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Molecular and Cellular Biology, April 2000, p. 2670-2675, Vol. 20, No. 8
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.
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
*
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.
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