C-terminal modifications regulate MDM2 dissociation and nuclear export of p53

Carter, Stephanie; Bischof, Oliver; Dejean, Anne; Vousden, Karen H.

doi:10.1038/ncb1562

Cited by 203 publications

(209 citation statements)

References 31 publications

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“…The proof of principle for this role of ubiquitin was shown with a linear p53-Ub fusion, which was shown to localize in the cytoplasm. Interestingly and somewhat surprisingly, given the very close homology to ubiquitin, p53 fused to NEDD8 was shown to localize exclusively in the nucleus (Brooks and Gu, 2006;Carter et al, 2007). The data in our study suggest that NEDD8 may have an active role in localizing p53 in the nuclear compartment, and decrease in p53 NEDDylation is part of p53 cytoplasmic localization.…”

Section: Discussionsupporting

confidence: 54%

“…This suggests that Mdm2 as an E3 ligase could promote p53 conjugation with Ub and Ubls, such as NEDD8, and therefore priming p53 for recognition by Ub and Ubl interacting proteins. Indeed, Mdm2-mediated p53 ubiquitination was proposed to allow the recruitment of PIASy SUMO E3 ligase to promote p53 SUMO conjugation (Carter et al, 2007). The p53 interacting protein Parc (p53-associated, Parkin-like cytoplasmic protein) was shown to anchor p53 in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

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NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

Liu

Xirodimas

2010

Oncogene

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Non-covalent recognition of ubiquitin (Ub) and ubiquitinlike molecules (Ubls) by interacting proteins has an important role in the regulation of protein function and initiation of signalling events. In addition, growing evidence suggests that regulation of p53 subcellular localization contributes to the biological outcome of the p53 response. Cytoplasmic p53 is shown to promote apoptosis and inhibit the induction of autophagy. In this study we show that NEDD8 ultimate buster 1 (NUB1), a non-covalent interactor of the Ubl NEDD8 (neural precursor cell expressed, developmentally downregulated 8), controls the localization of p53. Expression of NUB1 leads to decreased modification of p53 with NEDD8 and stimulation of p53 ubiquitination. The biological outcome is the cytoplasmic localization and inhibition of the transcriptional activity of p53. Although the effects of NUB1 on p53 depend on NEDDylation and the murine double minute 2 (Mdm2) E3-ligase, the cooperation of NEDD8 with ubiquitin is required. The data identify a role for NEDD8 in controlling p53 localization and suggest that NEDD8 can control protein function through its non-covalent recognition by interacting proteins.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

Liu

Xirodimas

2010

Oncogene

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“…For example, SUMO has been implicated in promoting the nuclear retention of the Elk-1 transcription factor (Salinas et al 2004), adenoviral E1B-55K protein (Kindsmuller et al 2007), and CtBP1 corepressor (Lin et al 2003b). In terms of SUMO promoting nuclear export, as our data suggest for Med, examples include the TEL repressor protein (Wood et al 2003), MEK1 kinase (Sobko et al 2002), ribosome biogenesis factors (Panse et al 2006), and p53 transcription factor (Carter et al 2007).…”

Section: Sumoylation Promotes Med Nuclear Exportmentioning

confidence: 81%

“…p53 is monoubiquitinated by MDM2, which exposes the NES and allows recruitment of the PIASy E3 ligase leading to p53 SUMOylation. As a result, MDM2 dissociates and p53 nuclear export occurs (Carter et al 2007). SUMOylation may re-expose the Med NES that has been inactivated upon signaling (Watanabe et al 2000), promoting nuclear export.…”

Section: Sumoylation Promotes Med Nuclear Exportmentioning

confidence: 99%

Medea SUMOylation restricts the signaling range of the Dpp morphogen in the Drosophila embryo

Miles¹,

Jaffray²,

Campbell³

et al. 2008

Genes Dev.

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Morphogens are secreted signaling molecules that form concentration gradients and control cell fate in developing tissues. During development, it is essential that morphogen range is strictly regulated in order for correct cell type specification to occur. One of the best characterized morphogens is Drosophila Decapentaplegic (Dpp), a BMP signaling molecule that patterns the dorsal ectoderm of the embryo by activating the Mad and Medea (Med) transcription factors. We demonstrate that there is a spatial and temporal expansion of the expression patterns of Dpp target genes in SUMO pathway mutant embryos. We identify Med as the primary SUMOylation target in the Dpp pathway, and show that failure to SUMOylate Med leads to the increased Dpp signaling range observed in the SUMO pathway mutant embryos. Med is SUMO modified in the nucleus, and we provide evidence that SUMOylation triggers Med nuclear export. Hence, Med SUMOylation provides a mechanism by which nuclei can continue to monitor the presence of extracellular Dpp signal to activate target gene expression for an appropriate duration. Overall, our results identify an unusual strategy for regulating morphogen range that, rather than impacting on the morphogen itself, targets an intracellular transducer. Med and its vertebrate ortholog Smad4 have been found to constitutively shuttle between the nucleus and cytoplasm in a signal-independent manner (Pierreux et al. 2000;Yao et al. 2008). Smad4 contains both a nuclear localization signal (NLS) and a CRM-1-dependent nuclear export signal (NES), and it has been proposed that the relative strengths of these two signals within a tissue regulate the amount of shuttling. Smad4, which shuttles into the nucleus in the absence of signal, is unable to activate transcription (Pierreux et al. 2000), possibly due to recruitment of a repressive complex harboring the SnoN oncoprotein (Stroschein et al. 1999).The small ubiquitin-like modifier protein SUMO is conjugated to its substrate through the sequential activities of E1, E2, and E3 enzymes. Ubc-9, the essential E2 enzyme, catalyzes the conjugation of SUMO to the target lysine, typically located in a ⌿KxE consensus motif (where ⌿ is a large hydrophobic residue and x is any residue) (Hay 2005). An extended SUMO motif compris-

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“…70 Monoubiquitylation directly promotes further modifications of p53 with ubiquitin-like proteins, and Mdm2 promotes the interaction of the SUMO E3 ligase PIASy with p53, enhancing both sumoylation and nuclear export. 70 Mdm2 may also function as a chaperone-like molecule for p53 and this function appears essential for ubiquitylation and export of p53. Recent data suggest that wild-type p53 undergoes an Mdm2-dependent conformational change before it is degraded by the proteasome.…”

Section: Mdm2-mediated P53 Ubiquitylationmentioning

confidence: 99%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

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The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

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C-terminal modifications regulate MDM2 dissociation and nuclear export of p53

Cited by 203 publications

References 31 publications

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

Medea SUMOylation restricts the signaling range of the Dpp morphogen in the Drosophila embryo

Mdm2-mediated ubiquitylation: p53 and beyond

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