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Sharp, Adam, Crabb, Simon J., Johnson, Peter W. M., Hague, Angela, Cutress, Ramsey, Townsend, Paul A., Ganesan, A. 
ORCID: https://orcid.org/0000-0003-4862-7999 and Packham, Graham
(2009)
Thioflavin S (NSC71948) interferes with Bcl-2-associated athanogene (BAG-1)-mediated protein-protein interactions.
Journal of Pharmacology and Experimental Therapeutics, 331 (2).
pp. 680-689.
ISSN 0022-3565
Abstract
The C-terminal BAG domain is thought to play a key role in BAG-1-induced survival and proliferation by mediating protein-protein interactions, for example, with heat shock proteins HSC70 and HSP70, and with RAF-1 kinase. Here, we have identified thioflavin S (NSC71948) as a potential small-molecule chemical inhibitor of these interactions. NSC71948 inhibited the interaction of BAG-1 and HSC70 in vitro and decreased BAG-1:HSC70 and BAG-1:HSP70 binding in intact cells. NSC71948 also reduced binding between BAG-1 and RAF-1, but had no effect on the interaction between two unrelated proteins, BIM and MCL-1. NSC71948 functionally reversed the ability of BAG-1 to promote vitamin D3 receptor-mediated transactivation, an activity of BAG-1 that depends on HSC70/HSP70 binding, and reduced phosphorylation of p44/42 mitogen-activate protein kinase. NSC71948 can be used to stain amyloid fibrils; however, structurally related compounds, thioflavin T and BTA-1, had no effect on BAG-1:HSC70 binding, suggesting that structural features important for amyloid fibril binding and inhibition of BAG-1:HSC70 binding may be separable. We demonstrated that NSC71948 inhibited the growth of BAG-1 expressing human ZR-75-1 breast cancer cells and wild-type, but not BAG-1-deficient, mouse embryo fibroblasts. Taken together, these data suggest that NSC71948 may be a useful molecule to investigate the functional significance of BAG-1 C-terminal protein interactions. However, it is important to recognize that NSC71948 may exert additional “off-target” effects. Inhibition of BAG-1 function may be an attractive strategy to inhibit the growth of BAG-1-overexpressing cancers, and further screens of additional compound collections may be warranted.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
| Faculty \ School: | Faculty of Science > School of Pharmacy |
| UEA Research Groups: | Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) |
| Depositing User: | Users 2731 not found. |
| Date Deposited: | 20 Oct 2011 11:02 |
| Last Modified: | 04 Jan 2024 01:57 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/35112 |
| DOI: | 10.1124/jpet.109.153601 |
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