal cleavage fragment increases p53 protein level and induces apoptosis of wild-type mouse embryonic fibroblast cells, but not p53(-/-) mouse embryonic fibroblast cells. These observations suggest that the protective function of OPN during Hyp/RO is inactivated via the proteolytic cleavage by caspase-8 and its cleavage product subsequently induces cell death via p53, postulating caspase-8 as a negative regulator of tumorigenic activity of OPN.
Hyo-Jin Kim; Ho-June Lee; Joon-Il Jun; Yumin Oh; Seon-Guk Choi; Hyunjoo Kim; Chul-Woong Chung; In-Ki Kim; Il-Sun Park; Han-Jung Chae; Hyung-Ryong Kim; Yong-Keun Jung
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-19
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  106     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-10-06     Completed Date:  2009-12-07     Revised Date:  2010-09-27    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15326-31     Citation Subset:  IM    
Creative Research Initiative Acceleration Research, School of Biological Science/Bio-Max Institute, Seoul National University, Seoul 151-747, Korea.
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MeSH Terms
Apoptosis / physiology*
Blotting, Western
Caspase 8 / metabolism*
Cell Hypoxia / physiology*
Hela Cells
Osteopontin / genetics,  metabolism*
Tumor Suppressor Protein p53 / metabolism*
Reg. No./Substance:
0/Tumor Suppressor Protein p53; 106441-73-0/Osteopontin; EC 3.4.22.-/Caspase 8

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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