Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells
            <i>in vivo</i>

Francoz, Sarah; Froment, Pascal; Bogaerts, Sven; Clercq, Sarah De; Maetens, Marion; Doumont, Gilles; Bellefroid, Éric; Marine, Jean–Christophe

doi:10.1073/pnas.0508476103

Cited by 244 publications

(250 citation statements)

References 34 publications

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“…Results consistent with the regulation model in Figure 2 were obtained in independent in vivo studies, in cell types including fibroblasts and neural progenitors Francoz et al, 2006). A recent analysis of the p53 response to ribosomal stress in HCT116 and U2OS cells is also consistent with this model .…”

Section: Biological Functionssupporting

confidence: 85%

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

216

162

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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 Functionssupporting

confidence: 85%

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

216

162

View full text Add to dashboard Cite

show abstract

“…To verify that our detection method could detect both forms of caspase-3, sections of E16.5 embryos expressing p53 specifically in post-mitotic neurons deficient for mdm2 were analyzed. 29 Clear and specific staining for pro-caspase-3 and activated form of caspase-3 was detected in these embryos (Figure 4), confirming the sensitivity and the specificity of the method.…”

Section: Caspase-3 Is Not Expressed In Intestinal Smcssupporting

confidence: 60%

“…Moreover, in situ end labeling (ISEL) 30 (Figure 5a) and TUNEL assays (data not shown) did not detect DNA fragmentation at any time points. In contrast, DNA fragmentation was evident in mdm2-deficient postmitotic neurons expressing p53 29 (Figure 5a).…”

Section: Absence Of Apoptotic Signatures In Intestinal Smcs Undergoinmentioning

confidence: 96%

Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

et al. 2006

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Abstractp53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death.

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“…8 However, recent data obtained with different mouse models suggest that the main function of MDMX is to repress p53-mediated transcription without having a major function in the regulation of p53 levels. 9,10 Some of these discrepancies may be due to the use of different cell lines, reflecting either tissuespecificity or transformation bias. MDMX is phosphorylated at multiple sites after cellular stresses, and that these modifications play a critical role in the stability and function of the protein upon DNA damage.…”

mentioning

confidence: 99%

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

et al. 2007

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MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid b precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.

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Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo

Cited by 244 publications

References 34 publications

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

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