热休克蛋白
热休克蛋白90
癌变
生物
癌症研究
缺氧(环境)
Hsp90抑制剂
细胞生物学
精子发生
基因剔除小鼠
化学
受体
基因
生物化学
内分泌学
氧气
有机化学
作者
Xin Tang,Cheng Chang,Michelle Hao,Mei Chen,David T. Woodley,Axel H. Schönthal,Wei Li
标识
DOI:10.1038/s41417-021-00316-6
摘要
Hypoxia-inducible factor-1 (HIF-1), a master transcriptional factor for protecting cells from hypoxia, plays a critical role in spermatogenesis and tumorigenesis. For the past two decades, numerous small molecule inhibitors that block mRNA synthesis, protein translation, or DNA binding of HIF-1α have entered clinical trials. To date, few have advanced to FDA approval for clinical applications due to limited efficacy at their toxicity-tolerable dosages. New windows for developing effective and safe therapeutics require better understanding of the specific mechanism of action. The finding that a chaperone-defective mutant heat shock protein-90-alpha (Hsp90α) blocks spermatogenesis, a known hypoxia-driven process in mouse testis prompted us to focus on the role of Hsp90α in HIF-1α. Here we demonstrate that Hsp90α gene knockout causes a dramatic reduction of the high steady-state level of HIF-1α in the testis, blocking sperm production and causing infertility of the mice. In HIF-1α-dependent tumor cells, we found that Hsp90α forms protein complexes with hypoxia-elevated HIF-1α and Hsp90α knockout prevents hypoxia-induced HIF-1α accumulation. In contrast, downregulation of Hsp90β had little effect on hypoxia-induced accumulation of HIF-1α. Instead, Hsp90β protects signaling molecules responsible for cellular homeostasis from assault by 17-AAG (17-N-allylamino-17-demethoxygeldanamycin), a general ATPase inhibitor of both Hsp90α and Hsp90β. Since targeting Hsp90β gene is lethal in both cultured cells and in mice, our new finding explains the toxicity of the previous inhibitor trials and identifies the specific binding of Hsp90α to HIF-1α as a new therapeutic window for developing safer and more effective treatment of male infertility and cancer.
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