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Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway. Mol Cell Biol 2000 Apr;20(8):2670-5

Date

03/25/2000

Pubmed ID

10733569

Pubmed Central ID

PMC85482

DOI

10.1128/mcb.20.8.2670-2675.2000

Scopus ID

2-s2.0-0034069656   89 Citations

Abstract

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.

Author List

Pirkkala L, Alastalo TP, Zuo X, Benjamin IJ, Sistonen L

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cysteine Endopeptidases
DNA-Binding Proteins
Gene Expression Regulation
Heat Shock Transcription Factors
Heat-Shock Proteins
Humans
K562 Cells
Multienzyme Complexes
Proteasome Endopeptidase Complex
Transcription Factors
Ubiquitins
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a