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Journal ArticleDOI

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

TL;DR: This work presents a novel and scalable approach to gene expression engineering that allows for real-time annotation of gene expression changes in response to cancerigenicity and shows promise in finding novel and efficient treatments for cancer.
Abstract: 1 Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Technologiepark, 927, Ghent B9052, Belgium 2 Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, CA 92037, USA 3 Gene Expression and Diseases Unit, Institut Pasteur, Paris, France 4 The University of Texas Graduate School of Biomedical Sciences and department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA * Corresponding author: J-C Marine, Laboratory For Molecular Cancer Biology, VIB, Technologiepark, 927, Ghent B-9052, Belgium. Tel: þ 32-93-313-640; Fax: þ 32-93-313-516; E-mail: chris.marine@dmbr.ugent.be

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Citations
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Journal ArticleDOI
TL;DR: There is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients, and the resequencing study uncovered two new unclassified variants at a low frequency.
Abstract: MDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage. It is unknown, however, whether MDM4 gene alterations play some role in the inherited component of breast cancer susceptibility. We sequenced the whole MDM4 coding region and flanking untranslated regions in genomic DNA samples obtained from 40 German patients with familial breast cancer. Selected variants were subsequently screened by RFLP-based assays in an extended set of breast cancer cases and controls. Our resequencing study uncovered two MDM4 coding variants in 4/40 patients. Three patients carried a silent substitution at codon 74 that was linked with another rare variant in the 5'UTR. No association of this allele with breast cancer was found in a subsequent screening of 133 patients with bilateral breast cancer and 136 controls. The fourth patient was heterozygous for the missense substitution D153G which is located in a less conserved region of the MDM4 protein but may affect a predicted phosphorylation site. The D153G substitution only partially segregated with breast cancer in the family and was not identified on additional 680 chromosomes screened. This study did not reveal clearly pathogenic mutations although it uncovered two new unclassified variants at a low frequency. We conclude that there is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients.

12 citations


Cites background from "Keeping p53 in check: essential and..."

  • ...One important antagonist, MDM2, is essential for ubiquitylation and subsequent degradation of p53 to maintain it at low levels in unstressed cells [6]....

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Journal ArticleDOI
04 Nov 2010-Oncogene
TL;DR: A new mechanism in the control of p53 basal activity is revealed that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins.
Abstract: Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length p90(MDM2), for a short protein, p76(MDM2) that lacks the p53-binding domain. Despite this property and at variance with p90(MDM2), this protein acts positively toward p53, although the molecular mechanism remains elusive. Here, we report that p76(MDM2) antagonizes MDM4 inhibitory function. We show that p76(MDM2) possesses intrinsic ubiquitinating and degrading activity, and through these activities controls MDM4 levels. Furthermore, the presence of p76(MDM2) decreases the association of MDM4 with p53 and p90(MDM2), and antagonizes p53 degradation by the heterodimer MDM4/p90(MDM2). The p76(MDM2)-mediated regulation of MDM4 occurs in the cytoplasm, under basal growth conditions. Conversely, upon DNA damage, phosphorylation of MDM4Ser403 dissociates p76(MDM2) and prevents MDM4 degradation. The overall negative control of MDM4 by p76(MDM2) reflects on p53 function as p76(MDM2) impairs MDM4-mediated inhibition of p53 activity. In agreement with the positive role of p76(MDM2) toward p53, the p76(MDM2)/p90(MDM2) ratio significantly decreases in a group of thyroid tumor samples compared with normal counterparts. Overall, these findings reveal a new mechanism in the control of p53 basal activity that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins. Moreover, these data suggest an oncosuppressive function for a product of the Mdm2 gene.

12 citations


Cites background from "Keeping p53 in check: essential and..."

  • ...Under normal growth conditions, p53 activity is tightly controlled by MDM family members, MDM2 and MDM4, and their derivative forms (Marine et al., 2006; Toledo and Wahl 2007; Mancini et al., 2009a)....

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  • ...In normal growing cells, p53 is regulated in a non-redundant manner by MDM family members, MDM4 and MDM2 (Marine et al., 2006)....

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  • ...Overall, the consequences of p76MDM2-mediated regulation of MDM4 are the attenuation of MDM4 and MDM2 inhibitory activity toward p53, pointing to p76MDM2 as an important factor in the positive control of p53 function....

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  • ...MDM4 is an inhibitor of p53 activity under normal growth conditions (Marine et al., 2006; Wang et al., 2009), whereas it exerts a positive function toward p53-mediated apoptosis upon lethal DNA damage (Mancini and Moretti, 2009)....

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Journal ArticleDOI
TL;DR: Although the researchers' results provide the proof of concept of the feasibility of blocking both MDM2 and MDMX regulatory functions for the development of novel and more incisive p53-based anticancer strategies, their invention supplies medicinal chemists with a new interesting lead compound to aid the design of novel small-molecule inhibitors of the oncogenic proteins with drug-like properties.
Abstract: Background: The evidence that some human cancers show wild-type p53 and overexpressed levels of MDM2 and/or MDMX has fueled the search for new therapeutic agents that could rescue p53 from the inhi...

12 citations


Cites background from "Keeping p53 in check: essential and..."

  • ...Conversely, the interaction of MDMX with the trans-activation function of p53 does not target the tumor suppressor protein for the degradation, but inactivates its transcriptional activity [3,4]....

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Journal ArticleDOI
TL;DR: A wide range of pharmaceutical drugs and radiotherapy treatments activate this protein and rely on p53 signalling for therapeutic outcome, and promising small molecular weight compounds are discussed in this review.
Abstract: Objectives For the past three decades of research, p53 has been identified as one of the most targetable molecules for developing anticancer treatments. This tumour suppressor protein is involved in apoptosis, cell cycle arrest and senescence. A wide range of pharmaceutical drugs and radiotherapy treatments activate this protein and rely on p53 signalling for therapeutic outcome. Promising small molecular weight compounds, some of which are undergoing clinical trials, are discussed in this review. Key findings The spectrum of potential therapeutic approaches trialled for p53 stretch from gene therapy to the more recent development of small molecules capable of activating wild-type p53 or reactivating mutant p53. Summary Our ever-growing knowledge leads us to better understand this protein, from its structure and activities to its potential therapeutic application, firstly for cancer and then for other diseases and maybe even for reversal of ageing.

12 citations


Cites background from "Keeping p53 in check: essential and..."

  • ...This physical interaction prevents p53 from interacting with its transcription factors.([22]) Mdm2 also induces p53 degradation by the ubiquitylation function of the E3 ubiquitin ligase....

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  • ...In cells undergoing stress, the physical interaction between p53 and Mdm2 (an E3 ubiquitin ligase that binds and targets p53 for proteasomal degradation) is perturbed,([22]) leaving p53 unchecked to perform its biological functions....

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Journal ArticleDOI
TL;DR: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but the data suggest that MDM2 SNP309 might modify the risk related to GC.
Abstract: Background: Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. Materials and Methods: A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR (AS-PCR). Results: There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). Conclusions: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.

12 citations


Cites background from "Keeping p53 in check: essential and..."

  • ...Several epidemiological studies have evaluated the connection of p53 R72P, MDM2 SNP309 and risk of different types of cancer (Marine et al., 2006; Sadeghi et al., 2013; Song et al., 2013)....

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  • ...Clinical studies and mouse models have shown that p53 is mutated in 50% of human cancers, and functionally inactivated in much more (Marine et al., 2006)....

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  • ...MDM2 is a crucial negative regulator of p53, that promote its degradation, as disclosed by models in which deletion of MDM2 gene is lethal in a p53-dependent manner (Marine et al., 2006; Ren et al., 2013)....

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References
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Journal ArticleDOI
19 Nov 1993-Cell
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.

8,339 citations

Journal ArticleDOI
06 Feb 2004-Science
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.

4,397 citations

Journal ArticleDOI
15 May 1997-Nature
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
Abstract: The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

4,311 citations

Journal ArticleDOI
15 May 1997-Nature
TL;DR: It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells.
Abstract: The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.

3,298 citations

Journal ArticleDOI
TL;DR: The data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus‐uninfected cells which do not have E6 protein.

1,962 citations