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HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis

Cited 86 time in Web of Science Cited 84 time in Scopus
Authors
Lee, Jae-Seon; Lee, Je-Jung; Seo, Jeong-Sun
Issue Date
2004-12-14
Publisher
American Society for Biochemistry and Molecular Biology
Citation
J Biol Chem. 2005 Feb 25;280(8):6634-41. Epub 2004 Dec 7.
Keywords
Animals*ApoptosisCaspase 3Caspases/antagonists & inhibitors/*metabolismCells, CulturedDual Specificity Phosphatase 1Embryo, Mammalian/cytologyExtracellular Signal-Regulated MAP Kinases/*metabolismHSP70 Heat-Shock Proteins/deficiency/genetics/*physiologyJNK Mitogen-Activated Protein Kinases/*metabolismMiceMice, KnockoutMice, Transgenic*Osmotic PressurePhosphorylationProtein Phosphatase 1Protein Tyrosine Phosphatases/metabolismTransfection
Abstract
In this study we examined the function of heat shock protein 70 (HSP70) in the hyperosmolarity-induced apoptotic pathway using hsp70.1-/-mouse embryonic fibroblasts (MEFs). When the cells were exposed to hyperosmotic stress, an absence of HSP70 negatively affected cell viability. Caspase-9 and caspase-3 were rapidly activated, and extensive cleavage occurred in focal adhesion and cytoskeletal molecules in the hsp70.1-/-MEFs. In contrast, hsp70.1+/+ MEFs exhibited no caspase-9 or caspase-3 activation and finally recovered intact cell morphology when cells were shifted back to an isosmotic state. Because HSP70 might be involved in the regulation of mitogen-activated protein kinase (MAPK) activities with regard to various cellular activities, we also monitored MAPK phosphorylation. The absence of HSP70 affected c-Jun N-terminal kinase phosphorylation. However, it had no effect on p38. Sustained phosphorylation of extracellular signal-regulated kinase (ERK) was observed during the hyperosmolarity-induced apoptosis of hsp70.1-/-MEFs. Inhibition of ERK activity by the treatment of PD98059 accelerated the apoptotic pathway. ERK phosphorylation was precisely correlated with shift of mitogen-activated protein kinase phosphatase-3 from the soluble to insoluble fraction. Our results demonstrate that the inhibitory effect of HSP70 on caspase-3 activation is sufficient to inhibit apoptosis and that HSP70 exhibits regulatory functions to c-Jun N-terminal kinase and ERK phosphorylation in hyperosmolarity-induced apoptosis.
ISSN
0021-9258 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15590690

http://hdl.handle.net/10371/29642
DOI
https://doi.org/10.1074/jbc.M412393200
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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