Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53 Export

@article{citeulike:5764517, abstract = {10.1073/pnas.0903704106 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.}, author = {Kim, Hyo-Jin and Lee, Ho-June and Jun, Joon-Il and Oh, Yumin and Choi, Seon-Guk and Kim, Hyunjoo and Chung, Chul-Woong and Kim, In-Ki and Park, Il-Sun and Chae, Han-Jung and Kim, Hyung-Ryong and Jung, Yong-Keun}, citeulike-article-id = {5764517}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0903704106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/36/15326.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/36/15326.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19706414}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19706414}, day = {8}, doi = {10.1073/pnas.0903704106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {8, caspase, cell, cleavage, death, psteopontin}, month = {September}, number = {36}, pages = {15326--15331}, posted-at = {2009-09-10 01:31:26}, priority = {2}, title = {Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53}, url = {http://dx.doi.org/10.1073/pnas.0903704106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5764517 L3 - citeulike-article-id:5764517 N2 - 10.1073/pnas.0903704106 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. IS - 36 JF - Proceedings of the National Academy of Sciences EP - 15331 TI - Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53 VL - 106 SP - 15326 KW - 8 KW - caspase KW - cell KW - cleavage KW - death KW - psteopontin AU - Kim, Hyo-Jin AU - Lee, Ho-June AU - Jun, Joon-Il AU - Oh, Yumin AU - Choi, Seon-Guk AU - Kim, Hyunjoo AU - Chung, Chul-Woong AU - Kim, In-Ki AU - Park, Il-Sun AU - Chae, Han-Jung AU - Kim, Hyung-Ryong AU - Jung, Yong-Keun PY - 2009/09/08/ UR - http://dx.doi.org/10.1073/pnas.0903704106 ER -