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The MDM2 RING-finger domain is required to promote p53 nuclear export

Nature Cell Biology volume 2, pages 569–573 (2000)Cite this article

Abstract

MDM2 can bind to p53 and promote its ubiquitination and subsequent degradation by the proteasome. Current models propose that nuclear export of p53 is required for MDM2-mediated degradation, although the function of MDM2 in p53 nuclear export has not been clarified. Here we show that MDM2 can promote the nuclear export of p53 in transiently transfected cells. This activity requires the nuclear-export signal (NES) of p53, but not the NES of MDM2. A mutation within the MDM2 RING-finger domain that inhibits p53 ubiquitination also inhibits the ability of MDM2 to promote p53 nuclear export. Finally, inhibition of nuclear export stabilizes wild-type p53 and leads to accumulation of ubiquitinated p53 in the nucleus. Our results indicate that MDM2-mediated ubiquitination, or other activities associated with the RING-finger domain, can stimulate the export of p53 to the cytoplasm through the activity of the p53 NES.

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Figure 1: MDM2 affects the localization of p53.
Figure 2: Quantification of p53 staining in transfected cells.
Figure 3: The RING-finger domain, but not the NES, of MDM2 is required for p53 nuclear export.
Figure 4: Ubiquitination, degradation and MDM2 binding of p53.
Figure 5: Ubiquitinated p53 accumulates in the nucleus when nuclear export is inhibited.
Figure 6: MDM2-mediated degradation in Saos-2 and HCT-116 cells.

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Acknowledgements

We thank P. Howley and P. Hinds for advice and critical reading of the manuscript. This work was supported by Public Health Service grant 1R01CA80918 and by a breast cancer research grant from the Massachusetts Department of Public Health (both to C.G.M.).

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  1. Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, USA

    Rory K. Geyer, Zhong K. Yu & Carl G. Maki

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Correspondence to Carl G. Maki.

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Geyer, R., Yu, Z. & Maki, C. The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol 2, 569–573 (2000). https://doi.org/10.1038/35023507

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