p53 Ubiquitination: Mdm2 and Beyond

Brooks, Chris; Gu, Wei

doi:10.1016/j.molcel.2006.01.020

Cited by 782 publications

(731 citation statements)

References 92 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: 55%

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: 55%

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

Liu

Xirodimas

2010

Oncogene

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“…In contrast, Mdm2-mediated monoubiquitination and subsequent cytoplasmic translocation of p53 would represent an important means of p53 regulation in unstressed cells. 21 Importantly, decreased expression of Mdm2 in mice harboring a hypomorphic and a null allele of mdm2 led to activation of p53 function without concomitant increase in p53 protein levels. 11 Thus, the reduced levels of Mdm2 in these mice (about 30% of the level in wild-type tissues) are sufficiently high to allow efficient degradation of p53.…”

Section: Constitutive Degradation Of P53 Is Strictly Dependent On Mdm2mentioning

confidence: 96%

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

et al. 2006

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“…In unstressed normal cells, p53 is present at low levels because of rapid degradation by the ubiquitin-dependent proteasome pathway (Brooks and Gu, 2006). Mdm2 is an important regulator of p53 turnover by binding p53 and acting as an E3 ubiquitin ligase (Haupt et al, 1997;Kubbutat et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

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p53 Ubiquitination: Mdm2 and Beyond

Cited by 782 publications

References 92 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

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

Role of Mdm4 in drug sensitivity of breast cancer cells

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