Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide.
Taxol, a plant-derived antitumor agent, stabilizes microtubules. Taxol also elicits cell signals in a manner indistinguishable from bacterial lipopolysaccharide (LPS). LPS-like actions of Taxol are controlled by the lps gene and are independent of binding to the known Taxol target, beta-tubulin. Using biotin-labeled Taxol, avidin-agarose affinity chromatography, and peptide mass fingerprinting, we identified two Taxol targets from mouse macrophages and brain as heat shock proteins (Hsps) of the 70- and 90-kDa families. Geldanamycin, a specific inhibitor of the Hsp 90 family, blocked the nuclear translocation of NF-kappaB and expression of tumor necrosis factor in macrophages treated with Taxol or with LPS. Geldanamycin did not block microtubule bundling by Taxol or macrophage activation by tumor necrosis factor. Thus, Taxol binds Hsps, and Hsp 90 helps mediate the activation of macrophages by Taxol and by LPS.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones; D019921:Biotinylation; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis; D017239:Paclitaxel / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology