The Mdm network and its regulation of p53 activities: a rheostat of cancer risk
Open accessAbstract
The potent transcriptional activity of p53 (Trp53, TP53) must be kept in check for normal cell growth and survival. Tumors, which drastically deviate from these parameters, have evolved multiple mechanisms to inactivate TP53, the most prevalent of which is the emergence of TP53 missense mutations, some of which have gain-of-function activities. Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2, and MDM4. Studies in humans and in mice reveal the complexity of TP53 regulation and the exquisite sensitivity of this pathway to small changes in regulation. Here, we summarize the factors that impinge on TP53 activity and thus cell death/arrest or tumor development.
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TL;DR
This review argues that p53 activity is controlled by the Mdm2/Mdm4 network as a rheostat, where even small changes in inhibitor levels or p53 dosage alter cancer risk. It synthesizes mouse and human data showing frequent MDM2/MDM4 overexpression, TP53 mutation/gain-of-function, and p53-independent Mdm functions.
Key findings
- TP53 missense mutations account for approximately 75% of all TP53 mutations in cancer (and approximately 80% in a later section); they can cause loss of tumor suppression and gain-of-function, with Li-Fraumeni syndrome patients carrying missense mutations showing higher cancer incidence and earlier tumor onset than those with truncating or splicing mutations. Deletion or mutation of TP53 accounts for approximately 50% of alterations in the pathway, while MDM2/MDM4 overexpression is the best example of other mechanisms.
- MDM4 is amplified in 65% of human retinoblastoma and approximately 65% of melanomas; MDM2 amplification occurs in about 30% of osteosarcomas. TCGA analyses showed MDM4 amplification in 6.6% (24/363) of uterine carcinomas with lower survival, while MDM2 amplification was rare there (0.28%; 1/363); in glioblastoma, MDM2 amplification was 10.7% (22/206) with reduced survival, and MDM4 amplification was 4.4% (9/206) with a non-significant trend toward lower survival.
- Mdm2/Mdm4 dosage is critical: 2-fold changes affect tumor phenotypes; mice with a hypomorphic and null Mdm2 allele expressing about 30% of wild-type Mdm2 levels have increased p53 activity and are small, lymphopenic, and radiosensitive. Heterozygosity of both Mdm2 and Mdm4 is lethal, with 30% of mice dying in utero and the rest from hematopoietic failure within 21 days after birth, rescued by deletion of a single p53 allele; as little as a 7% difference in p53 protein levels alters survival.
- Mdm2 and Mdm4 have p53-independent functions: Mdm2 binds Nbs1 of the MRN DNA repair complex and delays DNA break repair independent of p53 and its E3 ubiquitin ligase activity, and similar data exist for Mdm4. MDM2 SNP309G creates a better SP1 binding site, elevates MDM2, and contributes to earlier tumor onset in Li-Fraumeni syndrome; SNP285C reduces SP1 binding, lowers MDM2, and is associated with reduced breast and ovarian cancer risk.
Methods
- Narrative review of human and mouse literature on p53 regulation by Mdm2, Mdm4, ARF, Hausp/USP7, and related modifiers.
- Includes analyses of TCGA/cBioPortal data for ARF and TP53 co-inactivation, USP7 amplification, and MDM2/MDM4 amplification with survival outcomes.
- No systematic search strategy or primary experimental methods are stated.
Limitations
- Stated: technical issues with MDM2 antibodies and post-translational modifications likely cause the frequency of elevated MDM2 protein in human cancers to be significantly underestimated, and what constitutes MDM2 overexpression needs reevaluation.
- Stated: many questions remain, including the need to accurately measure both MDM2 and MDM4 levels and ratios in human malignancies; the glioblastoma MDM4 survival trend did not reach statistical significance because of low case numbers.
- Evident: as a narrative review, it lacks a systematic search or meta-analysis, and its conclusions rely on cited mouse models and descriptive TCGA analyses.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 128 cited sources checked · 0 supported · 0 flagged
- Findingcitation
In TCGA data, squamous cell carcinoma of the lung or head and neck co-inactivated ARF and TP53 in about 20% of tumors.
“For example, we evaluated ARF and TP53 status in the data from The Cancer Genome Atlas (TCGA) and determined that malignancies such as squamous cell carcinoma of the lung or head and neck co-inactivate ARF and TP53 in approximately 20% of these tumors (Table 1; (Cerami, et al., 2012; Gao, et al., 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingcitation
In the authors' TCGA evaluation, USP7 was rarely amplified in human cancer.
“Our evaluation of TCGA data revealed that USP7 is rarely amplified in human cancer (Cerami, et al., 2012; Gao, et al., 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data
In the authors' TCGA analysis, up to 6% of specific human malignancies had amplified MDM2 or MDM4 together with TP53 mutations.
“Our analysis of TCGA data showed that up to 6% of specific human malignancies have amplified MDM2 or MDM4 (and even more have increased MDM2 or MDM4 mRNA expression) with concomitant TP53 mutations”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingcitation
The authors generated similar data for Mdm4, showing that Mdm4 also regulates DNA break repair.
“We have also generated similar data for Mdm4 (Carrillo, et al., 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Carrillo, et al., 2013
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- Premisecitation
A second way tumors bypass TP53 function is by raising the levels of the TP53 inhibitors MDM2 and MDM4.
“Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2 and MDM4.”
Quote in the paperSubstantial claim0 of 2 sources checked
- Premisecitation
p53 is a central transcriptional regulator that activates genes involved in cell cycle arrest, senescence, apoptosis, metabolism, differentiation, and survival.
“p53 is a key transcriptional regulator that controls multiple signals by activating genes with roles in cell cycle arrest, senescence, apoptosis, metabolism, differentiation, and survival (Vousden and Prives, 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vousden and Prives, 2009 source
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- Premisecitation
Loss of Arf or overexpression of Mdm2 significantly reduced the selection for p53 mutations that normally occurs during Myc-induced B cell lymphomagenesis.
“Moreover, loss of Arf or overexpression of Mdm2 significantly reduced the selection for p53 mutations that normally arise during Myc-induced B cell lymphomagenesis (Eischen, et al., 1999; Wang, et al., 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
About 40% of pancreatic ductal adenocarcinomas have both mutated TP53 and deleted ARF.
“For example, approximately 40% of pancreatic ductal adenocarcinomas have mutated TP53 and deleted ARF (Heinmoller, et al., 2000; Hustinx, et al., 2005; Maitra, et al., 2003).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Changing any of five arginine residues that are TP53 mutation hotspots in human cancers abolishes TP53 sequence-specific DNA binding.
“Modification of any of five arginine residues that are hotspots for TP53 mutations in human cancers disables TP53 sequence-specific DNA binding (Cho, et al., 1994).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cho, et al., 1994 source
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- Premisecitation
Cells expressing the most common TP53 mutants show greater metastatic potential and invasiveness than cells lacking TP53.
“Cells expressing the most common TP53 mutants, in contrast to cells lacking TP53, show increased metastatic potential and invasiveness (Crook and Vousden, 1992; Hsiao, et al., 1994).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Crook and Vousden, 1992
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- cites Hsiao, et al., 1994
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- Interpretationreasoning
MDM4 has an important role in tumorigenesis.
“These data confirm an important role of MDM4 in tumorigenesis.”
Quote in the paperSubstantial claim - Premisecitation
Mice heterozygous for mutant p53 develop many metastatic tumors that are uncommon in mice lacking p53.
“Mutant p53-heterozygous mice develop many metastatic tumors that are rare in mice lacking p53 (Lang, et al., 2004; Olive, et al., 2004).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Deleting Arf or overexpressing Mdm2 accelerated Myc-driven B cell lymphoma at a rate similar to that caused by Myc overexpression plus p53 deficiency.
“Specifically, deletion of Arf or overexpression of Mdm2 accelerated Myc (MIM#190080) oncogene-induced B cell lymphoma development at a rate similar to that caused by Myc overexpression and p53 deficiency.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
In vitro and in vivo evidence supports a gain-of-function phenotype for mutant p53 in tumorigenesis.
“These in vitro and in vivo data support the gain-of-function phenotype of mutant p53 in tumorigenesis.”
Quote in the paperSubstantial claim - Premisecitation
Mdm4 negatively regulates p53 tumor suppressor function by binding and masking the amino terminal transcriptional activation domain of p53.
“The Mdm2-interacting protein Mdm4 (also known as MdmX) also negatively regulates the tumor suppressor function of p53 by binding and masking the amino terminal transcriptional activation domain of p53 (Shvarts, et al., 1996).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shvarts, et al., 1996 source
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- Premisecitation
Mice lacking Mdm4 have embryonic lethal phenotypes that are completely rescued by p53 deletion.
“Mice lacking Mdm4 exhibit embryonic lethal phenotypes that are also completely rescued by p53 deletion (Finch, et al., 2002; Migliorini, et al., 2002; Parant, et al., 2001).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
ARF binding to Mdm2 permits p53 activation and induction of apoptosis, cell cycle arrest, or senescence.
“This allows p53 activation and induction of apoptosis, cell cycle arrest, or senescence.”
Quote in the paperSubstantial claim - Interpretationreasoning
Cells expressing mutant p53 appear to have a survival or growth advantage over cells lacking p53.
“Thus, cells expressing mutant p53 appear to have a survival and/or growth advantage over cells lacking p53.”
Quote in the paperSubstantial claim - Premisecitation
In Li-Fraumeni syndrome, people with TP53 missense mutations have higher cancer incidence and earlier tumor onset than people with truncating or splicing mutations.
“In Li-Fraumeni syndrome (LFS), individuals with TP53 missense mutations show a higher cancer incidence and an earlier age of tumor onset than individuals with truncating or splicing mutations (Birch, et al., 1998).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Birch, et al., 1998 source
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- Premisecitation
TP53 missense mutations are more common than frameshift and nonsense mutations in cancer cells.
“TP53 missense mutations clearly predominate over frameshift and nonsense mutations in cancer cells (Olivier, et al., 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Olivier, et al., 2002 source
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- Premisecitation
The MDM4 gene is amplified in 65% of human retinoblastoma.
“Recent data indicate the MDM4 gene is amplified in 65% of human retinoblastoma, a tumor of the eye that often results from inherited mutations in the RB1 gene (MIM#614041) (Laurie, et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Laurie, et al., 2006 source
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- Premisecitation
MDM4 is overexpressed in many human cancers.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
ARF directly binds Mdm2 and holds it away from p53 in the nucleolus or nucleus.
“Oncogenic activity transcriptionally up regulates and post-translationally stabilizes ARF, which directly binds Mdm2 and holds Mdm2 away from p53 either in the nucleolus or the nucleus (Figure 1) (Chen, et al., 2010; Eischen, et al., 1999; Llanos, et al., 2001; Weber, et al., 1999; Zhang, et al., 1998; Zindy, et al., 1998).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Loss of Hausp by homologous recombination in human cell lines with wild-type p53 is incompatible with proliferation.
“Hausp loss by homologous recombination in human cell lines expressing wild-type p53 is incompatible with proliferation (Cummins, et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cummins, et al., 2004 source
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- Premisecitation
Cells from mice lacking both Mdm4 and p53 have increased genome instability.
“cells from these mice have increased genome instability”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Matijasevic, et al., 2008a
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- cites Matijasevic, et al., 2008b
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- Interpretationcitation
Mdm2 and Mdm4 have p53-independent functions that contribute to tumorigenesis.
“data generated over the past 20 years that indicate Mdm2 and Mdm4 have p53-independent functions that contribute to tumorigenesis (Melo and Eischen, 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Melo and Eischen, 2012 source
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- Interpretationcitation
Multiple independent studies have shown that Mdm2 can promote tumorigenesis independently of p53.
“Multiple independent investigations have shown that Mdm2 can contribute to tumorigenesis independent of p53.”
Quote in the paperSubstantial claim - Premisecitation
Higher Mdm2 levels are incompatible with life in vivo and in vitro, except in some cases when p53 is also inactivated.
“higher levels are incompatible with life in vivo and in vitro, except in some cases when p53 is also inactivated”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Only a small fraction of analyzed tumors, 0.84% (18 of 2148), carried p21 deletions or mutations.
“0.84% (18 of 2148) tumors analyzed had p21 deletions or mutations (Cerami, et al., 2012; Gao, et al., 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
A conditional loss-of-function Hausp allele in mice causes p53-dependent cell death in the developing neural system.
“The development of a conditional loss-of-function allele of Hausp in mice also leads to cell death in a p53-dependent manner in the developing neural system of the mouse (Kon, et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kon, et al., 2011 source
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- Interpretationcitation
Different cancer types alter the p53 pathway through distinct mechanisms.
“It is important to note that different cancers alter the p53 pathway by different mechanisms.”
Quote in the paperNot a substantial claim - Premisecitation
Some tumor cells contain both inactivated TP53 and overexpressed MDM2 and/or MDM4.
“some tumor cells contain both inactivated TP53 and overexpressed MDM2 and/or MDM4”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Gamma radiation or Myc overexpression causes cell death when cells are haploinsufficient for Mdm2.
“Consequently, gamma radiation or overexpression of the Myc oncogene leads to cell death when cells are haploinsufficient for Mdm2 (Alt, et al., 2003; O’Leary, et al., 2004; Terzian, et al., 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Deleting Arf together with Mdm2 overexpression accelerates tumorigenesis.
“deletion of Arf concurrently with Mdm2 overexpression accelerates tumorigenesis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Moore, et al., 2003 source
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- Interpretationreasoning
Mdm2 and Mdm4 have p53-independent functions in cancer that should be considered when targeting these proteins.
“Together, these data indicate that there are p53-independent functions of Mdm2 and Mdm4 in cancer that need to be considered when targeting these proteins.”
Quote in the paperSubstantial claim - Premisecitation
Mice lacking both Mdm4 and p53 develop tumors at an accelerated rate.
“Mice that lack both Mdm4 and p53 have an accelerated rate of tumor development”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Matijasevic, et al., 2008a
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- cites Matijasevic, et al., 2008b
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- Premisecitation
Mdm4 heterozygous mice with Mdm4 haploinsufficiency have increased sensitivity to gamma radiation.
“Similar results have been observed for Mdm4 heterozygous mice with Mdm4 haploinsufficiency resulting in increased sensitivity to gamma radiation (Terzian, et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Terzian, et al., 2007 source
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- Premisecitation
Tumors that overexpress MDM2 and/or MDM4 have reduced TP53 activity.
“tumors that overexpress MDM2 and/or MDM4 have less TP53 activity”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cordon-Cardo, et al., 1994
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- Premisecitation
Hausp also deubiquitinates Mdm4, another inhibitor of p53 activity.
“More recent data suggest that Hausp also deubiquitinates Mdm4, another inhibitor of p53 activity (Meulmeester, et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Meulmeester, et al., 2005 source
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- Premisecitation
Mdm2 overexpression leads to genome instability in vivo and in vitro regardless of p53 status.
“Mdm2 overexpression regardless of p53 status leads to genome instability in vivo and in vitro”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Small changes in Mdm2 and Mdm4 levels contribute significantly to developmental and tumor phenotypes.
“Small changes in the levels of Mdm2 and Mdm4 also significantly contribute to developmental and tumor phenotypes.”
Quote in the paperSubstantial claim - Premisecitation
Deleting Arf in a p53-null background does not change the rate of tumor development.
“deletion of Arf in a p53-null background does not alter the rate of tumor development”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Moore, et al., 2003 source
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- Premisecitation
About 30% of osteosarcomas have MDM2 amplification.
“30% of osteosarcomas have MDM2 amplification”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Oliner, et al., 1992 source
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- Premisecitation
Mdm2 overexpression in p53-null mice changes the tumor spectrum relative to p53-null mice.
“Mdm2 overexpression in p53-null mice results in an altered tumor spectrum compared to the tumor spectrum in p53-null mice”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jones, et al., 1998 source
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- Premisecitation
Normal cells tolerate small increases in Mdm2 levels.
“Small increases in Mdm2 levels in normal cells are tolerated”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Heterozygosity of both Mdm2 and Mdm4 causes lethality, with 30% of mice dying in utero and the rest dying of hematopoietic failure within 21 days after birth.
“Notably, heterozygosity of both Mdm2 and Mdm4 results in lethality, with 30% of mice dying in utero and the rest of hematopoietic failure within 21 days after birth.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Terzian, et al., 2007 source
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- Premisecitation
About 65% of retinoblastomas have MDM4 amplification.
“65% of retinoblastomas have MDM4 amplification”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Laurie, et al., 2006 source
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- Premisecitation
About half of lung tumors carry TP53 mutations.
“50% of lung tumors have TP53 mutations”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Cells lacking p53 and overexpressing Mdm2 show increased anchorage-independent growth compared with cells lacking p53 alone.
“There is increased anchorage-independent growth in cells lacking p53 and overexpressing Mdm2 compared to cells that only lack p53”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dubs-Poterszman, et al., 1995
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- Premisecitation
These chromosome abnormalities are also found in cells that overexpress Mdm2 and lack p53.
“these abnormalities have also been detected in cells overexpressing Mdm2 and lacking p53”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
Regulation of DNA break repair is a conserved function among Mdm family proteins.
“indicating the regulation of DNA break repair is a conserved function for the members of the Mdm family of proteins”
Quote in the paperSubstantial claim - Premisecitation
Mdm2 transgenic mice show increased polyploidy in mammary epithelial cells with or without p53.
“there was increased polyploidy in mammary epithelial cells in Mdm2 transgenic mice with or without p53”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lundgren, et al., 1997 source
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- Interpretationreasoning
Deregulation of Mdm2 and Mdm4 functions most likely contributes to tumor development in multiple ways.
“whose deregulation most likely contribute to tumor development in multiple ways”
Quote in the paperSubstantial claim - Premisecitation
Elevated Mdm2 levels increase chromatid and chromosome breaks and fusions.
“Elevated levels of Mdm2 result in increased chromatid and chromosome breaks as well as fusions”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationnone given
MDM2 and MDM4 are frequently selected for overexpression in human malignancies as a way to inactivate TP53.
“that are frequently selected for overexpression in human malignancies as a mechanism of inactivating TP53”
Quote in the paperSubstantial claim - Premisecitation
Mdm2 binding to Nbs1, rather than to p53, is required for Mdm2 to delay DNA break repair.
“Binding between Mdm2 and Nbs1, but not between Mdm2 and p53, was required for Mdm2 to delay DNA break repair.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Mdm2 inhibits the early DNA damage signal that phosphorylates multiple targets and marks broken DNA for repair.
“multiple lines of evidence indicate that Mdm2 inhibits the early DNA damage signal that results in phosphorylation of multiple protein targets and marks broken DNA for repair”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
These acquired compensatory TP53 mutations make the malignancy harder to treat.
“that make the malignancy more difficult to treat”
Quote in the paperSubstantial claim - Premisecitation
These drugs do lead to TP53 activation.
“Although these drugs do lead to TP53 activation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li and Lozano, 2013
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- Premisecitation
High Mdm2 levels cause genome instability even when p53 is absent.
“High levels of Mdm2 result in genome instability, and this occurs even in the absence of p53.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lundgren, et al., 1997 source
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- Premisecitation
Normal physiological levels of Mdm2 regulate Nbs1-mediated DNA break repair.
“normal physiological levels of Mdm2 were shown to regulate Nbs1-mediated DNA break repair”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bouska, et al., 2008 source
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- Interpretationreasoning
The p53 pathway is often altered during tumor development by various mechanisms.
“is thus, often altered in tumor development by various mechanisms described here”
Quote in the paperSubstantial claim - Interpretationnone given
MDM2 and MDM4 are critical inhibitors of TP53.
“MDM2 and MDM4 are critical inhibitors of TP53”
Quote in the paperSubstantial claim - Premisenone given
MDM2 also regulates the stability of mutant TP53.
“MDM2 also regulates mutant TP53 stability”
Quote in the paperSubstantial claim - Premisecitation
Mdm2 directly binds Nbs1 in the Mre11-Rad50-Nbs1 DNA repair complex.
“Mdm2 directly binds to Nbs1 (MIM#602667) of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Alt, et al., 2005 source
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- Interpretationreasoning
MDM2 and MDM4 overexpression in human malignancies also likely exploits their TP53-independent functions.
“and also likely capitalizing on TP53-independent functions”
Quote in the paperSubstantial claim - Premisecitation
Many drugs have been designed to activate TP53 by disrupting MDM2 and/or MDM4 binding.
“numerous drugs have been designed to activate TP53 by interfering with MDM2 and/or MDM4 binding (Li and Lozano, 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li and Lozano, 2013
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- Rests on an assumption: Tumors with high levels of MDM2 and MDM4 often have wild-type TP53.
- Interpretationreasoning
When Mdm2 or Mdm4 is high in tumors, inhibiting both p53 and Nbs1-mediated DNA break repair would increase genome instability.
“Therefore, when Mdm2 or Mdm4 is high in tumors, inhibition of both p53 and Nbs1-mediated DNA break repair would lead to increased genome instability.”
Quote in the paperSubstantial claim
- The quote only partly states this claim. 1
- May combine two claims. 26
- Classified as probably not a substantial claim. 1
The quote only partly states this claim.
Findingown dataMore than 6% of specific human malignancies had increased MDM2 or MDM4 mRNA expression together with TP53 mutations.
“even more have increased MDM2 or MDM4 mRNA expression”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
FindingcitationIn TCGA data, 5.3% of breast adenocarcinomas had amplified USP7, and 75% of those tumors retained wild-type TP53 allele status.
“However, 5.3% (40 of 760) of breast adenocarcinomas contained amplified USP7 and of those, 75% maintained wild-type TP53 allele status, which implies that USP7 may have other functions related to oncogenesis.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMdm2 and Mdm4 can reduce p53 activity and permit cells to survive and proliferate.
“Cellular proteins such as Mdm2 (MIM#164785) and Mdm4 (MIM#602704) can dampen p53 activity and allow the cell to live and propagate.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAbout 75% of TP53 mutations in cancer are missense mutations.
“In particular, missense mutations account for approximately 75% of all TP53 mutations in cancer (Hamroun, et al., 2006; Olivier, et al., 2010)”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTumors use several routes to disable TP53, and the most frequent route is missense mutation of TP53, with some mutants acquiring gain-of-function activities.
“Tumors, which drastically deviate from these parameters, have evolved multiple mechanisms to inactivate TP53, the most prevalent of which is the emergence of TP53 missense mutations, some of which have gain-of function activities.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTP53 deletion or mutation accounts for about half of TP53 pathway alterations, while other changes also disrupt the pathway.
“Although deletion or mutation of TP53 itself accounts for approximately 50% of the alterations in TP53, other modifications also derail the p53 pathway (Figure 1) (Vogelstein, et al., 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vogelstein, et al., 2000 source
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PremisecitationMelanoma rarely has TP53 mutations, but about 65% of melanomas have high MDM4 levels.
“Melanoma is another tumor in which TP53 is rarely mutated, but approximately 65% of these tumors also have high levels of MDM4 (Gembarska, et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gembarska, et al., 2012 source
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PremisecitationMissense mutations are frequent because they both remove TP53 tumor-suppressive functions and confer new gain-of-function activities.
“Thus, besides eliminating wild type TP53 transcriptional activity, another reason missense mutations are common is that these mutations lead not only to the loss of TP53 tumor suppressive functions but also to the acquisition of other activities known as gain of function (GOF) (Sigal and Rotter, 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sigal and Rotter, 2000
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May combine two claims.
PremisecitationMDM2 is highly expressed in many human tumors, and most of those tumors retain wild-type TP53.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMdm2 and Mdm4 interact through their RING domains, and this interaction is required for p53 inhibition.
“Mdm2 and Mdm4 also interact with each other through their respective RING domains, and this interaction is essential for inhibition of p53 (Figure 1).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationLoss of Mdm2 causes apoptosis and embryonic lethality at the blastocyst stage, and this phenotype is fully rescued by deleting p53 at the same time.
“Loss of Mdm2 leads to cell death by apoptosis and embryonic lethality at the blastocyst stage, and this phenotype is completely rescued by concomitant deletion of p53 (Chavez-Reyes, et al., 2003; Jones, et al., 1995; Montes de Oca Luna, et al., 1995).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningMdm4 is a key cofactor of Mdm2, and the Mdm2-Mdm4 complex is the most efficient inhibitor of p53 activity.
“These data indicate that Mdm4 is a key cofactor of Mdm2 and that the Mdm2-Mdm4 complex is the most efficient inhibitor of p53 activity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSome tumors in mice and humans contain mutant p53 and overexpress Mdm2, which suggests Mdm2 may have p53-independent functions.
“In addition, some tumors in mice and humans contain mutant p53 and overexpress Mdm2, indicating that Mdm2 may have functions independent of p53 (Alt, et al., 2003; Cordon-Cardo, et al., 1994; Eischen, et al., 1999; Lu, et al., 2002; Peng, et al., 2001; Sigalas, et al., 1996).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationARF is inactivated in human cancers mainly by deletion of the entire INK4A locus or by promoter methylation, and ARF is rarely mutated.
“The ARF promoter can also be methylated in malignancies, which prevents ARF expression, but ARF is rarely mutated in human cancers (Esteller, et al., 2000; Kim and Sharpless, 2006).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Esteller, et al., 2000
Not checked in the free run.
- cites Kim and Sharpless, 2006 source
Not checked in the free run.
May combine two claims.
InterpretationcitationARF has an essential role in preventing tumor development through Mdm2 regulation, but this function appears unnecessary in most tissues during development.
“Therefore, ARF has an essential role in preventing tumor development through regulation of Mdm2, but this function appears unnecessary in most tissues during development.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMouse studies show that Arf does not regulate Mdm2, and therefore p53, in proliferating tissues during development and homeostasis, except in germ cells.
“Studies in mice show that Arf does not regulate Mdm2 (and consequently p53) in proliferating tissues during development and under homeostatic conditions except germ cells (Li, et al., 2013; O’Leary, et al., 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Li, et al., 2013
Not checked in the free run.
- cites O’Leary, et al., 2004
Not checked in the free run.
May combine two claims.
PremisecitationMdm2 is an E3 ubiquitin ligase that ubiquitylates p53 and targets it for degradation.
“Mdm2 is an E3 ubiquitin ligase that ubiquitylates and targets p53 for degradation (Haupt, et al., 1997; Honda, et al., 1997; Kubbutat, et al., 1997).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMany tumors in mice and humans inactivate either p53 or ARF, which has led to the conclusion that the two proteins have an epistatic relationship.
“Many tumors in mice and humans inactivate either p53 or ARF, leading to the conclusion that these two proteins have an epistatic relationship (Sherr, 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sherr, 2006 source
Not checked in the free run.
May combine two claims.
PremisecitationUnder stress such as oncogene activation, loss of Arf leaves Mdm2 deregulated and prevents effective p53 activation.
“However, under stressful conditions, such as when oncogenes are activated, loss of Arf results in deregulated Mdm2 and the inability of a cell to effectively activate p53 (Eischen, et al., 1999; Schmitt, et al., 1999; Zindy, et al., 1998).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationHausp deubiquitinates Mdm2, allowing Mdm2 to keep p53 levels low.
“Hausp deubiquitinates Mdm2, which allows Mdm2 to functionally keep p53 levels low.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Cummins, et al., 2004 source
Not checked in the free run.
- cites Li, et al., 2004
Not checked in the free run.
May combine two claims.
PremisecitationAlthough heterozygosity for Mdm2 or Mdm4 is sufficient for homeostasis, p53 activity cannot be effectively regulated by these proteins under stress.
“Although Mdm2 or Mdm4 heterozygosity is sufficient for homeostasis, p53 activity cannot be effectively regulated by these proteins under conditions of stress.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMice with one hypomorphic and one null Mdm2 allele express about 30% of wild-type Mdm2, have increased p53 activity, and are small, lymphopenic, and radiosensitive.
“Moreover, mice carrying a hypomorphic and a null allele of Mdm2, which express about 30% of wild-type Mdm2 levels, have increased p53 activity and are small, lymphopenic, and radiosensitive (Mendrysa, et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mendrysa, et al., 2003 source
Not checked in the free run.
May combine two claims.
InterpretationcitationThe physiological consequence of Hausp loss is destabilization of Mdm2, which increases p53 levels and activity.
“Thus, the physiological consequence of Hausp loss is destabilization of Mdm2, which leads to increased p53 levels and activity (Cummins, et al., 2004; Li, et al., 2004).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Cummins, et al., 2004 source
Not checked in the free run.
- cites Li, et al., 2004
Not checked in the free run.
May combine two claims.
InterpretationreasoningThese drugs would stabilize mutant TP53, with adverse consequences.
“these drugs would then stabilize mutant TP53, with adverse consequences”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenThe p53 pathway is central to blocking proliferation and mediating apoptosis.
“The p53 pathway is central in blocking proliferation and mediating apoptosis”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThis Mdm2 function is not aberrant and is not merely a consequence of Mdm2 overexpression in cancer.
“which indicates that this function of Mdm2 is not aberrant and not a consequence of its overexpression in cancer”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe Mdm2-induced delay in DNA break repair increases genome instability and does not require Mdm2 E3 ubiquitin ligase activity.
“This delay in DNA break repair resulted in increased genome instability and did not require the E3 ubiquitin ligase activity of Mdm2”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationCancers can develop resistance to drugs that destroy them and can acquire compensatory TP53 mutations.
“cancers have a unique ability to develop resistance to drugs that cause their destruction and subsequently acquired compensatory TP53 mutations (Aziz, et al., 2011; Michaelis, et al., 2011)”
Quote in the paperSubstantial claim0 of 2 sources checked
The paper relies on this without support.
p53 transcriptional activity must be restrained for normal cell growth and survival.
“The potent transcriptional activity of p53 (TP53) must be kept in check for normal cell growth and survival.”
The paper relies on this without support.
Cellular distress signals activate p53, and cells respond by ceasing proliferation, senescing, differentiating, or dying.
“Cellular distress signals activate p53 (MIM#191170), and cells respond to this activation by ceasing proliferation, senescing, differentiating, or dying.”
The paper relies on this without support.
The relationship between p53 and its inhibitors is dynamic and is usurped by tumor cells.
“The relationship between p53 and its inhibitors is dynamic and is usurped by tumor cells.”
The paper relies on this without support.
Tumors with high levels of MDM2 and MDM4 often have wild-type TP53.
“Because tumors with high levels of MDM2 and MDM4 often have wild-type TP53”
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?
Roughly half of all human cancers have mutated or deleted p53, and some cancer types have even higher p53 mutation rates.
“Consequently, p53 is mutated or deleted in approximately half of all of human cancers, with some malignancies having higher p53 mutation rates (1).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [1]
Mdm2 is an E3 ubiquitin ligase that binds p53 directly and targets it for proteasomal degradation.
“Mdm2 is an E3 ubiquitin ligase that binds directly to p53, targeting it for proteosomal degradation (1).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [1]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Arf deletion is said to reduce a lymphoma rate already lowered by Mdm2 haploinsufficiency
MinorThe paper says Mdm2 heterozygosity delays Myc-induced lymphoma. If loss of one Arf allele fully rescues that effect and restores the wild-type rate, it would increase the lymphoma rate relative to Mdm2-haploinsufficient mice, not reduce it.
“loss of just one allele of Arf can fully rescue the effects of Mdm2 haploinsufficiency and reduce the rate of Myc-induced lymphoma development to wild-type levels”
“heterozygosity at the Mdm2 or Mdm4 locus delays tumor onset in mice carrying an Eμ-myc transgene”
The citation lists haven’t been fetched yet
References 156 · Cited by 79
- Authors
- Eischen, C. M., & Lozano, G.
- Affiliations
- Vanderbilt University Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Lozano, Guillermina
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2014-03-06
- Volume
- 35
- Issue
- 6
- Pages
- 728-737
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC4725600
- OpenAlex
- W2067341743
- Semantic Scholar
- 7105d66ba00d310ae879a6e750da1bea013874e5
- Cited by
- 79
- References
- 156
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 4 · 2019: 4 · 2018: 13 · 2017: 8 · 2016: 10 · 2015: 10 · 2014: 4
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA117935, R01CA160432, R01CA047296, P30CA016672, P30CA068485)
- 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
- p53, MDM2, MDM4, TP53 missense mutations, tumor suppression, cell death, cell cycle arrest, cancer risk
- MeSH terms
- Animals, Humans, Neoplasms, Nuclear Proteins, Proto-Oncogene Proteins, Risk Factors, Transcription, Genetic, Tumor Suppressor Protein p53, Cell Death, Cell Cycle Proteins, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2, Cell Cycle Checkpoints
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