The DOI matches its Crossref record; 174 of the 174 references it cites were found in a registry or an index; none of the 131 sources its claims cite is checked for support yet.
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
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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
“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
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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn 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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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, despite its ability to inhibit p53, MDMX overexpression alone is insufficient for the robust transformation of either human or mouse cells.”
§ MDM2, MDMX and p53 in oncogenesis and cancer therapy > MDM2 and MDMX as oncogenes: the evidence > Cell-based studies
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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
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None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
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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
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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
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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
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“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
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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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).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
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RING Domain E3 Ubiquitin Ligases
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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
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A restricted cell population propagates glioblastoma growth after chemotherapy
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Self-citation
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Cited by
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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
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Electrochemical Methods for the Analysis of Clinically Relevant Biomolecules
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“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).”
BackgroundBouaoun, L., Sonkin, D., Ardin, M., Hollstein, M., Byrnes, G., Zavadil, J., & Olivier, M. (2016) · Human Mutation · doi:10.1002/humu.23035 · Cited by 730
“The melanoma cell-line C32 for example has an MDM4 amplification which is known to result in TP53 inhibition via MDM4-TP53 protein–protein interaction [Wade et al., 2013] and may be the reason for C32 insensitivity to TP53-MDM2 inhibitor(s).”
BackgroundDrugging p53 in cancer: one protein, many targets
Hassin, O., & Oren, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00571-8 · Cited by 771
Pelay‐Gimeno, M., Glas, A., Koch, O., & Grossmann, T. N. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201412070 · Cited by 740
The role of ubiquitination in tumorigenesis and targeted drug discovery
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The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches
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“The tetrameric state of thismutant can be recovered by binding to tetraguanidiniomethylcalix[4]arene (152).”
Self‐assembled DNA nanoclews for the efficient delivery of CRISPR–Cas9 for genome editing
Sun, W., Ji, W., Hall, J. M., Hu, Q., Wang, C., Beisel, C. L., & Gu, Z. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201506030 · Cited by 629
Ubiquitin ligases in oncogenic transformation and cancer therapy
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Molecular basis of USP7 inhibition by selective small-molecule inhibitors.
Turnbull, A. P., Ioannidis, S., Krajewski, W. W., Pinto-Fernandez, A., Heride, C., Martin, A. C. L., Tonkin, L. M., Townsend, E. C., Buker, S. M., Lancia, D. R., et al. (2017) · Nature · doi:10.1038/nature24451 · Cited by 463
“Extended Data Table 1 FT671 FT827 USP enzymes USP1/UAF1 103 101 USP2 101 98 USP4 96 93 USP5 115 92 USP5 (1) 112 104 USP5 (2) 110 92 USP6 96 95 USP7 0 14 USP8 94 90 USP9x 93 95 USP11 107 103 USP14 (3) 99 97 USP15 100 104 USP16 96 89 USP19 99 108 USP20 104 115 USP21 100 110 USP25 97 107 USP28 105 108 USP30 103 112 USP35…”
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The p53 Pathway in Glioblastoma
Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., Saoud, K., et al. (2018) · Cancers · doi:10.3390/cancers10090297 · Cited by 440
“Under normal conditions, p53 activity is low and checked by MDM2 and MDM4 (MDMX) through ubiquitination and degradation [5].”
BackgroundRegulating tumor suppressor genes: post-translational modifications
Chen, L., Liu, S., & Tao, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0196-9 · Cited by 449
“The MDM2 oncoprotein is overexpressed in many types of human cancers and is a critical component of the p53 pathway.(262,263) MDM2 targets p53 for ubiquitination, and for proteasome-mediated degradation, and it maintains an appropriately low level of p53 under unstressed cell conditions.”
BackgroundA targeted mutational landscape of angioimmunoblastic T-cell lymphoma
Odejide, O. O., Weigert, O., Lane, A. A., Toscano, D. T., Lunning, M. A., Kopp, N., Kim, S. S., van Bodegom, D., Bolla, S., Schatz, J. H., et al. (2013) · Blood · doi:10.1182/blood-2013-10-531509 · Cited by 435
Detained introns are a novel, widespread class of post-transcriptionally spliced intronsPreprint
Boutz, P. L., Bhutkar, A. J., & Sharp, P. A. (2015) · Genes & Development · doi:10.1101/gad.247361.114 · Cited by 425
“Mdm4 negatively regulates p53, acting with the related protein Mdm2 as an E3 ubiquitin ligase that induces p53 degradation (for review, see Wade et al. 2013).”
BackgroundThe MDM2-p53 pathway revisited
Nag, S. A., Jiangjiang, Q., Kalkunte, S. S., Ming-hai, W., & Zhang, R. (2013) · Journal of Biomedical Research · doi:10.7555/jbr.27.20130030 · Cited by 438
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TP53 Mutations in Human Cancer: Database Reassessment and Prospects for the Next Decade
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Asymmetric organocatalysis: an enabling technology for medicinal chemistry
Han, B., He, X., Liu, Y., He, G., Peng, C. Y., & Li, J. (2021) · Chemical Society Reviews · doi:10.1039/d0cs00196a · Cited by 409
Post-translational regulation of ubiquitin signaling
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The Role of p53 Signaling in Colorectal Cancer
Liebl, M. C., & Hofmann, T. G. (2021) · Cancers · doi:10.3390/cancers13092125 · Cited by 350
“ATM and CHK2-dependent MDM4 phosphorylation enhances ubiquitination and degradation of MDM4, whereas AKT-dependent MDM4 phosphorylation increases MDM4 stability and thus MDM2 stability [27].”
BackgroundClinical Overview of MDM2/X-Targeted Therapies
Burgess, A., Chia, K. M., Haupt, S., Thomas, D., Haupt, Y., & Lim, E. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00007 · Cited by 315
“Other potential off-target effects on MDM2 inhibitors include the loss of its ability to ubiquitinate other proteins, such as the steroid hormone receptors [estrogen receptor (ER) and androgen receptor (AR)] and Rb, as well as interference with MDM2’s role in DNA repair and modifying chromatin structure (58).”
BackgroundMutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy
Yue, X., Zhao, Y., Xu, Y., Zheng, M., Feng, Z., & Hu, W. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.03.030 · Cited by 308
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Self-citationTumor suppressor p53 and metabolism
Liu, J., Zhang, C., Hu, W., & Feng, Z. (2018) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjy070 · Cited by 313
“To maintain its proper function in tumor suppression, p53 is tightly regulated through different mechanisms in cells, including ubiquitination and degradation of p53 by different E3 ubiquitin ligases such as MDM2 (Vousden and Prives, 2009; Wade et al., 2013; Zhao et al., 2014; Tavana and Gu, 2017; Zhou et al., 2017).”
BackgroundInfluentialTargeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges
Wang, S., Zhao, Y., Aguilar, A., Bernard, D., & Yang, C.-Y. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026245 · Cited by 300
“By controlling expression of a large number of genes, the transcription factor p53 plays a vital role in the regulation of many cellular processes, including cell-cycle progression, apoptosis, senescence, DNA repair, and metabolism, and functions as a powerful tumor suppressor (Vousden and Lu 2002; Toledo and Wahl 200…”
BackgroundThe Roles of MDM2 and MDMX in Cancer
Karni-Schmidt, O., Lokshin, M., & Prives, C. L. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040349 · Cited by 302
Small-Molecule Modulation of Protein Homeostasis
Burslem, G. M., & Crews, C. M. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00077 · Cited by 298
A positive feedback between p53 and miR-34 miRNAs mediates tumor suppressionPreprint
Okada, N., Lin, C., Ribeiro, M. C., Biton, A., Lai, G., He, X., Bu, P., Vogel, H. S., Jablons, D. M., Keller, A., et al. (2014) · Genes & Development · doi:10.1101/gad.233585.113 · Cited by 307
The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle
Shaltiël, I. A., Krenning, L., Bruinsma, W., & Medema, R. H. (2015) · Journal of Cell Science · doi:10.1242/jcs.163766 · Cited by 310
“Mdm2 is the main E3 ubiquitin ligase that targets p53 for proteasomal degradation and inhibits its function as a transcription factor (for a review on Mdm2 and p53, see Wade et al., 2013), whereas Wip1 dephosphorylates both p53 and Mdm2 to promote p53 degradation (Lu et al., 2005; Lu et al., 2007).”
Regulation of the p53 response and its relationship to cancer
Meek, D. W. (2015) · Biochemical Journal · doi:10.1042/bj20150517 · Cited by 311
Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases
Uversky, V. N., Davé, V., Iakoucheva, L. M., Malaney, P., Metallo, S. J., Pathak, R. R., & Joerger, A. C. (2014) · Chemical Reviews · doi:10.1021/cr400713r · Cited by 288
Pouyan, A., Ghorbanlo, M., Eslami, M., Jahanshahi, M., Ziaei, E., Salami, A., Mokhtari, K., Shahpasand, K., Farahani, N., Meybodi, T. E., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02267-0 · Cited by 338
MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodelingPreprint
Venkatesh, D., O'Brien, N. A., Zandkarimi, F., Tong, D. R., Stokes, M. E., Dunn, D., Kengmana, E. S., Aron, A. T., Klein, A. M., Csuka, J. M., et al. (2020) · Genes & Development · doi:10.1101/gad.334219.119 · Cited by 274
“Mouse models (Wade et al. 2013) have shown that the two proteins have functions that can be both independent of, and dependent on, each other, based on context (Bielskienė et al. 2015; Karni-Schmidt et al. 2016).”
BackgroundDual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Carvajal, L. A., Neriah, D. B., Senecal, A., Benard, L., Thiruthuvanathan, V., Yatsenko, T., Narayanagari, S.-R., Wheat, J. C., Todorova, T. I., Mitchell, K., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao3003 · Cited by 249
The nucleolus: an emerging target for cancer therapy
Hein, N., Hannan, K. M., George, A. J., Sanij, E., & Hannan, R. D. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.07.005 · Cited by 259
USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses
Zou, Q., Jin, J., Hu, H., Li, H. S., Romano, S., Xiao, Y., Nakaya, M., Zhou, X., Cheng, X., Yang, P., et al. (2014) · Nature Immunology · doi:10.1038/ni.2885 · Cited by 253
Analysis of TP53 Mutation Status in Human Cancer Cell Lines: A Reassessment
Leroy, B., Girard, L., Hollestelle, A., Minna, J. D., Gazdar, A. F., & Soussi, T. (2014) · Human Mutation · doi:10.1002/humu.22556 · Cited by 224
TP53 loss creates therapeutic vulnerability in colorectal cancer
Liu, Y., Zhang, X., Han, C., Wan, G., Huang, X., Ivan, C., Jiang, D., Rodriguez‐Aguayo, C., Lopez‐Berestein, G., Rao, P. H., et al. (2015) · Nature · doi:10.1038/nature14418 · Cited by 243
p53 as a target for the treatment of cancer
Duffy, M. J., Synnott, N. C., McGowan, P. M., Crown, J. P., O’Connor, D. P., & Gallagher, W. M. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.10.004 · Cited by 239
“Thus, MDM2 is especially overexpressed in specific sarcomas, melanomas and breast cancers, while MDM4 is frequently overexpressed in melanomas, colorectal cancer and breast cancers [16,17].”
BackgroundDual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells
Abraham, S. A., Hopcroft, L. E. M., Carrick, E., Drotar, M. E., Dunn, K., Williamson, A. J. K., Korfi, K., Baquero, P., Park, L. E., Scott, M. T., et al. (2016) · Nature · doi:10.1038/nature18288 · Cited by 225
PI3K/Akt-mediated regulation of p53 in cancer
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Relevance of the p53–MDM2 axis to aging
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Oxidative Stress in Placenta: Health and Diseases
Wu, F., Tian, F., & Lin, Y. (2015) · BioMed Research International · doi:10.1155/2015/293271 · Cited by 214
USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis.
Fan, Y.-H., Cheng, J., Vasudevan, S. A., Dou, J., Zhang, H., Patel, R. H., Ma, I. T., Rojas, Y., Zhao, Y., Yu, Y., et al. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.400 · Cited by 199
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Targeting the ubiquitin–proteasome system for cancer therapy
Shen, M., Schmitt, S. M., Buac, D., & Dou, Q. P. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.815728 · Cited by 204
The genomic landscape of retinoblastoma: a review
Thériault, B. L., Dimaras, H., Gallie, B. L., & Corson, T. W. (2013) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.12132 · Cited by 195
The Long Noncoding RNA MEG3 Contributes to Cisplatin Resistance of Human Lung Adenocarcinoma
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“MDM2 may inhibit the p53 transactivation function by engaging its amino-terminal transactivation domain [32], while the reactivation of p53 is a viable strategy for cancer treatment [33].”
BackgroundRaveendran, R., Braude, J. P., Wexselblatt, E., Novohradský, V., Stuchlíková, O., Brabec, V., Gandin, V., & Gibson, D. (2016) · Chemical Science · doi:10.1039/c5sc04205d · Cited by 183
Ribosomal Proteins RPL37, RPS15 and RPS20 Regulate the Mdm2-p53-MdmX Network
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Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth
Dewaele, M., Tabaglio, T., Willekens, K., Bezzi, M., Teo, S. X., Low, D. H. P., Koh, C. M., Rambow, F., Fiers, M. W. E. J., Rogiers, A., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci82534 · Cited by 182
p53-dependent non-coding RNA networks in chronic lymphocytic leukemia
Blume, C., Hotz‐Wagenblatt, A., Hüllein, J., Sellner, L., Jethwa, A., Stolz, T., Slabicki, M. M., Lee, K.-S., Arandkar, S., Benner, A., et al. (2015) · Leukemia · doi:10.1038/leu.2015.119 · Cited by 177
STAT3 regulated ARF expression suppresses prostate cancer metastasis
Pěnčík, J., Schlederer, M., Gruber, W., Unger, C., Walker, S. M., Chalaris, A., Marié, I. J., Hassler, M. R., Javaheri, T., Aksoy, O., et al. (2015) · Nature Communications · doi:10.1038/ncomms8736 · Cited by 172
E3 ubiquitin ligases in cancer and implications for therapies
Wang, D., Ma, L., Wang, B., Liu, J., & Wei, W. (2017) · Cancer and Metastasis Reviews · doi:10.1007/s10555-017-9703-z · Cited by 174
“Moreover, elevated expression of Mdm2 and MdmX was also detected in many other cancers, such as colorectal cancer, cutaneous melanoma, and breast cancer [71].”
BackgroundThe role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168
Limiting the power of p53 through the ubiquitin proteasome pathwayPreprint
Pant, V., & Lozano, G. (2014) · Genes & Development · doi:10.1101/gad.247452.114 · Cited by 170
Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer
Lim, H.-J., Crowe, P., & Yang, J.-L. (2015) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-014-1803-3 · Cited by 161
“Combination with targeted agents As tumorigenesis has been shown to be a multifaceted process involving a variety of signalling targets, further improvement may be achieved by combining different biological agents (Wade et al. 2013).”
BackgroundRecent advances in chemical protein synthesis: method developments and biological applications
Dong, S., Zheng, J., Li, Y., Wang, H., Chen, G., Chen, Y., Fang, G., Guo, J., He, C., Hu, H., et al. (2024) · Science China Chemistry · doi:10.1007/s11426-024-1950-1 · Cited by 167
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“This impacts p53 subcellular localization and negatively affects transcription-dependent and independent p53-mediated apoptosis.(66,89) Likewise, the constitutively activated NF-kB pathway, which is frequently detected in AML, mediates wtp53 dysfunction by upregulating MDM2-mRNA and protein levels.”
BackgroundInfluentialCaught in the cross fire: p53 in inflammation
Cooks, T., Harris, C. C., & Oren, M. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu134 · Cited by 162
Current developments of targeting the p53 signaling pathway for cancer treatment
Huang, J. L. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107720 · Cited by 157
Saleh, M. N., Patel, M. R., Bauer, T. M., Goel, S., Falchook, G. S., Shapiro, G. I., Chung, K. Y., Infante, J. R., Conry, R. M., Rabinowits, G., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0715 · Cited by 159
“To subvert this antitumor functionality, cancer cells neutralize p53 by deletion, mutation, degradation, or sequestration (2, 3).”
BackgroundRadiation Pneumonitis: Old Problem, New Tricks
Jain, V., & Berman, A. T. (2018) · Cancers · doi:10.3390/cancers10070222 · Cited by 154
“Early expression of TGF-β is seen during the immediate post radiation period and is thought to be a part of a homeostatic mechanism as the tissue attempts to regulate the wound-healing response [2].”
BackgroundRational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions
Wang, X., Ni, D., Liu, Y., & Lu, S. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.682675 · Cited by 162
Targeting MDM2-p53 Interaction for Cancer Therapy: Are We There Yet?
Nag, S. A., Zhang, X., Srivenugopal, K. S., Wang, M.-H., Wang, W., & Zhang, R. (2014) · Current Medicinal Chemistry · doi:10.2174/09298673113206660325 · Cited by 156
The importance of p53 pathway genetics in inherited and somatic cancer genomes
Stracquadanio, G., Wang, X., Wallace, M. D., Grawenda, A. M., Zhang, P., Hewitt, J., Zerón-Medina-Cuairán, J., Castro-Giner, F., Tomlinson, I. P. M., Goding, C. R., et al. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.15 · Cited by 143
“…also suggest that the high frequency inherited genetic variants of these genes should be considered when designing and testing patient stratification strategies, which are currently under development and are aimed at predicting responsiveness to conventional and targeted cancer therapies 29,31 .”
InfluentialTargeting the ubiquitin pathway for cancer treatment
Liu, J., Shaik, S., Dai, X., Wu, Q., Zhou, X., Wang, Z. P., & Wei, W. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.11.005 · Cited by 147
MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future
Wang, W., Albadari, N. G., Du, Y., Fowler, J. F., Sang, H. T., Xian, W., McKeon, F., Li, W., Zhou, J., & Zhang, R. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.123.001026 · Cited by 151
“In preclinical models of GBM, MDM2 inhibitors like Nutlin-3 (Luo et al., 2013) and RG7388 (Berberich et al., 2019) reduced tumor growth and increased radiation sensitivity when used with radiation therapy, especially in tumors resistant to standard chemotherapy.”
BackgroundInfluentialVanharanta, S., Marney, C. B., Shu, W., Valiente, M., Zou, Y., Mele, A., Darnell, R. B., & Massagué, J. (2014) · eLife · doi:10.7554/elife.02734 · Cited by 146
Mészáros, B., Kumar, M., Gibson, T. J., Uyar, B., & Dosztányi, Z. (2017) · Science Signaling · doi:10.1126/scisignal.aak9982 · Cited by 147
“These and several other new classes of small inhibitors targeting the MDM2-p53 binding interface or interferingwith this interaction in otherways are undergoing clinical trials for the treatment of various solid and hematological cancers (340, 341).”
BackgroundPRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers
Li, Y., Chitnis, N., Nakagawa, H., Kita, Y., Natsugoe, S., Yang, Y., Li, Z., Wasik, M., Klein-Szanto, A. J. P., Rustgi, A. K., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0625 · Cited by 143
“The retention of wild-type p53 is generally associated with the loss of key effectors such as p19 ARF (p14 ARF in human cells) or with the overexpression of MDM2 (18, 40-42).”
Self-citationChromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53
Riscal, R., Schrepfer, E., Arena, G., Cissé, M. Y., Bellvert, F., Heuillet, M., Rambow, F., Bonneil, É., Sabourdy, F., Vincent, C., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.04.033 · Cited by 146
“The MDM2 oncoprotein is an essential component of the p53 pathway that is frequently overexpressed in several types of human cancers (Biderman et al., 2012; Wade et al., 2013).”
BackgroundTranslational genomics of nasopharyngeal cancer
Tsang, C. M., Lui, V. W. Y., Bruce, J. P., Pugh, T. J., & Lo, K. W. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.09.006 · Cited by 148
Liu, J., Zhang, C., Zhao, Y., & Feng, Z. (2016) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25609 · Cited by 143
“In addition to MDM2, MDM4 (MDMX) has been identified as a protein sharing structural homology with MDM2 [Wade et al., 2013].”
InfluentialTP53 in bone and soft tissue sarcomas
Thoenen, E. A., Curl, A., & Iwakuma, T. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.06.010 · Cited by 140
Inhibition of p53 inhibitors: progress, challenges and perspectives
Sanz, G., Singh, M., Peuget, S., & Selivanova, G. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz075 · Cited by 140
“This makes them inefficient in tumors with deregulated MDMX (Wade et al., 2013).”
BackgroundE3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis
Liu, J., Zhang, C., Wang, X. L., Ly, P., Белый, В. А., Xu-Monette, Z. Y., Young, K. H., Hu, W., & Feng, Z. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.121 · Cited by 139
Dörsam, B., & Fahrer, J. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.11.019 · Cited by 134
Identification of Druggable Cancer Driver Genes Amplified across TCGA Datasets
Chen, Y., McGee, J., Chen, X., Doman, T. N., Gong, X., Zhang, Y., Hamm, N., Ma, X., Higgs, R. E., Bhagwat, S. V., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098293 · Cited by 138
The roles and regulation of MDM2 and MDMX: it is not just about p53Preprint
Klein, A. M., de Queiroz, R. M., Venkatesh, D., & Prives, C. L. (2021) · Genes & Development · doi:10.1101/gad.347872.120 · Cited by 138
Self‐Assembled DNA Nanoclews for the Efficient Delivery of CRISPR–Cas9 for Genome Editing
Sun, W., Ji, W., Hall, J. M., Hu, Q., Wang, C., Beisel, C. L., & Gu, Z. (2015) · Angewandte Chemie · doi:10.1002/ange.201506030 · Cited by 132
Tumor suppressor p53 and its gain-of-function mutants in cancer
Liu, J., Zhang, C., & Feng, Z. (2013) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmt144 · Cited by 133
Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review)
Khabibov, M., Гарифуллин, А., Boumber, Y., Khaddour, K., Fernandez, M., Khamitov, F., Халикова, Л. В., Kuznetsova, N. S., Kit, O. I., & Kharin, L. V. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5359 · Cited by 142
USP7: Novel Drug Target in Cancer Therapy
Wang, Z., Kang, W.-T., You, Y., Pang, J., Ren, H., Suo, Z., Liu, H., & Zheng, Y. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00427 · Cited by 131
Dissenting degradation: Deubiquitinases in cell cycle and cancer
Bonacci, T., & Emanuele, M. J. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.03.008 · Cited by 128
Zhou, C., Yang, F., Yuan, S., Ma, J., Liu, F., Yuan, J., Bi, F., Lin, K., Yin, J., Cao, G., et al. (2015) · Hepatology · doi:10.1002/hep.28393 · Cited by 122
“Inactivation of p53 is the most common event found in human cancer.((27,33)) Our results indicated that down-regulated lncRNA-PRAL may be the important factor to inactivate p53 in p53-wild HCC patients.”
BackgroundZeng, A.-L., Yan, W., Liu, Y.-W., Wang, Z., Hu, Q., Nie, E., Xin Min, Z. H. O. U., Li, R., Wang, X.-F., Jiang, T., et al. (2017) · Oncogene · doi:10.1038/onc.2017.134 · Cited by 125
Pal, S., Bhattacharjee, A., Ali, A., Mandal, N. C., Mandal, S. C., & Pal, M. (2014) · Journal of Inflammation · doi:10.1186/1476-9255-11-23 · Cited by 119
Long, J., Lin, J., Wang, A., Wu, L., Zheng, Y., Yang, X., Wan, X., Xu, H., Chen, S., & Zhao, H. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0511-2 · Cited by 115
“Hyperprogression may result from the ability of MDM2 amplification to inhibit the p53 tumor suppressor [111].”
BackgroundThe role of TP53 in acute myeloid leukemia: Challenges and opportunities
Barbosa, K., Li, S., Adams, P. D., & Deshpande, A. J. (2019) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22796 · Cited by 118
“Indeed, several smallmolecules directed at the TP53 binding pocket of MDM2 have been developed to disrupt their biochemical interaction.(117,120,124-128) This blockage leads to cell cycle arrest, apoptosis, and growth inhibition in cancer cells.”
BackgroundPPARγ neddylation essential for adipogenesis is a potential target for treating obesity
Park, H.-S., Ju, U.-I., Park, J.-W., Song, J. Y., Shin, D. H., Lee, K.-H., Jeong, L. S., Yu, J., Lee, H. W., Cho, J., et al. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.6 · Cited by 116
TRIM67 Activates p53 to Suppress Colorectal Cancer Initiation and Progression
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Wienken, M., Dickmanns, A., Nemajerová, A., Kramer, D., Najafova, Z., Weiss, M., Karpiuk, O., Kassem, M. S., Zhang, Y., Lozano, G., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.12.008 · Cited by 116
“MDM2 undergoes specific modifications in response to replicative stress and DNA damage (Wade et al., 2013), and it associates with damage response factors such as the MRN complex (Bouska and Eischen, 2009).”
BackgroundMitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53
Arena, G., Cissé, M. Y., Pyrdziak, S., Châtre, L., Riscal, R., Fuentes, M., Arnold, J. J., Kastner, M., Gayte, L., Bertrand‐Gaday, C., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.01.023 · Cited by 109
“Somatic mutations in TP53 occur in about 50% of human tumors, and many cancers retaining wild-type TP53 display functional inactivation of the p53 pathway by viral oncoproteins or alterations of p53 regulators, including the Mouse Double Minute 2 (MDM2) oncogene (Wade et al., 2013).”
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
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