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.
| Kijima, Toshiki; Eguchi, Takanori; Neckers, Len et al. (2018) Monitoring of the Heat Shock Response with a Real-Time Luciferase Reporter. Methods Mol Biol 1709:35-45 |
| Zuehlke, Abbey D; Moses, Michael A; Neckers, Len (2018) Heat shock protein 90: its inhibition and function. Philos Trans R Soc Lond B Biol Sci 373: |
| Zuehlke, Abbey D; Neckers, Leonard (2017) Out with the old: Hsp90 finds amino acid residue more useful than co-chaperone protein. Microb Cell 4:273-274 |
| Xu, Wanping; Neckers, Len (2017) A USE1ful Biomarker and Molecular Target in Lung Cancer? J Natl Cancer Inst 109: |
| Woodford, Mark R; Dunn, Diana; Miller, Jonelle B et al. (2016) Impact of Posttranslational Modifications on the Anticancer Activity of Hsp90 Inhibitors. Adv Cancer Res 129:31-50 |
| Yim, Kendrick H; Prince, Thomas L; Qu, Shiwei et al. (2016) Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90?. Proc Natl Acad Sci U S A 113:E4801-9 |
| Zuehlke, Abbey D; Neckers, Len (2016) Clients Place Unique Functional Constraints on Hsp90. Trends Biochem Sci 41:562-564 |
| Xu, Wanping; Neckers, Len (2016) Gr(i)p the ER to Stress Out Melanoma. Cancer Cell 29:769-71 |
| Calderwood, Stuart K; Neckers, Len (2016) Hsp90 in Cancer: Transcriptional Roles in the Nucleus. Adv Cancer Res 129:89-106 |
| Woodford, Mark R; Dunn, Diana M; Ciciarelli, Joseph G et al. (2016) Targeting Hsp90 in Non-Cancerous Maladies. Curr Top Med Chem 16:2792-804 |
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