The heat-shock protein 90 (HSP90) family is a group of highly conserved molecular chaperones with important functions in protein folding and in signal transduction. The HSP90 protein structure is so well conserved that some HSP90 antibodies are reactive with a broad range of species from humans to chickens (1). In humans there are 17 known genes encoding the HSP90 family members. The HSP90 family consists of 4 different classes: HSP90AA, HSP90AB, HSP90B, and TRAP. These classes are defined by their diversity of functions and sub cellular localization. HSP90 isoforms are known to localize to the cytosol, nucleoplasm, endoplasmic reticulum, mitochondria, and chloroplasts. HSP90 is an abundant protein that maintains cellular homeostasis by promoting the proper folding of hundreds of substrate proteins referred to as clients. These clients range from protein kinases to transcription factors making HSP90 an essential component of many signal transduction pathways. As an ATP-dependent chaperone, HSP90 binds to unfolded or partially folded client proteins and ATP triggering a conformational change to induce folding. Upon hydrolysis of ATP the folded client protein is released. HSP90 associates with various co-chaperones that can further regulate its activities through recruiting client proteins as wells as through inhibition or activation of HSP90’s ATPase activity. HSP90 antibodies have been an important tool to identify and characterize co-chaperone associations. A study of chloroplast protein folding used HSP90 antibodies in immunoprecipitation experiments to identify client proteins and characterize association with HSP90 and the co-chaperones HOP and FKBP (2).
HSP90's role in various cell signaling pathways make it an important player in cancer biology and an attractive candidate to target with anticancer therapies. HSP90 inhibitors may offer the potential to target multiple oncogenic signals with a single drug. A study of drug resistant prostate cancer used HSP90 antibodies for western blotting to demonstrate increased HSP90 protein expression in these drug resistant cells (3). A separate study of drug resistant melanoma cells used HSP90 antibodies to examine surface exposed HSP90, which is crucial for the immunogenicity of dying cancer cells (4). This study demonstrated that inhibition of autophagy was able to increase surface exposed HSP90 and restore cell death. Both of these studies furthered our understanding of HSP90 in cancer biology and drug resistance.
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