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Geldanamycin, an hsp90/GRP94‐binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway
Author(s) -
Lawson Beth,
Brewer Joseph W.,
Hendershot Linda M.
Publication year - 1998
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199802)174:2<170::aid-jcp4>3.0.co;2-l
Subject(s) - geldanamycin , hsp90 , endoplasmic reticulum , unfolded protein response , microbiology and biotechnology , chaperone (clinical) , chemical chaperone , cytosol , transcription factor , protein folding , biology , chemistry , heat shock protein , biochemistry , enzyme , gene , medicine , pathology
Geldanamycin, a benzoquinone ansamycin, binds specifically to hsp90 and GRP94 in vitro and in vivo. Treatment of cells with geldanamycin alters the molecular chaperone function of hsp90, and as a result, blocks certain cytosolic proteins from reaching their mature form, inhibits their activity, and/or affects their stability. In contrast, little is known about either the effects of geldanamycin on GRP94, the endoplasmic reticulum (ER) homologue of hsp90, or the role of GRP94 in protein folding. In this study, we demonstrate in a variety of cell lines that geldanamycin is a potent inducer of the cellular response to stress in the ER, resulting in the transcriptional up‐regulation of ER chaperones and expression of the gadd153/CHOP transcription factor. Their induction occurs through the unfolded protein response pathway originating in the ER and is not due to effects of the drug on hsp90. Geldanamycin increases the association of nascent proteins with BiP, which indicates that their folding and/or assembly has been altered. These data suggest that GRP94 may play an essential role in the maturation of a number of secretory pathway proteins. J. Cell. Physiol. 174:170–178, 1998. © 1998 Wiley‐Liss, Inc.