HSP90 Chaperone Proteins and Interactors in Cellular Signal Transduction

细胞信号转导中的 HSP90 伴侣蛋白和相互作用物

• 批准号: 10487190
• 负责人: Leonard Neckers
• 金额: $ 82.4万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487190
• 关键词: Address; Alternative Splicing; Androgen Receptor; Antiandrogen Therapy; Area; Carbon; Cells; Citric Acid Cycle; Client; Complex; Dependence; Development; Electron Transport; Genetic Transcription; Glutamine; HSF1; Heat-Shock Proteins 90; Homologous Gene; Knock-out; Length; Ligand Binding Domain; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Metabolic; Mitochondria; Molecular Chaperones; Neoplasm Metastasis; Oxidative Phosphorylation; Phosphotransferases; Production; Proteins; RNA Splicing; Renal carcinoma; Research; Resistance; Role; Signal Transduction; Source; Urologic Diseases; cancer site; castration resistant prostate cancer; drug development; inhibitor/antagonist; monomer; novel; novel strategies; preference

In FY2021, (1)We confirmed that alternatively spliced androgen receptor (lacking ligand binding domain with which Hsp90 interacts) interacts with and remains dependent on Hsp40 and Hsp70 for stability and transcriptional activity. Further, we showed that targeting the Hsp40/Hsp70 chaperone axis is a novel strategy to treat castration-resistant prostate cancer that has become resistant to standard antiandrogen therapy. (2) We identified a multichaperone complex in mitochondria comprised of Trap1, Hsp60 and mitochondrial Hsp70 as a regulator of oxidative phosphorylation and ATP synthase-mediated ATP production. Assembly of the multichaperone complex is sensitive to mitochondrial ATP level. We identified multiple subunits of ATP synthase and numerous electron transport chain components as Trap1 interactors (potential clients), and we demonstrated that Trap1 knockout leads to increased oxidative phosphorylation and a strong preference for glutamine as the primary carbon source for the TCA cycle. (3) We also demonstrated that Hsp70 inhibition blocked both heat-induced and Hsp90 inhibitor-potentiated HSF1 activation and transcriptional activity by causing the destabilization of HSF1. We showed that Hsp70 bound to both HSF1 monomers (inactive) and trimers (active).

在2021财年，(1)我们证实了选择性剪接的雄激素受体（缺乏与Hsp90相互作用的配体结合结构域）与Hsp40和Hsp70相互作用，并仍然依赖于Hsp40和Hsp70来维持稳定性和转录活性。此外，我们发现靶向Hsp40/Hsp70伴侣轴是一种治疗去势抵抗性前列腺癌的新策略，这种前列腺癌已经对标准抗雄激素治疗产生了耐药性。(2)我们在线粒体中发现了一个由Trap1、Hsp60和线粒体Hsp70组成的多伴侣复合体，作为氧化磷酸化和ATP合成酶介导的ATP生成的调节剂。多伴侣复合物的组装对线粒体ATP水平敏感。我们确定了ATP合成酶的多个亚基和许多电子传递链组分作为Trap1相互作用物（潜在客户），我们证明了Trap1敲除导致氧化磷酸化增加，并强烈倾向于谷氨酰胺作为TCA循环的主要碳源。(3)我们还证明了Hsp70抑制通过引起HSF1的不稳定来阻断热诱导和Hsp90抑制剂增强的HSF1激活和转录活性。我们发现Hsp70可以结合HSF1单体（非活性）和三聚体（活性）。