The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Inhibition of proteasome deubiquitinating activity as a new cancer therapy
Open accessAbstract
Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle–associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.
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DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139
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Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids
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Metadata
- Authors
- D'Arcy, P., Brnjic, S., Olofsson, M. H., Fryknäs, M., Lindsten, K., De Cesare, M., Perego, P., Sadeghi, B., Hassan, M., Larsson, R., & Linder, S.
- Venue
- Nature Medicine
- Published
- 2011-11-06
- Volume
- 17
- Issue
- 12
- Pages
- 1636-1640
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2051458654
- Cited by
- 492
- References
- 3
- FWCI
- 13.52
- Type
- journal article
- Language
- en
- Open access
- green
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
