The DOI matches its Crossref record; 174 of the 174 references it cites were found in a registry or an index; 4 of the 131 sources its claims cite were checked for support.
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Open accessAbstract
The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that MDM2 and MDMX are major negative regulators of p53 whose deregulation contributes to many cancers, but their full oncogenic potential generally requires cooperating lesions. It surveys mechanisms, mouse models, and drug development, concluding that p53 reactivation via MDM2/MDMX antagonists is promising but context-dependent and still limited by lack of selective MDMX inhibitors and clinical challenges.
Key findings
- MDM2 and MDMX inhibit p53 transactivation by binding its N-terminal domain; MDM2 homo-oligomers have E3 ubiquitin ligase activity via an intact C-terminal RING domain, whereas MDMX lacks intrinsic ligase activity but hetero-oligomerizes with MDM2, and this hetero-oligomerization is crucial for p53 suppression during embryonic development.
- In vivo evidence shows context dependence: MDM2 overexpression can induce carcinoma and lymphomas or sarcomas, and an MDM2 SNP knock-in accelerates tumorigenesis at a rate similar to Trp53-hemizygous animals; MDMX overexpression alone has yielded conflicting tumorigenicity results, while MDMX3SA mice are radioresistant and more prone to Myc-induced tumors, and MDM2-Ser394Ala mice show increased spontaneous tumors.
- In a Phase I proof-of-mechanism study of RG7112 in 20 patients with MDM2-amplified liposarcoma, the drug reached its target and increased MIC1/GDF15, but increases in p53 and p21 and decreased proliferation did not reach significance; at least one adverse event occurred in each patient, most frequently haematological toxicities.
- Nutlin 3a is 500-fold less potent against MDMX than MDM2; the dual inhibitor RO-5963 had better in vitro MDM2 binding affinity than nutlin 3a (IC50 17.3 nM versus 18.7 nM) but poorer pharmacological properties, and the stapled peptide SAH-p53-8 had tenfold better MDM2 IC50 than nutlin 3a and also disrupts p53–MDMX interactions.
Methods
- Design: narrative review of MDM2, MDMX, and p53 biology, oncogenesis, and therapeutic targeting.
- Data: published mechanistic studies, cell-based assays, mouse genetic models, and clinical trial data; no new primary data are reported.
- Analysis: qualitative synthesis of the core pathway, transcriptional/post-transcriptional regulation, oncogenic evidence, and small-molecule/peptidic inhibitor strategies.
Limitations
- The paper states that much remains unknown about MDM2 and MDMX transcriptional regulation, that in vivo mutation of p53 response elements in Mdm2 and Mdmx promoters is needed, that the biological importance of the p53–miRNA network remains to be clarified, and that the identity of the relevant E2 ubiquitin-conjugating enzymes is unknown.
- The paper states that no selective MDMX small-molecule inhibitor currently exists, that the RG7112 trial was preliminary with only 20 patients and heterogeneous tumour tissue, and that relying on MDM gene amplification alone for patient selection is inadequate.
- Evident from the text: as a narrative review, it does not perform a systematic search or quantitative meta-analysis, and it reports conflicting mouse-model results for MDMX overexpression, so conclusions depend on context and cited study designs.
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Claims the paper makes
83 Not checked yet · 26 Own interpretation · 11 No basis given · 1 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, many tumours exhibit high MDM2 and MDMX protein levels without increased copy number. These include melanoma10, Ewing's sarcoma22, colon carcinoma9 and retinoblastoma12,23.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM transcriptional regulation
What the sources say
- Partly supportedcites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. sourceExperimental — accuracy not yet measured
For the melanoma example cited to this paper, the Results section (‘MDM4 is overexpressed in ∼65% of human melanomas’; page unavailable) reports high MDM4/MDMX protein in about 65% of melanomas. It also says MDM2 protein was low or undetectable in most cases. The passages do not establish that the high protein levels occurred without increased gene copy number; the other tumour types have separate citations in the citing sentence. (LLM, conf=0.86)
- Partly supportedcites [22] Pishas, K. I. et al. Nutlin-3a is a potential therapeutic for ewing sarcoma. Clin. Cancer Res. 17, 494–504 (2011). sourceExperimental — accuracy not yet measured
Citation 22 is attached to Ewing’s sarcoma, not the other listed cancers. In “MDM4 is overexpressed in Ewing sarcoma cell lines” (page unavailable), the paper reports elevated MDM4/MDMX protein in several Ewing sarcoma cell lines without MDM4 gene amplification. It does not establish that those lines also have high MDM2 protein without increased copy number; its finding is limited to cell lines rather than tumours generally. (LLM, conf=0.85)
- Partly supportedcites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). sourceExperimental — accuracy not yet measured
The Results report high MDMX protein staining in 49 of 99 colon tumors, supporting colon carcinoma as an example of MDMX overexpression. The Discussion says MDMX overexpression in tumors often occurs without gene amplification, but the paper does not establish copy number in those colon tumors or report elevated MDM2 protein in them. The other tumor types have separate citations in the citing sentence and are not assessed against this source. (LLM, conf=0.86)
- Not checked yetcites [12] Laurie, N. A. et al. Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61–66 (2006). source
- Partly supportedcites [23] McEvoy, J. et al. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma. PLoS ONE 7, e42739 (2012). sourceExperimental — accuracy not yet measured
For the retinoblastoma example attributed to this paper, the Introduction reports high MDM4 expression irrespective of copy number and high MDM4 (MDMX) protein in xenografts. But the Introduction and Results report low or undetectable MDM2 protein in most retinoblastoma samples, contrary to the claim that both proteins are high. This paper is not cited for the other tumour types in the sentence. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these observations indicate that a major oncogenic role of MDM proteins is to block p53 transcriptional activity.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Although both MDM2 and MDMX can inhibit p53 transactivation function by engaging its amino-terminal transactivation domain via related N-terminal hydrophobic pockets2,11,12”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
What the sources say
- Not checked yetcites [2] Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992). The first demonstration that MDM2 could inhibit p53 activity. source
- Not checked yetcites [11] Kussie, P. H. et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948–953 (1996). The structure that described the hydrophobic p53-binding pocket of MDM2, on which many drug discovery efforts are now based. source
- Not checked yetcites [12] Laurie, N. A. et al. Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61–66 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In many cases, the frequency of MDM protein deregulation is higher in tumours that retain wild-type p53.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which now seem to be ‘druggable’ using a variety of strategies.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > Abstract
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In the paper
“Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [107] Montes de Oca Luna, R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995). source
- Not checked yetcites [108] Parant, J. et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genet. 29, 92–95 (2001). References 107 and 108 demonstrate that deletions of Mdm2 and Mdmx cause embryonic lethality that can be rescued by Trp53 deletion, thus providing genetic evidence that MDM2 and MDM4 are crucial p53 repressors with non-overlapping functions. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the gene amplification criterion may underestimate the number of tumours in which MDM2 or MDMX overexpression contributes to cancer initiation, maintenance or progression.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM transcriptional regulation
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Intriguingly, MDMX levels seem to be increased in B cells that overexpress MYC before tumorigenesis28.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM transcriptional regulation
What the sources say
- Not checked yetcites [28] De Clercq, S. et al. Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. Mol. Cell. Biol. 30, 5394–5405 (2010). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Hetero-oligomerization of MDM2 and MDMX via their RING domains is crucial for the suppression of p53 activity during embryonic development17,18.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
What the sources say
- Not checked yetcites [17] Huang, L. et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc. Natl Acad. Sci. USA 108, 12001–12006 (2011). source
- Not checked yetcites [18] Pant, V., Xiong, S., Iwakuma, T., Quintas-Cardama, A. & Lozano, G. Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability. Proc. Natl Acad. Sci. USA 108, 11995–12000 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the data suggest that p53, microRNAs, MDM2 and MDMX form regulatory circuits to facilitate the rapid activation of p53 on stress”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > miRNA links to p53 pathway control by MDM2 and MDMX
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 42
- Probably not a substantial claim. 3
None of the sources cited for this claim have been checked yet.
In the paper
“The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor.”
- Also stated in: § The core pathway · hedged
“Taken together, these observations indicate that a major oncogenic role of MDM proteins is to block p53 transcriptional activity.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > Abstract
What the sources say
- Not checked yetcites [3] Shibagaki, I. et al. p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin. Cancer Res. 1, 769–773 (1995).
- Not checked yetcites [4] Forslund, A. et al. MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers. Mol. Cancer Res. 6, 205–211 (2008). source
- Not checked yetcites [5] Ito, M. et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). source
- Not checked yetcites [6] Lam, S. et al. Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene 29, 2415–2426 (2010). source
- Not checked yetcites [7] Mejia-Guerrero, S. et al. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes Chromosomes Cancer 49, 518–525 (2010). source
- Not checked yetcites [8] Ito, M. et al. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin. Cancer Res. 17, 416–426 (2011). source
- Not checked yetcites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). source
- Not checked yetcites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § The core pathway · hedged
None of the sources cited for this claim have been checked yet.
In the paper
“Amplification of MDM genes or altered expression of MDM proteins is a feature of many tumours3–10 (Table 1).”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
What the sources say
- Not checked yetcites [3] Shibagaki, I. et al. p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin. Cancer Res. 1, 769–773 (1995).
- Not checked yetcites [4] Forslund, A. et al. MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers. Mol. Cancer Res. 6, 205–211 (2008). source
- Not checked yetcites [5] Ito, M. et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). source
- Not checked yetcites [6] Lam, S. et al. Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene 29, 2415–2426 (2010). source
- Not checked yetcites [7] Mejia-Guerrero, S. et al. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes Chromosomes Cancer 49, 518–525 (2010). source
- Not checked yetcites [8] Ito, M. et al. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin. Cancer Res. 17, 416–426 (2011). source
- Not checked yetcites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). source
- Not checked yetcites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Most p53 mutants in human tumours are transactivation-deficient, suggesting that blocking p53-dependent transcription is a crucial event in tumorigenesis1.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
What the sources say
- Not checked yetcites [1] Bieging, K. T. & Attardi, L. D. Deconstructing p53 transcriptional networks in tumor suppression. Trends Cell Biol. 22, 97–106 (2012). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The RAS signalling pathway converges on the activation of ETS transcription factors, and overexpression of RAS leads to ETS-dependent upregulation of both MDM2 and MDMX expression9,25.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM transcriptional regulation
What the sources say
- Not checked yetcites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). source
- Not checked yetcites [25] Ries, S. et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103, 321–330 (2000). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“By contrast, MDMX does not homo-oligomerize and has no intrinsic ubiquitin ligase function, although it can increase or decrease MDM2 ubiquitin ligase activity depending on MDMX abundance16.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
What the sources say
- Not checked yetcites [16] Linares, L. K., Hengstermann, A., Ciechanover, A., Muller, S. & Scheffner, M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl Acad. Sci. USA 100, 12009–12014 (2003). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“By contrast, the mutation of Ser394 to alanine (Ser394Ala) in mouse MDM2 in vivo removes an ATM phosphorylation site, engenders radioresistance and increases the rate of spontaneous tumorigenesis to that observed in Trp53-hemizygous animals47.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > In vivo studies
What the sources say
- Not checked yetcites [47] Gannon, H. S., Woda, B. A. & Jones, S. N. ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice. Cancer Cell 21, 668–679 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Surprisingly, although there was no increase in spontaneous tumour formation in MDMX3SA animals, these mice were more prone to Myc-induced tumorigenesis69 (discussed below).”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > In vivo studies
What the sources say
- Not checked yetcites [69] Park, S. S. et al. Insertion of Myc into Igh accelerates peritoneal plasmacytomas in mice. Cancer Res. 65, 7644–7652 (2005). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“MDMX can immortalize primary mouse embryonic fibroblasts and can accelerate the growth of human fibroblasts63,64.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cell-based studies
What the sources say
- Not checked yetcites [63] Danovi, D. et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol. Cell. Biol. 24, 5835–5843 (2004). source
- Not checked yetcites [64] Lenos, K. et al. Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts. Mol. Cancer 10, 111 (2011). source
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In the paper
“These studies have revealed that the mir-34 family does not have a substantial effect on p53 tumour suppressor functions in vivo54.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > miRNA links to p53 pathway control by MDM2 and MDMX
What the sources say
- Not checked yetcites [54] Concepcion, C. P. et al. Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet. 8, e1002797 (2012). This article forces a re-evaluation of the contexts in which miR-34 contributes to the p53 response in vivo. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This is probably because MDM2 overexpression at supraphysiological levels is toxic to many normal cells, suggesting that it may have other cellular targets61.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cell-based studies
What the sources say
- Not checked yetcites [61] Marine, J. C. & Lozano, G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 17, 93–102 (2010). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Kaposi's sarcoma-associated herpes virus (KSHV) expresses vIRF4, a factor that binds MDM2 and that seems to switch its ubiquitin ligase activity to p53 degradation57.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > miRNA links to p53 pathway control by MDM2 and MDMX
What the sources say
- Not checked yetcites [57] Lee, H. R. et al. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 targets MDM2 to deregulate the p53 tumor suppressor pathway. J. Virol. 83, 6739–6747 (2009). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Although activated p53 was thought to exclusively upregulate MDM2, new data have revealed p53-dependent increases in MDMX expression under certain conditions14.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM transcriptional regulation
What the sources say
- Not checked yetcites [14] Phillips, A. et al. HDMX-L is expressed from a functional p53-responsive promoter in the first intron of the HDMX gene and participates in an autoregulatory feedback loop to control p53 activity. J. Biol. Chem. 285, 29111–29127 (2010). source
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Multiple kinases are known to modify both MDM proteins and (perhaps unsurprisingly) the downstream effects cluster into those that inhibit and those that activate p53.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > PTMs
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In the paper
“Indeed, protein phosphatase 1D (PPM1D) can dephosphorylate both MDM2 and MDMX, thereby contributing to its oncogenic function43,44.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > PTMs
What the sources say
- Not checked yetcites [43] Lu, X., Nguyen, T. A., Zhang, X. & Donehower, L. A. The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability. Cell Cycle 7, 164–168 (2008). source
- Not checked yetcites [44] Zhang, X. et al. Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response. Cancer Res. 69, 7960–7968 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Phosphorylation of MDM2 at Ser166 and Ser186 (Ref. 32), and of MDMX at Ser367 (Ref. 33), leads to their stabilization, and is associated with p53 inhibition.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > PTMs
What the sources say
- Not checked yetcites [32] Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA 98, 11598–11603 (2001). source
- Not checked yetcites [33] Lopez-Pajares, V., Kim, M. M. & Yuan, Z. M. Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding. J. Biol. Chem. 283, 13707–13713 (2008). source
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In the paper
“However, co-expression of MDMX leads to cellular transformation in vitro63,64,70. Importantly, this requires the p53-binding domain of MDMX, suggesting that p53-inhibitory activity of MDMX is crucial for transformation63.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cooperating lesions
What the sources say
- Not checked yetcites [63] Danovi, D. et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol. Cell. Biol. 24, 5835–5843 (2004). source
- Not checked yetcites [64] Lenos, K. et al. Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts. Mol. Cancer 10, 111 (2011). source
- Not checked yetcites [70] Miller, K. R., Kelley, K., Tuttle, R. & Berberich, S. J. HdmX overexpression inhibits oncogene induced cellular senescence. Cell Cycle 9, 3376–3382 (2010).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Following genotoxic stress, DNA-dependent protein kinase (DNA-PK) phosphorylates Ser17 of MDM2 (Ref. 35), and ABL (also known as ABL1) phosphorylates Tyr99 of MDMX36. In each case, this leads to the dissociation of p53 from its negative regulators.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM post-transcriptional regulation > PTMs
What the sources say
- Not checked yetcites [35] Mayo, L. D., Turchi, J. J. & Berberich, S. J. Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res. 57, 5013–5016 (1997).
- Not checked yetcites [36] Zuckerman, V. et al. c-Abl phosphorylates Hdmx and regulates its interaction with p53. J. Biol. Chem. 284, 4031–4039 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“On binding, MDM2 ubiquitylates p53 and leads to its proteasomal degradation; this keeps p53 levels and activity low in unstressed cells.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > The core pathway
What the sources say
- Not checked yetcites [15] Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H. & Weissman, A. M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 275, 8945–8951 (2000). This paper revealed that MDM2 controls the stability of both itself and p53, and that the RING domain was required for these functions. source
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In the paper
“However, a more recent mouse model used a knock-in of a human tumour-associated MDM2 SNP at the endogenous Mdm2 locus. Data from this model confirm that a subtle increase in MDM2 levels engenders tumorigenesis at a rate that is similar to that observed in Trp53-hemizygous animals67.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > In vivo studies
What the sources say
- Not checked yetcites [67] Post, S. M. et al. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18, 220–230 (2010). In vivo evidence that an MDM2 SNP is associated with increased cancer incidence in women is causally associated with tumorigenesis. source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Differences in transgene introduction strategies and mouse genetic backgrounds may contribute to these disparate results, which underscores the idea that the context in which MDMX is overexpressed is probably a major determinant of its oncogenic activity.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > In vivo studies
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In the paper
“In Mdm2+/−- and Mdmx+/−-heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma26,27.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM transcriptional regulation
What the sources say
- Not checked yetcites [26] Alt, J. R., Greiner, T. C., Cleveland, J. L. & Eischen, C. M. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J. 22, 1442–1450 (2003). source
- Not checked yetcites [27] Terzian, T. et al. Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol. Cell. Biol. 27, 5479–5485 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“MDM2 and MDMX have oncogenic properties in vitro, but this is only manifest in the context of other oncogenic lesions.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cell-based studies
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In the paper
“Interestingly, although RG7112 treatment generally correlated with increased p53 and p21 levels, and decreased proliferation, the data did not reach significance.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [98] Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). source
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In the paper
“Unfortunately, siRNA therapy is still hampered by delivery and cellular uptake issues87, making this approach currently unrealistic.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Modulating protein expression
What the sources say
- Not checked yetcites [87] Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nature Rev. Drug Discov. 11, 125–140 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Treating cells with these compounds stabilized p53 and MDM2 and subsequently led to p53 activation.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting ubiquitin ligase activity
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mouse models clearly demonstrate that the inactivation of p53 promotes tumorigenesis, whereas restoration of p53 causes the regression of established tumours78–80.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy
What the sources say
- Not checked yetcites [78] Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006). source
- Not checked yetcites [79] Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007). source
- Not checked yetcites [80] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). source
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In the paper
“Although nutlin 3a and MI-219 robustly activate p53 in cancer cells with overexpressed MDM2, they do not consistently elicit p53-dependent effects in cancer cells that overexpress MDMX99–102.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [99] Patton, J. T. et al. Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res. 66, 3169–3176 (2006). source
- Not checked yetcites [100] Wade, M., Rodewald, L. W., Espinosa, J. M. & Wahl, G. M. BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death. Cell Cycle 7, 1973–1982 (2008). source
- Not checked yetcites [101] Hu, B., Gilkes, D. M., Farooqi, B., Sebti, S. M. & Chen, J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J. Biol. Chem. 281, 33030–33035 (2006). source
- Not checked yetcites [102] Wade, M., Wong, E. T., Tang, M., Stommel, J. M. & Wahl, G. M. Hdmx modulates the outcome of p53 activation in human tumor cells. J. Biol. Chem. 281, 33036–33044 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Loss of the PTEN tumour suppressor leads to the activation of the AKT kinases and increases the level of MDM2 (Ref. 74).”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cooperating lesions
What the sources say
- Not checked yetcites [74] Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K. & Donner, D. B. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J. Biol. Chem. 277, 5484–5489 (2002). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Following melanocyte-specific expression of MDMX and RAS, the time to onset of melanomas was reduced and the tumours that developed were more aggressive10.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cooperating lesions
What the sources say
- Not checked yetcites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, p53 pathway reactivation resulted in at least one adverse event in each patient, the most frequent being related to haematological toxicities.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [98] Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108 and that they exert non-overlapping inhibitory activities towards p53 (Refs 24,109).”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [107] Montes de Oca Luna, R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995). source
- Not checked yetcites [108] Parant, J. et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genet. 29, 92–95 (2001). References 107 and 108 demonstrate that deletions of Mdm2 and Mdmx cause embryonic lethality that can be rescued by Trp53 deletion, thus providing genetic evidence that MDM2 and MDM4 are crucial p53 repressors with non-overlapping functions. source
- Not checked yetcites [24] Francoz, S. et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc. Natl Acad. Sci. USA 103, 3232–3237 (2006). source
- Not checked yetcites [109] Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Liu, G. & Lozano, G. Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc. Natl Acad. Sci. USA 103, 3226–3231 (2006). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the data indicate that RG7112 reaches its target in a solid tumour, and increases the level of macrophage inhibitory cytokine 1 (MIC1; also known as GDF15), which is a secreted protein product of a p53 target gene.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [98] Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicate that wild-type p53 is a valid therapeutic target, and that reactivation of p53 via selective targeting of either MDM2 or MDMX is a viable strategy for cancer therapy.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, subtle structural differences in the MDMX N-terminal p53-binding pocket dramatically reduce the binding affinity of both nutlin 3a and MI-219 for MDMX; this is supported by in vitro binding studies showing that nutlin 3a is 500-fold less potent against MDMX compared with MDM2 (Ref. 103).”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [103] Graves, B. et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc. Natl Acad. Sci. USA 109, 11788–11793 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, SAH-p53-8 is far less efficient at disrupting the p53–MDM2 interaction in cells and it requires nutlin 3a for optimal activity in cells that overexpress both MDM2 and MDMX.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists75,76.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cooperating lesions
What the sources say
- Not checked yetcites [75] Cipriano, R., Patton, J. T., Mayo, L. D. & Jackson, M. W. Inactivation of p53 signaling by p73 or PTEN ablation results in a transformed phenotype that remains susceptible to Nutlin-3 mediated apoptosis. Cell Cycle 9, 1373–1379 (2010). source
- Not checked yetcites [76] Tabe, Y. et al. MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin. Cancer Res. 15, 933–942 (2009). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Co-treatment of such cancer cells with 17-AAG to downregulate MDMX, and nutlin 3a to antagonize the MDM2–p53 interaction, yielded synergistic cytotoxic effects, probably owing to enhanced p53 activation92.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Modulating protein expression
What the sources say
- Not checked yetcites [92] Vaseva, A. V., Yallowitz, A. R., Marchenko, N. D., Xu, S. & Moll, U. M. Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors. Cell Death Dis. 2, e156 (2011). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The small molecule SJ-172550 was identified as an MDMX–p53-selective antagonist105 that exhibited additive cytotoxicity with nutlin 3a in MDMX-amplified retinoblastoma cells. However, subsequent analyses showed that SJ-172550 forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [105] Reed, D. et al. Identification and characterization of the first small molecule inhibitor of MDMX. J. Biol. Chem. 285, 10786–10796 (2010). source
- Not checked yetcites [106] Bista, M. et al. On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53. PLoS ONE 7, e37518 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is important from a clinical perspective because retinoblastomas retain wild-type TP53 and may therefore benefit from treatment with MDM2 and/or MDMX antagonists.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cooperating lesions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“RG7112 (also known as RO5045337), a derivative of nutlin 3a with better potency and pharmacological properties, is in Phase I clinical trials”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Despite these issues, it is noteworthy that SAH-p53-8 is effective at high concentrations in a mouse model of melanoma in which MDMX is overexpressed10. In this model, SAH-p53-8 treatment increased cytotoxicity and sensitized melanomas to the chemotherapeutic agent cisplatin and the BRAF-V600E inhibitor vemurafenib (also known as PLX4032).”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Targeting protein–protein interactions
What the sources say
- Not checked yetcites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Around 22 million cancer patients have defects in p53 signalling77.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy
What the sources say
- Not checked yetcites [77] Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R. & Lane, D. P. Awakening guardian angels: drugging the p53 pathway. Nature Rev. Cancer 9, 862–873 (2009). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A benzofuroxan derivative (NSC207895) that selectively inhibits MDMX expression has been identified88. This molecule downregulates MDMX levels and causes p53-dependent transactivation of proapoptotic genes in several cancer cell lines.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > p53 reactivation in cancer therapy > Modulating protein expression
What the sources say
- Not checked yetcites [88] Wang, H., Ma, X., Ren, S., Buolamwini, J. K. & Yan, C. A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Mol. Cancer Ther. 10, 69–79 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As MDMX3SA mice have an attenuated response to DNA damage, and because MYC is known to induce genotoxic stress, disruption of the MYC–DNA damage–MDMX circuit might contribute to increased tumorigenesis in MDMX3SA mice.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cooperating lesions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A reliance simply on MDM gene amplification is inadequate.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > Concluding remarks
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper relies on this without support.
p53 is mutated or functionally inactivated in most human cancers.
“Thirty years of research have shown that the tumour suppressor p53 has a crucial role in many physiological processes, and that it is mutated or functionally inactivated in most human cancers.”
The paper relies on this without support.
In a substantial proportion of cancers, TP53 is wild type but the p53 protein is inactivated.
“In a substantial proportion of cancers TP53 (which encodes p53) is wild type but the protein is inactivated; this offers an attractive strategy for cancer therapy based on p53 reactivation.”
The paper relies on this without support.
Single-agent cancer therapy makes resistance more likely.
“Conventional single-agent cancer therapy increases the likelihood of resistance.”
The paper relies on this without support.
The PI3K–AKT pathway generally promotes cancer cell survival by opposing apoptosis.
“The PI3K–AKT pathway usually has an anti-apoptotic role to promote cancer cell survival.”
The paper relies on this without support.
Resistance to MDM2 antagonists can result from several mechanisms, such as p53 mutation, dominant survival pathways, or blocked death pathways.
“Insensitivity to MDM2 antagonists can arise from a variety of mechanisms, including p53 mutation, the presence of dominant survival pathways or the inhibition of death-inducing pathways.”
The paper relies on this without support.
ATM kinase activates p53 after DNA damage.
“ATM kinase activates p53 in response to DNA damage.”
The paper relies on this without support.
The intracellular E2 enzymes needed for p53 ubiquitylation in vivo remain unidentified.
“the intracellular E2s that are required for p53 ubiquitylation have not been identified.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“MDM2 encodes a nuclear-localized E3 ubiquitin ligase that mediates the degradation of p53 and RB162 in a proteasome-dependent and ubiquitin-independent manner64.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [62]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Both genes are highly expressed in the testis (http://www.gtexportal.org/) and have been implicated in cancer62, 63.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [62]
In the citing paper
“The E3 ubiquitin ligase Mdm2, a negative regulator of the p53 tumor suppressor, is frequently overexpressed in many human malignancies.1–3”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]
In the citing paper
“The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor.”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]
In the citing paper
“Moreover, human tumors with MDMX overexpression may also have inactivated p53,3,19,30,31 which indicates a potential oncogenic benefit to the cancer cells from Mdmx overexpression in addition to its inhibition of p53.”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]
In the citing paper
“MDMX, also known as MDM4, is overexpressed or amplified in at least 15% of human cancers.3,18–20”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]
In the citing paper
“elevated Mdmx levels are observed in many tumors.3,18–22”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]
In the citing paper
“the identification of Mdmx overexpression in tumors with mutated or deleted p53 and effects of Mdmx on genome instability in cells lacking p53 indicate p53-independent functions of Mdmx.3,19,30–33”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]
In the citing paper
“Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2 and MDM4.”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Wade, et al., 2013
In the citing paper
“As with MDM2, MDM4 is overexpressed in many human cancers (Danovi, et al., 2004; Gembarska, et al., 2012; Han, et al., 2007; Leventaki, et al., 2012; Ramos, et al., 2001; Riemenschneider, et al., 1999; Valentin-Vega, et al., 2007; Wade, et al., 2013).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Wade, et al., 2013
In the citing paper
“MDM2 is highly expressed in numerous types of human tumors, and the majority of these retain wild-type TP53 (Rayburn, et al., 2005; Wade, et al., 2013).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Wade, et al., 2013
Citations
Cites
1 retracted
Pichiorri, F., Suh, S.-S., Rocci, A., De Luca, L., Taccioli, C., Santhanam, R., Zhou, W., Benson, D. M., Hofmainster, C., Alder, H., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.09.005 · Cited by 436
RetractedThe Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113
RING Domain E3 Ubiquitin Ligases
Deshaies, R. J., & Joazeiro, C. A. P. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.101807.093809 · Cited by 2,679
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., Greninger, P., Thompson, I. R., Luo, X., Soares, J., et al. (2012) · Nature · doi:10.1038/nature11005 · Cited by 2,456
A restricted cell population propagates glioblastoma growth after chemotherapy
Chen, J., Li, Y., Yu, T.-S., McKay, R. M., Burns, D. K., Kernie, S. G., & Parada, L. F. (2012) · Nature · doi:10.1038/nature11287 · Cited by 2,354
Self-citation
Cited by
Sorted by citations
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Ubiquitination in disease pathogenesis and treatment
Popovic, D., Vucic, D., & Đikić, I. (2014) · Nature Medicine · doi:10.1038/nm.3739 · Cited by 1,443
Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review
Azmi, A. S., Bao, B., & Sarkar, F. H. (2013) · Cancer and Metastasis Reviews · doi:10.1007/s10555-013-9441-9 · Cited by 1,187
Electrochemical Methods for the Analysis of Clinically Relevant Biomolecules
Labib, M., Sargent, E. H., & Kelley, S. O. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00220 · Cited by 994
(2017) · doi:10.1158/1078-0432.ccr-16-3133 · Cited by 831
“MDM2 amplification is found in about 7% of cancers; it inhibits the p53 tumor suppressor (MDM4 is a homolog of MDM2 that interacts with it and also inhibits p53) (21).”
Background
Metadata
- Authors
- Wade, M., Li, Y.-C., & Wahl, G. M.
- Affiliations
- Center for Genomic Science (IT)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Wahl, Geoffrey M.
- Venue
- Nature Reviews Cancer
- Published
- 2013-01-10
- Volume
- 13
- Issue
- 2
- Pages
- 83-96
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC4161369
- OpenAlex
- W1976295398
- Semantic Scholar
- 934adde696496e55f90e9c60fcd0c09e3d18b3cb
- Cited by
- 1,279
- References
- 174
- Citations by year
- 2026: 76 · 2025: 81 · 2024: 73 · 2023: 83 · 2022: 92 · 2021: 104 · 2020: 109 · 2019: 117 · 2018: 89 · 2017: 98 · 2016: 100 · 2015: 90 · 2014: 118 · 2013: 49
- FWCI
- 12.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Sanofi
- National Institutes of Health
- National Institute of Mental Health (R03MH089489, R03‑MH089489‑01)
- National Cancer Institute (CA014195, R01CA061449, R01‑CA61449, P30CA014195)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2, MDMX, p53, p53 reactivation, MDM2 inhibitors, HDMX, MDM4, carcinogenesis, cancer therapy, signaling networks, tissue homeostasis, anticancer agents
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Humans, Neoplasms, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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