The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation
Abstract
Genetic loss of function analysis is a powerful method for the study of protein function. However, some cell biological questions are difficult to address using traditional genetic strategies often due to the lack of appropriate genetic model systems. Here, we present a general strategy for the design and syntheses of molecules capable of inducing the degradation of selected proteins in vivo via the ubiquitin-proteasome pathway. Western blot and fluorometric analyses indicated the loss of two different targets: green fluorescent protein (GFP) fused with FK506 binding protein (FKBP12) and GFP fused with the androgen receptor (AR), after treatment with PROteolysis TArgeting Chimeric moleculeS (PROTACS) incorporating a FKBP12 ligand and dihydrotestosterone, respectively. These are the first in vivo examples of direct small molecule-induced recruitment of target proteins to the proteasome for degradation upon addition to cultured cells. Moreover, PROTAC-mediated protein degradation offers a general strategy to create "chemical knockouts," thus opening new possibilities for the control of protein function.
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Cites
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609
Self-citationOhh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577
Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL
Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., & Jones, E. Y. (2002) · Nature · doi:10.1038/nature00767 · Cited by 751
Harnessing the Ubiquitination Machinery to Target the Degradation of Specific Cellular Proteins
Zhou, P., Bogacki, R., McReynolds, L., & Howley, P. M. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00074-5 · Cited by 164
Cited by
Function and regulation of cullin–RING ubiquitin ligases
Petroski, M. D., & Deshaies, R. J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1547 · Cited by 2,148
Self-citationPhthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
An auxin-based degron system for the rapid depletion of proteins in nonplant cells
Nishimura, K., Fukagawa, T., Takisawa, H., Kakimoto, T., & Kanemaki, M. (2009) · Nature Methods · doi:10.1038/nmeth.1401 · Cited by 1,663
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Self-citationCatalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
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Metadata
- Authors
- Schneekloth, J. S., Fonseca, F. N., Koldobskiy, M., Mandal, A., Deshaies, R., Sakamoto, K., & Crews, C. M.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2004-03-01
- Volume
- 126
- Issue
- 12
- Pages
- 3748-3754
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2025031463
- Cited by
- 487
- References
- 4
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- closed
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- Schneekloth, J. S., Fonseca, F. N., Koldobskiy, M., Mandal, A., Deshaies, R., Sakamoto, K., & Crews, C. M. (2004). Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation. Journal of the American Chemical Society. https://doi.org/10.1021/ja039025z
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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