The contribution of the acidic domain of MDM2 to p53 and MDM2 stability

Argentini, Manuela; Barboule, Nadia; Wasylyk, Bohdan

doi:10.1038/sj.onc.1204241

Cited by 73 publications

(65 citation statements)

References 64 publications

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“…There is also data showing that this acidic domain is important for the stability of Mdm2. As reported by Argentini et al (2001), deletion of the acidic domain (residues 222 -272) increases the stability of the protein without decreasing its ubiquitination. Additionally, the interaction site for the amino terminus of p14ARF, which is necessary for p14ARF to increase the levels of Mdm2 and its ubiquitinated forms (Xirodimas et al, 2001a), is also in this acidic region (Midgley et al, 2000;Bothner et al, 2001).…”

Section: Discussionmentioning

confidence: 68%

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Nuclear export inhibitor leptomycin B induces the appearance of novel forms of human Mdm2 protein

et al. 2003

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The nuclear export inhibitor leptomycin B (LMB) prevents the export of proteins from the nucleus to the cytoplasm, protects p53 from Mdm2-mediated degradation and is a very potent inducer of the p53 transcriptional activity. Here we suggest that LMB can also interfere with the degradation of human Mdm2. In the presence of this drug, we observed two novel forms of this protein: a slow mobility form and an amino-terminal fragment with an apparent molecular mass of 32 kDa. The presence of this 32 kDa band is abolished with proteasome inhibitors, indicating that its appearance could be because of limited processing by the proteasome. These results may be useful in understanding the mechanism of degradation of Mdm2 by the proteasome.

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Section: Discussionmentioning

confidence: 68%

“…Accordingly, Argentini et al (2001) found that LMB partly decreases the export of Mdm2 from the nucleus using heterokaryon assays. However, this is not reflected by any convincing changes in the localisation of Mdm2 in the presence Figure 3 The appearance of the 32 kDa is a post-transcriptional event and is prevented by proteasome inhibitors.…”

Section: Resultsmentioning

confidence: 96%

Nuclear export inhibitor leptomycin B induces the appearance of novel forms of human Mdm2 protein

et al. 2003

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“…This may be of relevance as the central part of HDM2 is involved in the degradation and ubiquitination of p53 (19,26,27). The central region of HDM2 interacts also with several other proteins that are responsible for p53 regulation, such as L5 (28), L23 (29), L11 (30), p14ARF (31), TBP (32), and Retinoblastoma (Rb) protein (33).…”

Section: Discussionmentioning

confidence: 99%

The central region of HDM2 provides a second binding site for p53

Rüdiger

Veprintsev

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

132

141

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HDM2 is a negative regulator of p53 that inhibits its transcriptional activity and subjects it to degradation by an E3 ligase activity. The primary binding site for HDM2 on p53 is located in its N-terminal domain. A second site on the p53 core domain (p53C) binds to an unidentified site in HDM2. We found that this site is in its acidic domain and part of the zinc finger domain by examining the interaction of full-length and domain constructs of p53 with the N-terminal region of HDM2 and peptide arrays derived from the full-length protein. NMR spectroscopy showed that peptides derived from this region of HDM2 bound to residues in the specific DNA-binding site of p53C. The peptides were displaced from the site by gadd45 sequencespecific DNA. Phosphorylation of single amino acids in the central domain of HDM2 did not abolish the interaction between the HDM2-derived peptides and p53C. We speculate that this second binding site helps in stabilizing the interaction between HDM2 and p53 during p53 degradation.isothermal titration calorimetry ͉ Mdm2 ͉ NMR T he tumor suppressor protein p53 is important in maintaining genome stability and in preventing cancer development (1, 2). In response to various stress signals, p53 mediates cell-cycle arrest and apoptosis (3). p53 is a homotetramer consisting of an N-terminal transactivation domain, proline-rich regulatory domain, DNA-binding core domain (p53C), tetramerization domain, and C-terminal negative regulatory domain. Its major regulator, HDM2, is induced by p53 and acts as a feedback inhibitor (4). HDM2 regulates the activity of p53 in at least three ways. First, the N-terminal domain of HDM2 binds directly to p53's transactivation domain and inhibits its transcriptional function (5). Second, HDM2 acts as a ubiquitin ligase, targeting p53 and promoting its degradation (6, 7). Third, upon binding, HDM2 exports p53 from the nucleus to the cytoplasm (8).The interaction between peptides derived from the p53 N terminus and the HDM2-N-terminal domain has been extensively studied (9-12), and several compounds have been proposed to abolish this interaction (13-16). Recently, a new HDM2-binding site has been reported in p53C that plays a regulatory role in modulating p53 ubiquitination (17), although the exact binding site on HDM2 involved in this interaction has not yet been identified. There are conflicting speculations on its location at either the HDM2 N terminus (18) or in the acidic domain (19).Here, we examined the interaction of full-length and domain constructs of p53 with the N-terminal region of HDM2 and peptide arrays derived from the full-length protein. We found that the HDM2 N-terminal domain interacts only with p53's N-terminal domain, whereas from the peptide-array screen, we identified a second binding site for p53C located in the central domain (residues 221-302) of HDM2. We measured the binding affinity of the peptides to p53C by analytical ultracentrifugation. We identified the binding site on p53C by NMR and fluorescence anisotropy to be its DNA-binding site....

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“…We previously mapped the interaction domain of MDM2 with Vif to aa 168-320, which are located in its central acidic and zinc-finger domains (17). This central domain is different from the primary TP53-binding site located in the N-terminal region, but was recently reported as a second TP53-binding site important for regulation of TP53 stability (23)(24)(25)(26). Interestingly, several proteins, including P300, P14ARF, and pRB, bind to the central domain of MDM2 and regulate the stability and function of TP53 via MDM2 (24,27).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Izumi

Io²,

Matsui³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the Nterminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.AIDS | NL4-3 | HXB2 | APOBEC3G | infectivity

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The contribution of the acidic domain of MDM2 to p53 and MDM2 stability

Cited by 73 publications

References 64 publications

Nuclear export inhibitor leptomycin B induces the appearance of novel forms of human Mdm2 protein

Nuclear export inhibitor leptomycin B induces the appearance of novel forms of human Mdm2 protein

The central region of HDM2 provides a second binding site for p53

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

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