S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biochemistry & Molecular Biology (생화학교실) Journal Papers (저널논문_생화학교실)
HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis
- Lee, Jae-Seon; Lee, Je-Jung; Seo, Jeong-Sun
- Issue Date
- J Biol Chem. 2005 Feb 25;280(8):6634-41. Epub 2004 Dec 7.
- Animals; *Apoptosis; Caspase 3; Caspases/antagonists & inhibitors/*metabolism; Cells, Cultured; Dual Specificity Phosphatase 1; Embryo, Mammalian/cytology; Extracellular Signal-Regulated MAP Kinases/*metabolism; HSP70 Heat-Shock Proteins/deficiency/genetics/*physiology; JNK Mitogen-Activated Protein Kinases/*metabolism; Mice; Mice, Knockout; Mice, Transgenic; *Osmotic Pressure; Phosphorylation; Protein Phosphatase 1; Protein Tyrosine Phosphatases/metabolism; Transfection
- 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.
- 0021-9258 (Print)
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