Limiting the power of p53 through the ubiquitin proteasome pathway

Pant, Vinod; Lozano, Guillermina

doi:10.1101/gad.247452.114

Cited by 139 publications

(139 citation statements)

References 156 publications

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“…4E). MDM4 (also known as MDMX) is another regulator of TP53 that is structurally related to MDM2 but acts differently on TP53 by regulating its transcriptional activity independently of MDM2 or its protein level coordinately with MDM2 (45,46). Our results thus provide evidence that Mdm4 overexpression (Fig.…”

Section: Identification Of Mechanisms Of Resistance To Tp53-mdm2 Inhisupporting

confidence: 52%

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf −/− mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.drug resistance | MDM2 inhibitor | piggyBac screen | cancer A mong the genes most commonly altered in human cancer, regardless of tumor type, are tumor protein 53 (TP53) tumor suppressor (1) and CDKN2A (INK4a/ARF) (2). The latter gene encodes two tumor suppressor proteins: p16INK4a (3), an inhibitor of cyclin D-dependent kinases that, at least in part, regulates the function of the retinoblastoma protein (RB), and p19ARF (4), a negative regulator of double minute 2 protein (MDM2) function that activates TP53, thereby inducing cell cycle arrest or apoptosis. TP53 protein levels are regulated through MDM2-mediated degradation.Toward the goal of reactivating TP53 in cells harboring inactivating upstream pathway alterations, compounds inhibiting the interaction between MDM2 and TP53, preventing TP53 degradation, have been discovered. Such agents induce TP53 reactivation in tumors in which the TP53 gene is wild type (5-8).Although preclinical studies of such MDM2 inhibitors have demonstrated significant antitumor activity, tumors commonly relapse (9, 10).Rapid emergence of resistance is...

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Section: Identification Of Mechanisms Of Resistance To Tp53-mdm2 Inhisupporting

confidence: 52%

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Decreased miR-31 expression was also reported to enhance chemoresistance of ovarian cancer cells due to up-regulation of its target, receptor tyrosine kinase MET (Mitamura et al 2013). Finally, gains in 12q12-q21.1 encompassing MDM2 would favor p53 degradation (Pant and Lozano 2014), while gains in 12q24.11-q24.32, as mentioned above, would favor inhibition of p53 translation by MSI1 (Liu et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

et al. 2015

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Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment.

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“…This includes several key oncogenes and tumor suppressor proteins. [4][5][6][7][8] Since cancer cells are in an accelerated metabolic state required to support their rapid rate of proliferation, they are highly dependent on the proteasome function for their survival. Disruption of proteasome activity would result in build-up of cellular waste, which would overwhelm the cancer cells and cause cell death.…”

Section: Introductionmentioning

confidence: 99%

A New Garbage Disposal System – Cancer Cells Unveils A New Trick?

Elangovan¹

2016

MOJPB

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Proteasomes play an important role in maintaining cellular homeostasis by degrading unwanted and misfolded proteins in cells through regulated proteolysis. The increased dependence of cancer cells on proteasomes to drive their rapid proliferation have been successfully exploited in developing anti-cancer therapies aimed at targeting proteasome function. However, recent reports highlighting emergence of drug resistance to existing proteasome inhibitors together with undesired side-effects associated with these drugs as a result of inhibiting proteasomes in normal cells have underscored the need for strategies that can disrupt proteasome function selectively in cancer cells. The recent discovery of a new proteasome isoform in human cells ('α4-α4' proteasomes) and their potential role in enabling cancer cells adapt to cellular stress has opened up new potential avenues for targeting proteasomes in cancer. This review highlights this discovery and discusses the potential of targeting these novel proteasome isoforms in cancer. MOJ Proteomics & Bioinformatics

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Limiting the power of p53 through the ubiquitin proteasome pathway

Cited by 139 publications

References 156 publications

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

A New Garbage Disposal System – Cancer Cells Unveils A New Trick?

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Limiting the power of p53 through the ubiquitin proteasome pathway

Cited by 139 publications

References 156 publications

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

A New Garbage Disposal System – Cancer Cells Unveils A New Trick?

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Product

Resources

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model