Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity

Xirodimas, Dimitris P.; Saville, Mark K.; Bourdon, Jean-Christophe; Hay, Ronald T.; Lane, David P.

doi:10.1016/j.cell.2004.06.016

Cited by 495 publications

(477 citation statements)

References 56 publications

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“…Finally, Pin1 stimulates acetylation of p53 and p73 by p300 and dissociation from the inhibitor iASPP, thus enhancing the transcriptional activity of p53 and p73 towards proapoptotic target genes catalyzing its NEDDylation. 65 It will be interesting to determine whether Pin1 activity can also affect the pathways, yet elusive, which engage the p53 DNA-binding domain with the ubiquitin ligases Pirh2 and COP1. 66,67 p53 transcriptional activity is also regulated by interaction with acetyltransferases and stress-activated isomerization of p53 stimulates the acetylation of p53 C-terminal lysine residues by p300/CBP (G Del Sal, unpublished data), analogous to p73.…”

Section: The Prolyl Isomerase Pin1mentioning

confidence: 99%

Some p53-binding proteins that can function as arbiters of life and death

2006

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Four sets of p53-binding proteins are discussed in this review. These are the E2F family, the ASPP family, Y-boxbinding protein YB1, and the prolyl isomerase Pin1. Each appears to play a role in the decision by p53 to induce an arrest of cell proliferation or apoptosis and they may also be independent markers of cancer. Their activities appear to be linked with the cell cycle and they may also interact with each other. In this review, the properties of each protein class are discussed as well as how they affect p53 functions. A model is proposed as to how their activities might be coordinated.

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Section: The Prolyl Isomerase Pin1mentioning

confidence: 99%

Some p53-binding proteins that can function as arbiters of life and death

2006

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“…The murine double minute 2 (Mdm2) oncogene product is a major regulator of p53 function and as an E3-ligase controls p53 modification with Ub and Ubls. In particular, Mdm2 has a dual specificity for Ub and NEDD8 and can promote p53 modification with both molecules (Xirodimas et al, 2004). Although Mdm2 can promote ubiquitination and degradation of p53 in both nucleus and cytoplasm (Xirodimas et al, 2001b), it is suggested that the levels of Mdm2 can have a differential effect on p53 ubiquitination with distinct biological outcomes.…”

Section: Introductionmentioning

confidence: 99%

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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“…These lysine residues are also the potential ubiquitination sites. Importantly, NEDDylation appears to have a negative impact on the transactivation activity of p53 (Xirodimas et al, 2004). We show that 14-3-3s can antagonize MDM2-mediated p53 NEDDylation, which in turn will take away the inhibitory effect of NEDDylation on p53 transcriptional activity.…”

Section: Discussionmentioning

confidence: 78%

“…In addition to ubiquitination activity, MDM2 uses its C-terminal RING domain to promote p53 NEDDylation at three lysine residues of p53 (Xirodimas et al, 2004). These lysine residues are also the potential ubiquitination sites.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, MDM2 is involved in promoting the degradation of tumor suppressor RB protein (Sdek et al, 2005;Miwa et al, 2006), and thus contributes to cancer development. In addition, MDM2 is shown to NEDDylate p53, thereby antagonizing the transcriptional activity of tumor suppressor p53 (Xirodimas et al, 2004). We then examined the impact of 14-3-3s on these biological activities of MDM2 using HCT116 14-3-3sÀ/À and 14-3-3s þ / þ cells.…”

Section: -3-3r As a Negative Regulator Of Mdm2mentioning

confidence: 99%

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Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

Yang

Wen

et al. 2007

Oncogene

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The 14-3-3r, upregulated by p53 in response to DNA damage, can have a positive-feedback impact driving p53 activities and is a human cancer epithelial marker downregulated in various tumors. However, the precise roles of 14-3-3r during tumorigenesis are not well characterized. Here, we show that 14-3-3r is a critical regulator of murine double minute oncogene (MDM2). 14-3-3r interacts with MDM2 at the RING domain. The C-terminal region of 14-3-3r binds to MDM2 very efficiently. Importantly, 14-3-3r overexpression leads to destabilization of MDM2 through enhancing MDM2 selfubiquitination and accelerating turnover rate. Conversely, loss of 14-3-3r results in a significant increase in MDM2 protein. Moreover, live-cell images indicated that 14-3-3r can affect the location of MDM2 from the nucleus to the cytoplasm, and that MDM2-mediated cytoplasmic localization of p53 can be reversed by the presence of 14-3-3r. Significantly, we further showed that 14-3-3r causes MDM2 downregulation, thereby stabilizing p53 and inhibiting tumor growth in animal tumors. Also, 14-3-3r blocks MDM2-mediated retinoblastoma degradation and p53 NEDDylation. Our results provide evidence that 14-3-3r is a pivotal MDM2 regulator involved in blocking a variety of activities of MDM2.

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Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity

Cited by 495 publications

References 56 publications

Some p53-binding proteins that can function as arbiters of life and death

Some p53-binding proteins that can function as arbiters of life and death

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

Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

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