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Molecular and Cellular Biology, November 2002, p. 7721-7730, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7721-7730.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Heat Shock Protein Hsp72 Is a Negative Regulator of Apoptosis Signal-Regulating Kinase 1

National Creative Research Initiative Center for Cell Death,¹ Graduate School of Biotechnology, Korea University, Seoul 136-701,³ Department of Biochemistry and Ilchun Molecular Medicine Institute MRC, Seoul National University College of Medicine, Seoul 110-799,² National Creative Research Initiative Center for ARS Network, Seoul National University, Seoul, South Korea⁴

Received 19 March 2002/ Returned for modification 22 April 2002/ Accepted 12 August 2002

Heat shock protein 72 (Hsp72) is thought to protect cells against cellular stress. The protective role of Hsp72 was investigated by determining the effect of this protein on the stress-activated protein kinase signaling pathways. Prior exposure of NIH 3T3 cells to mild heat shock (43°C for 20 min) resulted in inhibition of H₂O₂-induced activation of apoptosis signal-regulating kinase 1 (ASK1). Overexpression of Hsp72 also inhibited H₂O₂-induced activation of ASK1 as well as that of downstream kinases in the p38 mitogen-activated protein kinase (MAPK) signaling cascade. Recombinant Hsp72 bound directly to ASK1 and inhibited ASK1 activity in vitro. Furthermore, coimmunoprecipitation analysis revealed a physical interaction between endogenous Hsp72 and ASK1 in NIH 3T3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ASK1 and ASK1-dependent apoptosis. Hsp72 antisense oligonucleotides prevented the inhibitory effects of mild heat shock on H₂O₂-induced ASK1 activation and apoptosis. These observations suggest that Hsp72 functions as an endogenous inhibitor of ASK1.

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