ZIA SC 010074 (ZIA) | |||
---|---|---|---|
Title | HSP90 Chaperone Proteins & Chaperone Interactors in Cellular Signal Transduction | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Neckers, Leonard | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $620,818 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Metastasis (100.0%) |
Bladder (20.0%) Kidney Disease (20.0%) Prostate (20.0%) Urinary System (40.0%) Kidney Cancer (20.0%) |
||
Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Systemic Therapies - Discovery and Development |
|||
Abstract | |||
In 2018, (1) we demonstrated that Hsp90 inhibitors disrupt a transient Hsp90-HSF1 interaction that leads to potentiation of the transcriptional activity of HSF1 by increasing the duration of binding to DNA. We found that activated Hsp90 interacts well with HSF1 and serves to terminate the heat shock response by removing HSF1 trimers from DNA. Thus, we have proposed a noncanonical model of Hsp90-mediated HSF1 regulation. (2)We also demonstrated 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. (3) 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 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. |