Geldanamycin, an hsp90/GRP94-binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway.
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.
Lawson
B
B
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Brewer
J W
JW
Hendershot
L M
LM
D016475:3T3 Cells; D000818:Animals; D016227:Benzoquinones; D016466:CHO Cells; D019556:COS Cells; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D051379:Mice; D017510:Protein Folding; D011809:Quinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects*
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; C001277:geldanamycin