Disruption of Heat Shock Factor 1 Reveals an Essential Role in the Ubiquitin Proteolytic Pathway

doi:10.1128/MCB.20.8.2670-2675.2000

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Molecular and Cellular Biology, April 2000, p. 2670-2675, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Disruption of Heat Shock Factor 1 Reveals an Essential Role in the Ubiquitin Proteolytic Pathway

Lila Pirkkala,¹^,² Tero-Pekka Alastalo,¹^,³ XiaoXia Zuo,⁴ Ivor J. Benjamin,⁴^,^* and Lea Sistonen¹^,^*

Turku Centre for Biotechnology, University of Turku, Åbo Akademi University,¹ Department of Biology, Åbo Akademi University,² and Department of Anatomy, University of Turku,³ FIN-20521 Turku, Finland, and Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8573⁴

Received 7 September 1999/Returned for modification 12 October 1999/Accepted 13 January 2000

Inhibition of proteasome-mediated protein degradation machinery is a potent stress stimulus that causes accumulation of ubiquitinatedproteins and increased expression of heat shock proteins (Hsps).Hsps play pivotal roles in homeostasis and protection in a cell,through their well-recognized properties as molecular chaperones.The inducible Hsp expression is regulated by the heat shock transcriptionfactors (HSFs). Among mammalian HSFs, HSF1 has been shown to beimportant for regulation of the heat-induced stress gene expression,whereas the function of HSF2 in stress response is unclear. Recentreports have suggested that both HSF1 and HSF2 are affected duringdown-regulation of ubiquitin-proteasome pathway (Y. Kawazoe etal., Eur. J. Biochem. 255:356-362, 1998; A. Mathew et al., Mol.Cell. Biol. 18:5091-5098, 1998; D. Kim et al., Biochem. Biophys.Res. Commun. 254:264-268, 1999). To date, however, no unambiguousevidence has been presented as to whether a single specific HSFor multiple members of the HSF family are required for transcriptionalinduction of heat shock genes when proteasome activity is down-regulated.Therefore, by using loss-of-function and gain-of-function strategies,we investigated the specific roles of mammalian HSFs in regulationof the ubiquitin-proteasome-mediated stress response. Here wedemonstrate that HSF1, but not HSF2, is essential and sufficientfor up-regulation of Hsp70 expression during down-regulation ofthe ubiquitin proteolytic pathway. We propose that specificityof HSF1 could be an important therapeutic target during diseasepathogenesis associated with abnormal ubiquitin-dependent proteasomefunction.

^* Corresponding author. Mailing address for Lea Sistonen: Turku Centre for Biotechnology, P.O. Box 123, FIN-20521 Turku, Finland.Phone: 358-2-3338028. Fax: 358-2-3338000. E-mail: lea.sistonen{at}btk.utu.fi.Mailing address for Ivor J. Benjamin: Department of Internal Medicine,University of Texas Southwestern Medical Center, 5323 Harry HinesBlvd. NB11.110, Dallas, TX 75235-8573. Phone: (214) 648-1405.Fax: (214) 648-1475. E-mail: ivor.benjamin{at}emailswmed.edu.

Molecular and Cellular Biology, April 2000, p. 2670-2675, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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