Amplification of <i>Mdmx</i> (or <i>Mdm4</i>) Directly Contributes to Tumor Formation by Inhibiting p53 Tumor Suppressor Activity

Danovi, Davide; Meulmeester, Erik; Pasini, Diego; Migliorini, Domenico; Capra, Maria; Frenk, Ruth; Graaf, Petra de; Francoz, Sarah; Gasparini, Patrizia; Gobbi, A.; Helin, Kristian; Pelicci, Pier Giuseppe; Jochemsen, Aart G.; Marine, Jean–Christophe

doi:10.1128/mcb.24.13.5835-5843.2004

Cited by 273 publications

(313 citation statements)

References 43 publications

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“…98 Somatic MDM2 amplification has been considered an alternative mechanism of p53 inactivation, and is commonly recorded in soft tissue and osteosarcomas and gliomas, less frequently in melanomas and colon cancer. [99][100][101][102] Amplifications of MDM4 has been reported albeit at low incidence in breast cancers and gliomas, 102,103 and in retinoblastomas (RBs), for which experimental evidence indicates a role in tumour progression. 104 Interestingly, MDM4 overexpression has been associated with lack of response to the MDM2 antagonist nutlin in chronic lymphoma cells in vitro.…”

Section: Tp53 Analogues Tp63 and Tp73mentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Tp53 Analogues Tp63 and Tp73mentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…In addition, it has been reported that Mdm4 can enhance Mdm2-mediated ubiquitination and degradation of p53 (Stad et al, 2000. Similar to Mdm2, Mdm4 has been found overexpressed in a significant number of various human tumors and tumor cell lines, in general correlating with the expression of wild-type p53, suggesting that Mdm4 contributes to p53 inactivation during tumorigenesis (Riemenschneider et al, 1999(Riemenschneider et al, , 2003Ramos et al, 2001;Danovi et al, 2004;Laurie et al, 2006). As both Mdm2 and Mdm4 are overexpressed in many tumors that retain wild-type p53, they are attractive targets for the development of anti-cancer agents.…”

Section: Introductionmentioning

confidence: 99%

Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

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“…Suppression of Mdm2 causes cell cycle arrest and in some cases apoptosis in tumourderived cells expressing wild-type p53 (Vassilev, 2007). Inhibiting MdmX can also have anti-tumour activity (Danovi et al, 2004;Gilkes et al, 2006). However, targeting both Mdm2 and MdmX in cancer cells has been observed to have a greater pro-apoptotic effect than targeting either alone (Hu et al, 2006;Patton et al, 2006;Wade et al, 2006;Xia et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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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Amplification of Mdmx (or Mdm4) Directly Contributes to Tumor Formation by Inhibiting p53 Tumor Suppressor Activity

Cited by 273 publications

References 43 publications

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Role of Mdm4 in drug sensitivity of breast cancer cells

MdmX is a substrate for the deubiquitinating enzyme USP2a

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