Sreedhar Amere Subbarao, Soti Csaba, Csermely Péter
Department of Medical Chemistry, Semmelweis University Medical School, P.O. Box 260, H-1444 Budapest 8, Hungary.
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):233-42. doi: 10.1016/j.bbapap.2003.11.027.
The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a number of other chaperones, promotes the conformational maturation of a large variety of protein kinases. Inhibition of Hsp90 function results in the collapse of the metastable conformation of most of these kinases and leads to their proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90 inhibitors have been developed in recent years. Some of these inhibitors are also involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti-cancer drugs. Here we review these novel protein kinase inhibitors and their emerging role in various cellular processes, apart from their inhibition of Hsp90 protein function. We focus not only on Hsp90-tumor progression, but also on cytoarchitecture, as the higher levels of cellular organization need constant remodeling, where the role of Hsp90 requires investigation. Our last major aspect deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant effects.
90千道尔顿热休克蛋白（Hsp90）是真核细胞质中一种普遍存在、进化上高度保守的分子伴侣。Hsp90与许多其他伴侣蛋白一起，促进多种蛋白激酶的构象成熟。抑制Hsp90功能会导致这些激酶中大多数的亚稳态构象崩溃，并导致它们被蛋白酶体进行蛋白水解清除。近年来已开发出许多天然和合成的Hsp90抑制剂。其中一些抑制剂还参与使肿瘤细胞对促凋亡刺激敏感，因此可作为抗癌药物。在此，我们综述这些新型蛋白激酶抑制剂及其在各种细胞过程中的新作用，除了它们对Hsp90蛋白功能的抑制作用。我们不仅关注Hsp90与肿瘤进展，还关注细胞结构，因为更高层次的细胞组织需要不断重塑，而Hsp90在其中的作用有待研究。我们最后一个主要方面涉及蛋白质氧化，因为几种Hsp90抑制剂具有促氧化作用。
