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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 ubiquitinated proteins 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 transcription factors (HSFs). Among mammalian HSFs, HSF1 has been shown to be important for regulation of the heat-induced stress gene expression, whereas the function of HSF2 in stress response is unclear. Recent reports have suggested that both HSF1 and HSF2 are affected during down-regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., 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 unambiguous evidence has been presented as to whether a single specific HSF or multiple members of the HSF family are required for transcriptional induction 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 regulation of the ubiquitin-proteasome-mediated stress response. Here we demonstrate that HSF1, but not HSF2, is essential and sufficient for up-regulation of Hsp70 expression during down-regulation of the ubiquitin proteolytic pathway. We propose that specificity of HSF1 could be an important therapeutic target during disease pathogenesis associated with abnormal ubiquitin-dependent proteasome function.

* 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 Hines Blvd. 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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