HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53

Linares, Laëtitia K.; Hengstermann, Arnd; Ciechanover, Aaron; Müller, Stefan; Scheffner, Martin

doi:10.1073/pnas.2030930100

Cited by 311 publications

(324 citation statements)

References 38 publications

(75 reference statements)

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“…Importantly, various studies have shown that Mdm2-Mdm4 interactions also regulate p53 stability and function. In human cells, Mdm4 (also called Hdmx) enhances Mdm2 (also called Hdm2) ligase activity and p53 degradation (40). On the basis of structural analysis, Kostic et al (41) proposed that Mdm2 and Mdm4 heterodimerization via their respective RING domains contributes to enhanced Mdm2 activity.…”

Section: Discussionmentioning

confidence: 99%

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

Barboza

Iwakuma

Terzian

et al. 2008

Molecular Cancer Research

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Mutational inactivation of p53 is a hallmark of most human tumors. Loss of p53 function also occurs by overexpression of negative regulators such as MDM2 and MDM4. Deletion of Mdm2 or Mdm4 in mice results in p53-dependent embryo lethality due to constitutive p53 activity. However, Mdm2 À/À and Mdm4 À/À embryos display divergent phenotypes, suggesting that Mdm2 and Mdm4 exert distinct control over p53. To explore the interaction between Mdm2 and Mdm4 in p53 regulation, we first generated mice and cells that are triple null for p53, Mdm2, and Mdm4. These mice had identical survival curves and tumor spectrum as p53 À/À mice, substantiating the principal role of Mdm2 and Mdm4 as negative p53 regulators. We next generated mouse embryo fibroblasts null for p53 with deletions of Mdm2, Mdm4, or both; introduced a retrovirus expressing a temperature-sensitive p53 mutant, p53A135V; and examined p53 stability and activity.

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Section: Discussionmentioning

confidence: 99%

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

Barboza

Iwakuma

Terzian

et al. 2008

Molecular Cancer Research

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“…35 However, MDMX and MDM2 heterodimerize to augment p53 degradation, and hence both proteins can potentially influence p53 stability. 36,37 Both MDM2-and MDMX-deficient mice die in utero as a consequence of p53 hyperactivity, showing the crucial role of these proteins in restraining p53 function during development. 38,39 Not surprisingly, high levels of MDM2 or MDMX are found in many human cancers.…”

Section: Mdm2mentioning

confidence: 99%

p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

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The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53. The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway. Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73. Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects. In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment.

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“…14 A further factor that may affect drug sensitivity is MDMX, a negative regulator of TP53 that forms heterocomplexes with MDM2 and is essential for the MDM2-mediated polyubiquitinilation of TP53. 15 Despite the close similarity between the TP53 binding domains of MDM2 and MDMX, Nutlin-3A fails to inhibit the TP53/MDMX complex in vivo and in vitro, 16,17 possibly because its binding affinity for MDMX is less than that for MDM2. 17 Like MDM2, MDMX also has splice variants, the most widely investigated of which is MDMX-S, a truncated form of MDMX that retains the TP53 binding domain responsible for TP53 inhibition.…”

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confidence: 99%

In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas

Bozzi

Conca

Laurini

et al. 2013

Laboratory Investigation

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The molecular marker of well-differentiated/de-differentiated liposarcomas is MDM2 gene amplification coupled with protein overexpression and wild-type TP53. MDMX is a recently identified MDM2 homolog and its presence in this tumor is unexplored. Our aim was to investigate the role of full-length MDM2 and MDMX proteins and their isoforms in surgical specimens of well-differentiated/de-differentiated liposarcomas in view of Nutlin-3A (a MDM2 inhibitor) treatment. Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens was examined by means of: (1) fluorescence in situ hybridization to determine MDM2 and MDMX gene copy numbers; (2) RT-PCR and densitometry to analyze alternative splicing forms of mdm2 and mdmx; (3) immunoblotting and immunohistochemistry to assess the corresponding translated proteins; and (4) in vitro and in silico assays to determine their affinity for Nutlin-3A. All these cases showed MDM2 gene amplification with an MDMX disomic pattern. In all cases, the full-length mdm2 transcript was associated with the mdm2-b transcript, with ratios ranging from 0.07 to 5.6, and both were translated into protein; mdmx and mdmx-s were co-transcripted, with ratios ranging from 0.1 to 5.6. MDMX-S was frequently more upregulated than MDMX at both transcriptional and protein level. Each case showed different amounts of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and the corresponding proteins. In vitro assays showed that Nutlin-3A was ineffective against MDM2-B and was unable to disrupt the MDMX/TP53 and MSMX-S/TP53 complexes. Molecular simulations confirmed these in vitro findings by showing that MDM2 has high Nutlin-3A affinity, followed by MDMX-S, MDMX, and MDM2-B. Nutlin-3A is predicted to be a good therapeutic option for well-differentiated/de-differentiated liposarcomas. However, our findings predict heterogeneous responses depending on the relative expression of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and proteins. Well-differentiated/de-differentiated (WD/DD) liposarcomas (LPS) account for 40% of all liposarcomas. With a few exceptions, 1,2 the DD component is defined as a usually abrupt and generally a phenotypic time-dependent transition to a non-lipogenic sarcoma.WD/DD LPS characteristically involve the retroperitoneum and are characterized by a high rate of local recurrences. The inability of even aggressive surgery to obtain negative margins leads to high local failure rates, worsening the long-term prognosis of WD/DD patients and favors the use of multiple treatment modalities albeit with limited benefit. 3,4 The molecular hallmark of WD/DD LPS is MDM2 gene amplification coupled with protein overexpression and wild-type TP53, 5-7 which provides the rationale supporting the therapeutic potential of the MDM2 antagonist Nutlin-3A. MDM2 is an E3 ubiquitin ligase that, in addition to targeting TP53 for proteasomal degradation, blocks TP53

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HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53

Cited by 311 publications

References 38 publications

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

p53-family proteins and their regulators: hubs and spokes in tumor suppression

In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas

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