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Importazole, a Small Molecule Inhibitor of the Transport Receptor Importin-β
Open accessAbstract
During interphase, the transport receptor importin-β carries cargoes into the nucleus, where RanGTP releases them. A similar mechanism operates in mitosis to generate a gradient of active spindle assembly factors around mitotic chromosomes. Importin-β and RanGTP have been implicated in additional cellular processes, but the precise roles of the Ran/importin-β pathway throughout the cell cycle remain poorly understood. We implemented a FRET-based, high-throughput small molecule screen for compounds that interfere with the interaction between RanGTP and importin-β and identified importazole, a 2,4-diaminoquinazoline. Importazole specifically blocks importin-β-mediated nuclear import both in Xenopus egg extracts and cultured cells, without disrupting transportin-mediated nuclear import or CRM1-mediated nuclear export. When added during mitosis, importazole impairs the release of an importin-β cargo FRET probe and causes both predicted and novel defects in spindle assembly. Together, these results indicate that importazole specifically inhibits the function of importin-β, likely by altering its interaction with RanGTP. Importazole is a valuable tool to evaluate the function of the importin-β/RanGTP pathway at specific stages during the cell cycle.
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Blangy, A., Lane, H. A., d'Hérin, P., Harper, M., Kress, M., & Niggt, E. A. (1995) · Cell · doi:10.1016/0092-8674(95)90142-6 · Cited by 952
Cited by
Müllers, E., Cascales, H. S., Jaiswal, H., Saurin, A. T., & Lindqvist, A. (2014) · Cell Cycle · doi:10.4161/15384101.2015.945831 · Cited by 84
Ran-dependent TPX2 activation promotes acentrosomal microtubule nucleation in neurons
Chen, W.-S., Chen, Y.-J., Huang, Y.-A., Hsieh, B.-Y., Chiu, H.-C., Kao, P.-Y., Chao, C.-Y., & Hwang, E. (2017) · Scientific Reports · doi:10.1038/srep42297 · Cited by 41
Importin β-dependent nuclear import of TopBP1 in ATR–Chk1 checkpoint in Xenopus egg extracts
Bai, L., Michael, W. M., & Yan, S. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.01.006 · Cited by 19
Metadata
- Authors
- Soderholm, J. F., Bird, S. L., Kalab, P., Sampathkumar, Y., Hasegawa, K., Uehara-Bingen, M., Weis, K., & Heald, R.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-04-21
- Volume
- 6
- Issue
- 7
- Pages
- 700-708
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W1978028702
- Cited by
- 274
- References
- 1
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- green
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- Soderholm, J. F., Bird, S. L., Kalab, P., Sampathkumar, Y., Hasegawa, K., Uehara-Bingen, M., Weis, K., & Heald, R. (2011). Importazole, a Small Molecule Inhibitor of the Transport Receptor Importin-β. ACS Chemical Biology. https://doi.org/10.1021/cb2000296
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