Hdmx Stabilizes Mdm2 and p53

Stad, Robert; Ramos, Y.F.; Little, Natalie A.; Grivell, Shula; Attema, Joline; Eb, Alex J. van de; Jochemsen, Aart G.

doi:10.1074/jbc.m003496200

Cited by 125 publications

(110 citation statements)

References 27 publications

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“…Mdm4 stabilizes p53 presumably by inhibiting p53-Mdm2 interactions because Mdm2 and Mdm4 bind the same domain of p53 (15)(16)(17)(18)(19). However, other reports implicate Mdm4 in the down-regulation of p53 protein levels (22,33).…”

Section: Loss Of Mdm2 or Mdm4 Determines P53 Protein Levelsmentioning

confidence: 80%

“…However, the role of Mdm4 in p53 protein stability is murky at best. Overexpression of MDM4 inhibits MDM2-mediated degradation of p53 in immortalized human tumor cell lines, suggesting that MDM4 stabilizes p53 (16)(17)(18)(19). Likewise, loss of Mdm4 in MEFs containing a p53 mutant that lacks the proline-rich domain yielded lower p53 levels, albeit a more active p53 (20).…”

Section: Introductionmentioning

confidence: 99%

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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: Loss Of Mdm2 or Mdm4 Determines P53 Protein Levelsmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

Barboza

Iwakuma

Terzian

et al. 2008

Molecular Cancer Research

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“…In this study, we observed that many tumors expressed high levels of both, MDM2 and MDM4. The interaction between MDM2 and MDM4 inhibits autoubiquitination and degradation of MDM2 [20][21][22]. Thus, MDM4 overexpression in HNSC may stabilize MDM2, enhancing p53 inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Despite this structural similarity, MDM4 does not share all functional properties of MDM2. For example, although MDM4 binds and inhibits the transcriptional activation domain of p53 [18], it does not target p53 for degradation [20][21][22]. However, loss of MDM4 in the mouse leads to defects in cell proliferation and death during embryogenesis, a phenotype that is completely rescued by concomitant deletion of p53 [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

et al. 2007

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The p53 tumor suppressor is mutated in the majority of human tumors. MDM2, a well-known inhibitor of p53, is overexpressed in a large number of tumors suggesting that increased levels of MDM2 also contribute to tumorigenesis. A novel p53 inhibitor, MDM4, was more recently identified. The role of MDM4 in cancer development is not well understood. We set out to examine the levels of MDM4 by immunohistochemistry in Head and Neck Squamous Carcinomas (HNSC) to ask whether high MDM4 levels could contribute to its development and progression. In addition, MDM2 and p53 levels were examined to identify overlapping expression patterns. MDM4 is present at high levels in 50% of HNSC. Additionally, overexpression of MDM2 was detected in 80% of tumors, many of which were also positive for MDM4. A subset of tumors displayed high levels of all three proteins. Sequencing of the p53 gene revealed that tumors with positive immunoreactivity for MDM2 or MDM4, some of which also had high levels of p53, did not carry mutations in this gene. Thus, the detection of p53 by immunohistochemistry was not synonymous with the presence of p53 mutations. Expression of both MDM2 and MDM4 in tumors without p53 mutations strongly suggests that MDM2 and MDM4 inhibit the activity of this tumor suppressor in HNSC.

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“…The primary function of Mdm4 seems to be inhibition of p53-mediated transcriptional activation. In addition, it has been reported that Mdm4 can enhance Mdm2-mediated ubiquitination and degradation of p53 (Stad et al, 2000. Similar to Mdm2, Mdm4 has been found overexpressed in a significant number of various human tumors and tumor cell lines, in general correlating with the expression of wild-type p53, suggesting that Mdm4 contributes to p53 inactivation during tumorigenesis (Riemenschneider et al, 1999(Riemenschneider et al, , 2003Ramos et al, 2001;Danovi et al, 2004;Laurie et al, 2006).…”

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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Hdmx Stabilizes Mdm2 and p53

Cited by 125 publications

References 27 publications

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

Role of Mdm4 in drug sensitivity of breast cancer cells

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