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Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML
Abstract
Arsenic on the Fingers: Arsenic, an ancient drug used in traditional Chinese medicine, has attracted wide interest because it has therapeutic activity in patients with acute promyelocytic leukemia (APL). The drug acts by promoting degradation of an oncogenic protein, PML-RARα, a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor α, which is found specifically in APL cells and helps drive their growth. Zhang et al. (p. 240 ; see the Perspective by Kogan ) now explain how arsenic initiates the molecular events leading to PML-RARα degradation. Arsenic was found to bind directly to cysteine residues within zinc finger domains of PML. Arsenic binding then induced oligomerization of PML, which in turn enhanced its association with an enzyme that helps catalyze SUMOylation, a posttranslational modification that can target proteins for degradation.
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“One of the mechanisms by which ATO treats APL is its ability to bind directly to the cysteine in the zinc finger structure of the fusion protein, mediating the ubiquitinated degradation of PML-RARα.427”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [427]
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Cited by
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016
Targeted protein degradation: from mechanisms to clinic
Tsai, J. M., Nowak, R. P., Ebert, B. L., & Fischer, E. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00729-9 · Cited by 438
Retinoic acid receptors: From molecular mechanisms to cancer therapy
di Masi, A., Leboffe, L., De Marinis, E., Pagano, F., Cicconi, L., Rochette-Egly, C., Lo-Coco, F., Ascenzi, P., & Nervi, C. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2014.12.003 · Cited by 403
Beauchamp, E. M., Ringer, L., Bulut, G., Sajwan, K. P., Hall, M. D., Lee, Y.-C., Peaceman, D., Özdemirli, M., Rodriguez, O., Macdonald, T. J., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42874 · Cited by 351
Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.11.017 · Cited by 346
Metadata
- Authors
- Zhang, X.-W., Yan, X.-J., Zhou, Z.-R., Yang, F.-F., Wu, Z.-Y., Sun, H.-B., Liang, W.-X., Song, A.-X., Lallemand-Breitenbach, V., Jeanne, M., Zhang, Q.-Y., Yang, H.-Y., Huang, Q.-H., Zhou, G.-B., Tong, J.-H., Zhang, Y., Wu, J.-H., Hu, H.-Y., de Thé, H., Chen, S.-J., & Chen, Z.
- Venue
- Science
- Published
- 2010-04-09
- Volume
- 328
- Issue
- 5975
- Pages
- 240-243
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2170325085
- Cited by
- 785
- References
- 0
- FWCI
- 24.69
- Type
- journal article
- Language
- en
- Open access
- closed
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- Zhang, X.-W., Yan, X.-J., Zhou, Z.-R., Yang, F.-F., Wu, Z.-Y., Sun, H.-B., Liang, W.-X., Song, A.-X., Lallemand-Breitenbach, V., Jeanne, M., Zhang, Q.-Y., Yang, H.-Y., Huang, Q.-H., Zhou, G.-B., Tong, J.-H., Zhang, Y., Wu, J.-H., Hu, H.-Y., de Thé, H., . . . Chen, Z. (2010). Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML. Science. https://doi.org/10.1126/science.1183424
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