The loss of mdm2 induces p53 mediated apoptosis

Rozieres, Sohela de; Maya, Ruth; Oren, Moshe; Lozano, Guillermina

doi:10.1038/sj.onc.1203468

Cited by 115 publications

(84 citation statements)

References 69 publications

(60 reference statements)

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“…The interaction between Mdm2 and the N-terminus of p53 obstructs p53-directed transcription and promotes the ubiquitination of lysine residues in the p53 C-terminus and the subsequent targeting of p53 for proteosomal degradation. The Mdm2 gene is itself a transcriptional target of p53 which has led to the proposal of a negative feedback loop between the two proteins, ensuring that p53 levels are kept low under normal conditions (de Rozieres et al, 2000). In contrast, the translational regulation of the p53 mRNA has with some exceptions remained relatively unexplored.…”

Section: Introductionmentioning

confidence: 99%

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

et al. 2006

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P53 controls the growth and survival of cells by acting in response to a multitude of cellular stresses. It is, however, not yet fully understood how different p53 activation pathways result in either cell cycle arrest or apoptosis. We and others have described an N-terminally truncated p53 protein (p53/47) originating from a second translation initiation site in the p53 messenger RNA (mRNA), which can interact with p53 and impose altered stability and transactivation properties to p53 complexes. Here we show that cap-dependent and cap-independent mechanisms of initiation govern the translation of the p53 mRNA. Changes in synthesis of full-length p53 or p53/47 are regulated through distinct cell stress-induced pathways acting through separate regions of the p53 mRNA. We also show that some cytotoxic drugs require the presence of full-length p53 to induce apoptosis, whereas for others p53/47 is sufficient. This indicates that by harbouring alternative translation initiation sites, the p53 mRNA gives rise to different levels of the p53 isoforms which help to orchestrate the cell biological outcome of p53 activation in response to different types of cell stress. This sheds new light into the way p53 can integrate and differentiate a large multiplicity of changes in the cellular environment.

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Section: Introductionmentioning

confidence: 99%

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

et al. 2006

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“…The importance of Mdm2 in p53 regulation was shown in vivo by the lethality of Mdm2 À/À embryos at 3.5 days postcoitum whereas p53 À/À Mdm2 À/À mice develop without abnormalities (7,8). Mdm2 À/À blastocysts undergo spontaneous apoptosis, and reintroduction of p53 into p53 À/À Mdm2 À/À mouse embryo fibroblasts (MEF) also induces an apoptotic response (9,10). Similarly, tissue-specific deletion of Mdm2 in cardiomyocytes, smooth muscle cells, and the central nervous system results in p53-dependent apoptosis (11)(12)(13)(14).…”

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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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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“…Mdm2 has been proposed to negatively regulate p53-mediated cell death following DNA damage (de Rozieres et al, 2000;Chavez-Reyes et al, 2003). To explore the effects of Mdm2 on apoptosis in the presence or absence of Mdm4, E1A-transduced MEFs were treated with doxorubicin, a well-established inducer of p53-mediated apoptosis in oncogene-activated MEFs (Attardi et al, 2000).…”

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confidence: 99%

Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development

et al. 2005

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The Mdm2 and Mdm4 genes are amplified and overexpressed in a variety of human cancers and encode structurally related oncoproteins that bind to the p53 tumor suppressor protein and inhibit p53 activity. Mice deleted for either Mdm2 or Mdm4 die during embryogenesis, and the developmental lethality of either mouse model can be rescued by concomitant deletion of p53. However, the phenotypes of Mdm2 and Mdm4-deficient mice suggest that Mdm2 and Mdm4 play nonoverlapping roles in regulating p53 activity during development, with Mdm2 regulating p53-mediated cell death and Mdm4 regulating p53-mediated inhibition of cell growth. Here, we describe complete rescue of Mdm4-deficient mice by expression of an Mdm2 transgene, and demonstrate that Mdm2 can regulate both p53-mediated apoptosis and inhibition of cell growth in the absence of Mdm4 in primary cells. Furthermore, deletion of Mdm4 enhances the ability of Mdm2 to promote cell growth and tumor formation, indicating that Mdm4 has antioncogenic properties when Mdm2 is overexpressed

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The loss of mdm2 induces p53 mediated apoptosis

Cited by 115 publications

References 69 publications

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

Mdm2 and Mdm4 Loss Regulates Distinct p53 Activities

Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development

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