Puzzling over MDM4–p53 network

Mancini, Francesca; Conza, Giusy Di; Monti, Olimpia; Macchiarulo, Antonio; Pellicciari, Roberto; Pontecorvi, Alfredo; Moretti, Fabiola

doi:10.1016/j.biocel.2010.04.010

Cited by 24 publications

(28 citation statements)

References 31 publications

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“…MdmX is a critical negative regulator of p53 (Marine and Jochemsen 2005;Marine et al 2007;Wade and Wahl 2009;Mancini et al 2010), necessary to restrain the lethal consequences of unbridled p53 activity at various points in normal development (Parant et al 2001;Migliorini et al 2002;Francoz et al 2006;Grier et al 2006;Xiong et al 2006). However, the embryonic lethality of p53-competent MdmX-null mice has confounded genetic analysis of any role that MdmX might play in governing p53 activity in adult tissues.…”

Section: Discussionmentioning

confidence: 99%

“…MdmX, also known as Mdm4, has recently emerged as a discrete critical negative regulator of p53 (Marine and Jochemsen 2005;Marine et al 2007;Wade and Wahl 2009;Mancini et al 2010). While MdmX is structurally related to Mdm2, it does not target p53 for degradation via ubiquitin ligation, but instead acts as a direct transcriptional squelcher of p53 (Marine and Jochemsen 2005;Marine et al 2007; Kruse and Gu 2009;Wade and Wahl 2009).…”

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confidence: 99%

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Validation of MdmX as a therapeutic target for reactivating p53 in tumors

Garcia¹,

Warr²,

Martins³

et al. 2011

Genes Dev.

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MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX -/-mice into the p53ER TAM knockin background. In place of wild-type p53, p53ER TAM knockin mice express a variant of p53, p53ER TAM , that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient mice. We show that MdmX is continuously required to buffer p53 activity in adult normal tissues and their stem cells. Importantly, the effects of transient p53 restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal. We also show that the therapeutic impact of restoring p53 in a tumor model is enhanced in the absence of MdmX, affording a significant extension of life span over p53 restoration in the presence of MdmX. Hence, systemic inhibition of MdmX is both a feasible therapeutic strategy for restoring p53 function in tumors that retain wild-type p53 and likely to be significantly safer than inhibition of Mdm2.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Validation of MdmX as a therapeutic target for reactivating p53 in tumors

Garcia¹,

Warr²,

Martins³

et al. 2011

Genes Dev.

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“…MDM4 also seems to exert a positive effect on stress-activated p53 proapoptotic function (37) and modulates tumorigenesis and chromosomal stability in p53-null cells and mice (38). These, or other yet unknown p53-independent activities, may explain why rs4245739 is not correlated with a decreased frequency in p53 mutations.…”

Section: Mdmxmentioning

confidence: 98%

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

et al. 2010

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Overexpression of MDM4 (also known as MDMX or HDMX) is thought to promote tumorigenesis by decreasing p53 tumor suppressor function. Even modest decrease in Mdm4 levels affects tumorigenesis in mice, suggesting that genetic variants of MDM4 might have similar effects in humans. We sequenced the MDM4 gene in a series of ovarian cancer cell lines and carcinomas to identify mutations and/or single nucleotide polymorphisms (SNPs). We identified an SNP (SNP34091) in the 3 0 -UTR of MDM4 that creates a putative target site for hsa-miR-191, a microRNA that is highly expressed in normal and tumor tissues. Biochemical evidence supports specific miR-191-dependent regulation of the MDM4-C, but not MDM4-A, variant. Consistently, the A-allele was associated with statistically significant increased expression of MDM4 mRNA and protein levels in ovarian carcinomas. Importantly, the wild-type genotype (A/A) is more frequent (57.8% vs. 42.2% for A/C and C/C, respectively) in patients with high-grade carcinomas than in patients with low-grade carcinomas (47.2% vs. 52.5% for A/A and A/C þ C/C, respectively). Moreover, A/A patients who do not express the estrogen receptor had a 4.2-fold [95% confidence interval (CI) ¼ 1.2-13.5; P ¼ 0.02] increased risk of recurrence and 5.5-fold (95% CI ¼ 1.5-20.5; P ¼ 0.01) increased risk of tumor-related death. Unexpectedly, the frequency of p53 mutations was not significantly lower in A/A patients. We conclude that acquisition of an illegitimate miR-191 target site causes downregulation of MDM4 expression, thereby significantly delaying ovarian carcinoma progression and tumor-related death. Importantly, these effects appear to be, at least partly, independent of p53. Cancer Res; 70(23); 9641-9. Ó2010 AACR.

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“…70 The ratio of Mdm4 to Mdm2 determines the effect on p53 levels. 71 When Mdm4 levels fall below a 2-to-1 ratio with Mdm2, the stability of p53 is decreased.…”

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confidence: 99%