Lawson B, Brewer J W, Hendershot L M
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
J Cell Physiol. 1998 Feb;174(2):170-8. doi: 10.1002/(SICI)1097-4652(199802)174:2<170::AID-JCP4>3.0.CO;2-L.
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.
格尔德霉素是一种苯醌安莎霉素，在体外和体内均能特异性结合热休克蛋白90（hsp90）和葡萄糖调节蛋白94（GRP94）。用格尔德霉素处理细胞会改变hsp90的分子伴侣功能，结果会阻止某些胞质蛋白达到其成熟形式，抑制其活性和/或影响其稳定性。相比之下，对于格尔德霉素对GRP94（hsp90的内质网（ER）同源物）的影响以及GRP94在蛋白质折叠中的作用知之甚少。在本研究中，我们在多种细胞系中证明，格尔德霉素是内质网应激细胞反应的有效诱导剂，导致内质网伴侣蛋白的转录上调以及gadd153/CHOP转录因子的表达。它们的诱导通过起源于内质网的未折叠蛋白反应途径发生，而不是由于药物对hsp90的作用。格尔德霉素增加新生蛋白与结合免疫球蛋白蛋白（BiP）的结合，这表明它们的折叠和/或组装发生了改变。这些数据表明，GRP94可能在许多分泌途径蛋白的成熟中起重要作用。
