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

Marine, Jean–Christophe; Francoz, Sarah; Maetens, Marion; Wahl, Geoffrey M.; Toledo, Franck; Lozano, Guillermina

doi:10.1038/sj.cdd.4401912

Cited by 301 publications

(307 citation statements)

References 52 publications

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“…This dual regulation would itself be regulated by a negative feedback loop, as the MDM2 gene is a target for p53-mediated transactivation. The notion that MDM2 is a major p53 regulator was confirmed in vivo when MDM2-deficient embryos were found to die around 4 days post-coitum (dpc) from p53-dependent apoptosis (reviewed in Marine et al, 2006)). …”

Section: Biological Functionsmentioning

confidence: 99%

“…Among these, MDM2 and MDM4 stand out because, in addition to their frequent altered expression in cancers, they were shown to act as essential and specific p53 inhibitors during embryonic development. Indeed, both MDM2-deficient and MDM4-deficient mice die in utero, but these deficiencies are viable in a p53-deficient background (reviewed in Marine et al, 2006). These early mouse studies also indicated that MDM2 and MDM4 are non-redundant p53 inhibitors, as normal levels of either regulator cannot compensate for the loss of the other.…”

Section: Introductionmentioning

confidence: 99%

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MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

203

157

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The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification / overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity.

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Section: Biological Functionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

203

157

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“…In addition, no difference in the rate of Mdm2 degradation was observed in wild-type mouse embryonic fibroblasts and mouse embryonic fibroblasts derived from MdmX knockout mice, indicating that in at least some circumstances endogenous MdmX does not influence the half-life of Mdm2 Toledo et al, 2006). These observations suggest that the predominant role of MdmX is to bind to p53 and repress its transcriptional activity; however, it is not clear to what extent the increased level of Mdm2 because of transcriptional activation of p53 can compensate for the loss of MdmX (Marine et al, 2006).…”

Section: Introductionmentioning

confidence: 97%

“…p53 is repressed by Mdm2 and its homologue MdmX, which share high sequence similarity particularly in the p53-binding domain and the RING finger domains (Marine et al, 2007). Mdm2 and MdmX are both essential negative regulators of p53 (Marine et al, 2006). Mdm2 or MdmX null mice die during embryogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Mdm2 and MdmX interact through their RING fingers and this interaction can stabilize Mdm2 and promote Mdm2-mediated degradation of p53 (Tanimura et al, 1999;Gu et al, 2002). However, in mice MdmX knockout increases p53 transcriptional activity but has little or no effect on p53 levels (Marine et al, 2006). In addition, no difference in the rate of Mdm2 degradation was observed in wild-type mouse embryonic fibroblasts and mouse embryonic fibroblasts derived from MdmX knockout mice, indicating that in at least some circumstances endogenous MdmX does not influence the half-life of Mdm2 Toledo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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MdmX is a substrate for the deubiquitinating enzyme USP2a

et al. 2009

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It has previously been shown that ubiquitin-specific protease 2a (USP2a) is a regulator of the Mdm2/p53 pathway. USP2a binds to Mdm2 and can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination. Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2. Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. This correlates with the ability of wild-type USP2a to deubiquitinate MdmX. siRNA-mediated knockdown of USP2a in NTERA-2 testicular embryonal carcinoma cells and MCF7 breast cancer cells causes destabilization of MdmX and results in a decrease in MdmX protein levels, showing that endogenous USP2a participates in the regulation of MdmX stability. The therapeutic drug, cisplatin decreases MdmX protein expression. USP2a mRNA and protein levels were also reduced after cisplatin exposure. The magnitude and time course of USP2a downregulation suggests that the reduction in USP2a levels could contribute to the decrease in MdmX expression following treatment with cisplatin. Knockdown of USP2a increases the sensitivity of NTERA-2 cells to cisplatin, raising the possibility that suppression of USP2a in combination with cisplatin may be an approach for cancer therapy.

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Developing Genetically Engineered Mouse Models to Study Tumor Suppression

2012

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Since the late 1980s, the tools to generate mice with deletions of tumor suppressors have made it possible to study such deletions in the context of a whole animal. Deletion of some tumor suppressors results in viable mice while deletion of others yield embryo lethal phenotypes cementing the concept that genes that often go awry in cancer are also of developmental importance. More sophisticated mouse models were subsequently developed to delete a gene in a specific cell type at a specific time point. Additionally, incorporation of point mutations in a specific gene as observed in human tumors has also revealed their contributions to tumorigenesis. On the other hand, some models never develop cancer unless combined with other deletions suggesting a modifying role in tumorigenesis. This review will describe the technical aspects of generating these mice and provide examples of the outcomes obtained from alterations of different tumor suppressors.

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

Cited by 301 publications

References 52 publications

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

MdmX is a substrate for the deubiquitinating enzyme USP2a

Developing Genetically Engineered Mouse Models to Study Tumor Suppression

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