Ubiquitin Exposes the Nuclear Export Sequence

The mechanism by which the E3 ubiquitin ligase MDM2 promotes the nuclear export of the tumor suppressor and regulator of cell proliferation p53 remains controversial. The ubiquitin ligase activity of MDM2 is required to promote p53 nuclear export. One model is that ubiquitination disrupts a p53 oligomer, thus exposing the nuclear export signal (NES). Another model is that ubiquitination promotes the degradation of p53, which results in decreased formation of p53 oligomers and allows exposure of the NES. Gu et al. used chimeras between p53 and p73 (a related protein that is restricted to the nucleus by the presence of MDM2) to define the mechanism by which MDM2 promotes the nuclear export of p53. Chimeras with the p53 NES fused to p73 were localized to the cytoplasm, suggesting that in the context of p73, the NES is exposed and not "hidden" as it is in p53 in the absence of MDM2. In order to restore nuclear localization, the chimera had to have the entire COOH-terminus of p53. However, this protein did not redistribute to the cytoplasm in response to MDM2 expression. A third domain was required to restore MDM2-mediated nuclear export: the DNA binding domain. All of these protein chimeras were capable of interacting with MDM2 and of forming tetramers, suggesting that disruption of tetramers does not account for nuclear export of p53. Gu et al. and Lohrum et al. both provide evidence that the ubiquination of p53, and not simply binding to MDM2, promotes MDM2-mediated nuclear export of p53. Both groups found that mutation of the six lysines in the COOH-terminus disrupted MDM2-dependent nuclear export. Gu et al. also found that mutation of one lysine in the domain between the DNA binding domain and the oligomerization domain resulted in a cytoplasmically localized p53 that was independent of the presence of MDM2, suggesting that this region is essential for maintaining the structure that controls the accessibility of the NES. Thus, control of p53 distribution is complex and most likely based on conformational changes induced by ubiquitination that exposes the NES. J. Gu, L. Nie, D. Wiederschain, Z.-M. Yuan, Identification of p53 sequence elements that are required for MDM2-mediated nuclear export. Mol. Cell. Biol. 21 , 8533-8546 (2001). [Abstract] [Full Text] M. A. Lohrum, D. B. Woods, R. L. Ludwig, É. Bálint, K. H. Vousden, C-terminal ubiquitination of p53 contributes to nuclear export. Mol. Cell. Biol. 21 , 8521-8532 (2001). [Abstract] [Full Text]