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Biological validation that SF3b is a target of the antitumor macrolide pladienolide
Open accessAbstract
Pladienolide is a naturally occurring macrolide that binds to the SF3b complex to inhibit mRNA splicing. It has not been fully validated whether the splicing impairment is a relevant mechanism for the potent antitumor activity of pladienolide. We established pladienolide‐resistant clones from WiDr and DLD1 colorectal cancer cells that were insensitive to the inhibitory action of pladienolide on cell proliferation and splicing. An mRNA‐Seq differential analysis revealed that these two cell lines have an identical mutation at Arg1074 in the gene for SF3B1, which encodes a subunit of the SF3b complex. Reverse expression of the mutant protein transferred pladienolide resistance to WiDr cells. Furthermore, immunoprecipitation analysis using a radiolabeled probe showed that the mutation impaired the binding affinity of paldienolide to its target. These results clearly demonstrate that pladienolide exerts its potent activity by targeting SF3b and also suggest that inhibition of SF3b is a promising drug target for anticancer therapy. Structured digital abstract SF3B1physically interacts with SF3B2 and SF3B3 by anti bait coimmunoprecipitation (View interaction)
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Cites
Frequent pathway mutations of splicing machinery in myelodysplasia
Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011) · Nature · doi:10.1038/nature10496 · Cited by 2,029
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Therapeutic targeting of splicing in cancer
Lee, S. C.-W., & Abdel-Wahab, O. (2016) · Nature Medicine · doi:10.1038/nm.4165 · Cited by 561
SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts
Malcovati, L., Karimi, M., Papaemmanuil, E., Ambaglio, I., Jädersten, M., Jansson, M., Elena, C., Gallì, A., Walldin, G., Della Porta, M. G., et al. (2015) · Blood · doi:10.1182/blood-2015-03-633537 · Cited by 434
Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1
Nguyen, H. D., Yadav, T., Giri, S., Saez, B., Graubert, T. A., & Zou, L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.029 · Cited by 267
RNA‐PROTACs: Degraders of RNA‐Binding Proteins
Ghidini, A., Cléry, A., Halloy, F., Allain, F. H. T., & Hall, J. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202012330 · Cited by 197
Myeloid malignancies: mutations, models and management
Murati, A., Brecqueville, M., Devillier, R., Mozziconacci, M.-J., Gelsi-Boyer, V., & Birnbaum, D. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-304 · Cited by 139
Metadata
- Authors
- Yokoi, A., Kotake, Y., Takahashi, K., Kadowaki, T., Matsumoto, Y., Minoshima, Y., Sugi, N. H., Sagane, K., Hamaguchi, M., Iwata, M., & Mizui, Y.
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2011-10-31
- Volume
- 278
- Issue
- 24
- Pages
- 4870-4880
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W1553320576
- Cited by
- 177
- References
- 1
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Yokoi, A., Kotake, Y., Takahashi, K., Kadowaki, T., Matsumoto, Y., Minoshima, Y., Sugi, N. H., Sagane, K., Hamaguchi, M., Iwata, M., & Mizui, Y. (2011). Biological validation that SF3b is a target of the antitumor macrolide pladienolide. The FEBS Journal. https://doi.org/10.1111/j.1742-4658.2011.08387.x
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