Alternative titles; symbols
HGNC Approved Gene Symbol: MDM2
Cytogenetic location: 12q15 Genomic coordinates (GRCh38): 12:68,808,172-68,850,686 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q15 | ?Lessel-Kubisch syndrome | 618681 | Autosomal recessive | 3 |
| {Accelerated tumor formation, susceptibility to} | 614401 | Autosomal dominant | 3 |
The tumor suppressor p53 (TP53; 191170) induces cell cycle arrest or apoptosis in response to cellular stress. MDM2 is an E3 ubiquitin ligase that targets the p53 protein for proteasomal degradation (summary by Sasaki et al., 2011).
The MDM2 gene was originally identified by virtue of its amplification in a spontaneously transformed derivative of mouse BALB/c cells (Fakharzadeh et al., 1991), and the MDM2 protein was subsequently shown to bind to p53 in rat cells transfected with p53 genes (Momand et al., 1992). Momand et al. (1992) characterized, purified, and identified a cellular phosphoprotein with an apparent molecular mass of 90 kD that formed a complex with both mutant and wildtype p53 protein. The protein was identified as a product of the 'murine double minute 2' gene (mdm2).
Oliner et al. (1992) cloned the human MDM2 gene.
De Oca Luna et al. (1996) showed that the murine mdm2 gene contains at least 12 exons spanning about 25 kb of DNA.
Oliner et al. (1992) used MDM2 clones to localize the human gene to chromosome 12q13-q14 by analysis of human-hamster somatic cell hybrids. By fluorescence in situ hybridization onto simultaneously DAPI-banded metaphase chromosomes and interphase nuclei, Mitchell et al. (1995) mapped MDM2 to 12q14.3-q15 distal to CDK4 (123829) and flanked by Genethon microsatellites D12S80 and D12S83. On both the physical and the genetic maps of chromosome 12, Bureau et al. (1995) mapped the IFG gene (147570) close to the D12S335 and D12S313 microsatellites. They also physically mapped it close to the locus of the MDM2 oncogene on 12q15, a localization proximal to that arrived at earlier. They described the organization of the Ifg, Myf6 (159991), Mdm1 (613813), and Mdm2 loci on mouse chromosome 10 in a region with homology of synteny to human 12q15.
Momand et al. (1992) found that the mdm2 gene enhances the tumorigenic potential of cells when it is overexpressed and encodes a putative transcription factor. Forming a tight complex with the p53 gene, the MDM2 oncogene can inhibit p53-mediated transactivation. De Oca Luna et al. (1996) observed ubiquitous low levels of mdm2 mRNA in embryonic and adult tissues which, by RT-PCR, did not include several splice variants seen in 3T3DM cells.
Because the 12q13-q14 region, to which the MDM2 gene maps, is often aberrant in human sarcomas, Oliner et al. (1992) performed Southern blot analysis on DNA from such cancers. A striking amplification of MDM2 sequences was found in 17 of 47 sarcomas, including common bone and soft tissue forms. The results were considered consistent with the hypothesis that MDM2 binds to p53 and that amplification of MDM2 in sarcomas leads to escape from p53-regulated growth control. This mechanism of tumorigenesis parallels that for virus-induced tumors in which viral oncogene products bind to and functionally inactivate p53. Bueso-Ramos et al. (1993) found overexpression of the MDM2 oncogene in leukemias.
Inactivation of tumor suppressor genes leads to deregulated cell proliferation and is a key factor in human tumorigenesis. Mutations in the p53 and RB1 (614041) genes are frequently associated with human cancers, and simultaneous inactivation of both RB and p53 is frequently observed in naturally occurring tumors. Additionally, 3 distinct DNA tumor virus groups (papovaviruses, adenoviruses, and human papillomaviruses) transform cells by targeting and inactivating certain functions of both the p53 and RB1 gene products. Xiao et al. (1995) showed that MDM2 interacts physically and functionally with the RB protein and can inhibit its growth regulatory capacity. They thus demonstrated that both RB and p53 can be subjected to negative regulation by the product of a single cellular protooncogene.
Sdek et al. (2005) found that MDM2 promoted RB degradation in a proteasome-dependent and ubiquitin-independent manner in human tumor cell lines. RB, MDM2, and the C8 subunit of the 20S proteasome (PSMA3; 176843) interacted in vitro and in vivo, and MDM2 promoted RB-C8 interaction. Expression of wildtype MDM2, but not mutant MDM2 defective either in RB interaction or in its RING finger domain, promoted cell cycle S-phase entry independent of p53. Furthermore, MDM2 ablation using small interfering RNA resulted in RB accumulation and inhibition of DNA synthesis. Sdek et al. (2005) concluded that MDM2 is a critical negative regulator for RB and that MDM2 overexpression contributes to cancer development by destabilizing RB.
Freedman et al. (1997) studied the amino acids of MDM2 that are critical for binding to p53 and inhibition of its antioncogenic functions. MDM2 mutations (G58D and C77Y) were found to disrupt binding to p53 in vitro without altering the conformation of MDM2 as determined by conformation-sensitive monoclonal antibodies. Mutations in 2 additional amino acids were found to prevent binding to p53 in vitro. The crystal structure of the MDM2-p53 complex shows that 2 of the 4 critical residues contact p53 directly, while the remaining 2 residues play important structural roles in the MDM2 domain of the complex. Thus, the interference of binding to p53 prevents the interaction of MDM2 and its regulation of the transcriptional activity of p53 in vivo.
Shieh et al. (1997) showed that, upon DNA damage, p53 is phosphorylated at ser15 and that this event leads to reduced interaction of p53 with MDM2. They also demonstrated that the phosphorylation of p53 at ser15 and ser37 by purified DNA-dependent protein kinase (600899) impairs the ability of MDM2 to inhibit p53-dependent transactivation. They presented evidence that these effects are most likely due to a conformational change induced by phosphorylation of p53.
Direct association of p53 with the cellular protein MDM2 results in ubiquitination and subsequent degradation of p53. Based on evidence for JNK association with p53, Fuchs et al. (1998) sought to elucidate the role of nonactive JNK2 (602896) in regulating p53 stability. JNK-p53 and MDM2-p53 complexes were preferentially found in G0/G1 and S/G2M phases of the cell cycle, respectively. Altogether, data indicated that JNK is an MDM2-independent regulator of p53 stability in nonstressed cells.
Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Ries et al. (2000) showed that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19(ARF) (600160). This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19(ARF). Levels of p53 are therefore determined by opposing effects of Raf-induced p19(ARF) and Mdm2.
Boyd et al. (2000) identified the mouse Mtbp gene (605927) which encodes a cellular protein that binds to Mdm2. Mtbp can induce G1 arrest, which in turn can be blocked by Mdm2. This suggested the existence of another growth control pathway that may be regulated, at least in part, by Mdm2.
MDM2 regulates p53 either through inhibiting p53's transactivating function in the nucleus or by targeting p53 degradation in the cytoplasm. Zhang and Xiong (2001) identified a previously unknown nuclear export signal in the N terminus of p53, spanning residues 11 to 27 and containing 2 serine residues phosphorylated after DNA damage, which was required for p53 nuclear export in collaboration with the C-terminal nuclear export signal. Serine-15-phosphorylated p53 induced by UV irradiation was not exported. Zhang and Xiong (2001) concluded that DNA damage-induced phosphorylation may achieve optimal p53 activation by inhibiting both MDM2 binding to, and the nuclear export of, p53.
The MDM2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. To regulate p53, MDM2 must gain nuclear entry; Mayo and Donner (2001) identified the mechanism that induces this. Mitogen-induced activation of phosphatidylinositol 3-kinase (see PIK3CA; 171834) and its downstream target, the AKT/PKB serine-threonine kinase (164730), results in phosphorylation of MDM2 on serine-166 and serine-186. Phosphorylation on these sites is necessary for translocation of MDM2 from the cytoplasm into the nucleus. Pharmacologic blockade of PI3-kinase/AKT signaling or expression of dominant-negative PI3-kinase or AKT inhibits nuclear entry of MDM2, increases cellular levels of p53, and augments p53 transcriptional activity. Expression of constitutively active AKT promotes nuclear entry of MDM2, diminishes cellular levels of p53, and decreases p53 transcriptional activity. Mutation of the AKT phosphorylation sites in MDM2 produces a mutant protein that is unable to enter the nucleus and increases p53 activity. The demonstration that PI3-kinase/AKT signaling affects MDM2 localization provided insight into how this pathway, which is inappropriately activated in many malignancies, affects the function of p53. Testa and Bellacosa (2001) reviewed the central role of AKT in tumorigenesis.
Yin et al. (2002) determined that MDM2 induces translation of p53 mRNA from 2 alternative initiation sites. Translation from the second site results in a protein with an apparent molecular mass of 47 kD. The truncated protein, which they called p53/47, lacks the MDM2-binding site and the most N-terminal transcriptional activation domain of full-length p53. The authors showed that translation induction requires MDM2 to interact directly with the nascent p53 polypeptide and leads to a change in the ratio of p53 to p53/47 by inducing translation of both proteins followed by selective degradation of full-length p53.
Shenoy et al. (2001) demonstrated that agonist stimulation of endogenous or transfected beta-2-adrenergic receptors (109690) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin (107941). Moreover, proteasome inhibitors reduce receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta-2 adrenergic receptor. Receptor ubiquitination required beta-arrestin, which bound the E3 ubiquitin ligase MDM2. Abrogation of beta-arrestin ubiquitination, either by expression in MDM2-null cells or by dominant-negative forms of MDM2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, a beta-2 adrenergic receptor mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. Shenoy et al. (2001) concluded that their results delineated an adaptor role of beta-arrestin in mediating the ubiquitination of the beta-2 adrenergic receptor and indicated that ubiquitination of the receptor and of beta-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic G protein-coupled receptor.
Rapid turnover of the tumor suppressor protein p53 requires the MDM2 ubiquitin ligase, and both interact with p300 (602700)-CREB-binding protein (600140) transcriptional coactivators. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Grossman et al. (2003) observed that purified p300 exhibited intrinsic ubiquitin ligase activity but was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, Grossman et al. (2003) concluded that generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.
The tumor suppressor p53 is usually studied by experiments that are averaged over cell populations, potentially masking the dynamic behavior in individual cells. Lahav et al. (2004) presented a system for following, in individual living cells, the dynamics of p53 and its negative regulator Mdm2. They found that p53 was expressed in a series of discrete pulses after DNA damage. Genetically identical cells had different numbers of pulses: 0, 1, 2, or more. The mean height and duration of each pulse were fixed and did not depend on the amount of DNA damage. The mean number of pulses, however, increased with DNA damage. The findings suggested that the p53-Mdm2 feedback loop generates a 'digital' clock that releases well-timed quanta of p53 until damage is repaired or the cell dies.
Xirodimas et al. (2004) showed that MDM2 can promote NEDD8 (603171) modification of p53. They found that MDM2 is itself modified with NEDD8 with similar characteristics to the autoubiquitination activity of MDM2. Using a cell line with a temperature-sensitive mutation in the NEDD8 conjugation pathway and a p53 mutant that could not be NEDDylated, Xirodimas et al. (2004) demonstrated that MDM2-dependent NEDD8 modification of p53 inhibits its transcriptional activity. These findings expanded the role of MDM2 as an E3 ligase, providing evidence that MDM2 is a common component of the ubiquitin and NEDD8 conjugation pathway and indicating the diverse mechanisms by which E3 ligases can control the function of substrate proteins.
Sui et al. (2004) found that YY1 (600013) ablation resulted in p53 accumulation due to a reduction of p53 ubiquitination in vivo. Conversely, YY1 overexpression stimulated p53 ubiquitination and degradation. Recombinant YY1 was sufficient to induce MDM2-mediated p53 polyubiquitination in vitro, suggesting that this function of YY1 is independent of its transcriptional activity. There was direct physical interaction of YY1 with MDM2 and p53, and the basis for YY1 regulating p53 ubiquitination was its ability to facilitate MDM2-p53 interaction. The tumor suppressor p14(ARF) (600160) compromised the MDM2-YY1 interaction. Sui et al. (2004) concluded that YY1 is a potential cofactor for MDM2 in the regulation of p53 homeostasis.
By yeast 2-hybrid analysis and in vitro binding assays, Juven-Gershon et al. (1998) demonstrated direct binding between NUMB (603728) and mouse Mdm2. The binding required the N-terminal domain of Mdm2, and the interaction was enhanced in the presence of a tyrosine phosphatase inhibitor. When coexpressed in HEK293 or osteosarcoma cell lines, Mdm2 reduced the steady-state level of NUMB. In contrast, the steady-state level of Mdm2 was augmented by cotransfection with NUMB. When expressed alone, NUMB localized exclusively to the cytoplasm, but when coexpressed with Mdm2, about 20% of the cells showed nuclear NUMB accumulation. The localization of Mdm2 was unaffected by NUMB expression.
Yogosawa et al. (2003) showed that MDM2 induced proteasome-dependent degradation of NUMB in intact cells. The induction of degradation required the ring finger domain of MDM2.
Using in vitro ubiquitination assays and small interfering RNA-mediated downregulation of HDMX (MDM4; 602704) expression in human cell lines, Linares et al. (2003) determined that HDMX stimulated HDM2 E3 ligase activity and that HDMX was required to keep p53 at low levels under normal growth conditions. HDMX did not function as an E3 on its own, but was active in complex with HDM2. In addition, HDMX stimulated autoubiquitination of HDM2, and HDMX was a substrate for ubiquitination by HDM2.
Using a direct genetic screen, Wu et al. (2004) identified seladin-1 (606418) as a key mediator of Ras-induced senescence. Following oncogenic and oxidative stress, seladin-1 binds the p53 amino terminus and displaces E3 ubiquitin ligase MDM2 from p53, thus resulting in p53 accumulation. Additionally, seladin-1 associates with MDM2 independently of p53, potentially affecting other MDM2 targets.
Yu et al. (2006) determined that the HDM2 N-terminal domain interacted only with the N-terminal domain of p53. They identified a central acidic domain within HDM2 that bound the core domain of p53. Phosphorylation within the central region of HDM2 did not alter the interaction between HDM2 and p53.
Aylon et al. (2006) found that LATS2 (604861) had a role in the p53-dependent G1/S arrest following damage to the mitotic spindle and centrosome dysfunction. LATS2 interacted physically with MDM2 to inhibit p53 ubiquitination and to promote p53 activation.
Rinaldo et al. (2007) stated that phosphorylation of p53 on ser46 shifts the affinity of p53 for promoters of genes involved in cell cycle arrest to promoters of genes involved in apoptosis. They observed that lethal DNA damage increased expression of HIPK2, a kinase that phosphorylates p53 on ser46. In contrast, sublethal DNA damage repressed HIPK2 expression. Rinaldo et al. (2007) identified HIPK2 as a target for MDM2-mediated ubiquitin-dependent degradation and found that HIPK2 degradation only occurred in growth-arresting conditions when MDM2 was efficiently induced by p53.
Impeding ribosomal biogenesis generates ribosomal stress that activates p53 to stop cell growth. Dai et al. (2006) stated that the ribosomal proteins L5 (RPL5; 603634), L11 (RPL11; 604175), and L23 (RPL23; 603662) interact with MDM2 and inhibit MDM2-mediated p53 ubiquitination and degradation in response to ribosomal stress. They found that L5 and L23 inhibited ubiquitination of both p53 and MDM2 in human cell lines. In contrast, L11 inhibited proteasome-mediated degradation of ubiquitinated MDM2, but not p53, resulting in stabilization of p53.
Using mutation analysis and isolated Mdm2 peptides, Kulikov et al. (2010) showed that N- and C-terminal domains of Mdm2, but not its central domain, bound proteins within the 19S regulatory proteasome subunit, in particular S6b (PSMB6; 600307). The region of the Mdm2 N-terminal domain that bound proteasome subunits largely overlapped with the p53-binding domain, suggesting that the C-terminal domain of Mdm2 is the main proteasome-binding region. Association of Mdm2 with the proteasome was not affected by Mdm2 ubiquitination, but it was enhanced by phosphorylation of several serines within the Mdm2 central domain. The central domain, including a critical EDY motif, also functioned as an autoinhibitory domain that bound the Mdm2 C-terminal domain through intra/intermolecular interaction and inhibited interaction of Mdm2 with proteasomal proteins.
Using reciprocal immunoprecipitation analysis, Deisenroth et al. (2010) showed that the central acidic domain of MDM2 interacted with nuclear HEP27 (DHRS2; 615194), resulting in p53 stabilization and upregulation of p53 transcriptional targets.
Using an in vitro ubiquitination assay with mouse and human UBE4B (613565) and MDM2, Wu et al. (2011) showed that either UBE4B or MDM2 alone led to monoubiquitination of p53, while UBE4B in combination with MDM2 promoted p53 polyubiquitination. Overexpression and knockdown studies in mouse and human cell lines revealed that interaction of UBE4B with MDM2 reduced the half-life of p53 via proteasome-mediated degradation and caused repression of p53-dependent transactivation and apoptosis.
Sasaki et al. (2011) found that conditional deletion of Pict1 (GLTSCR2; 605691) expression in mouse embryonic stem (ES) cells inhibited cell growth due to cell cycle arrest and enhanced apoptosis. Mass spectrometric analysis of peptides that immunoprecipitated with epitope-tagged PICT1 in transfected 293T cells showed that PICT1 interacted with RPL11. Knockdown of Pict1 in mouse ES cells resulted in translocation of Rpl11 from the nucleolus to the nucleoplasm, permitting its interaction with Mdm2 and inhibition of p53 ubiquitination. Sasaki et al. (2011) concluded that PICT1 is a potent regulator of the MDM2-p53 pathway.
By immunoblot analysis and immunoprecipitation, Hu et al. (2011) found that the nucleolar protein ZNF668 (617103) interacted with p53 and MDM2 in human osteosarcoma cells. Mutation analysis showed that ZNF668 bound MDM2 and p53 via regions in its N-terminal half, and these regions were also required for nucleolar localization of ZNF668. The central region of MDM2 mediated its interaction with ZNF668. ZNF668 regulated p53 stability and activity by disrupting MDM2-mediated ubiquitination and degradation of p53. Overexpression of ZNF668 repressed proliferation of a breast cancer cell line and prevented tumor formation in mice in both p53-dependent and -independent manners. Hu et al. (2011) concluded that ZNF668 is a breast tumor suppressor gene that regulates p53 stability by targeting the MDM2-p53 interaction.
Xuan et al. (2013) found that the transcriptional repressor RBB (NACC2; 615786) recruited the nucleosome remodeling and deacetylase (NURD) complex (see 603526) to the internal P2 promoter of the MDM2 gene and inhibited MDM2 expression, leading to stabilization of p53, suppression of cell proliferation, and increased DNA damage-induced apoptosis. RT-PCR analysis showed that knockdown of RBB in MCF-7 cells via short hairpin RNA increased transcription of MDM2 via the P2 promoter.
Accelerated Tumor Formation, Susceptibility to
Bond et al. (2004) identified a SNP in the MDM2 promoter (rs2279744; 164785.0001) that they designated 'SNP309.' They found that SNP309 was associated with accelerated tumor formation (614401) in both Li-Fraumeni syndrome (LFS1; 151623) patients and sporadic cancer patients.
Among 61 French carriers of an R72P mutation in the p53 gene (191170.0005), Bougeard et al. (2006) demonstrated that those who also carried the SNP309 G allele had a significantly earlier age of tumor onset than those who were homozygous for the T allele.
In 25 Dutch and 11 Finnish p53 mutation carriers, Ruijs et al. (2007) confirmed the previously observed significantly earlier age of tumor onset in SNP309 G allele carriers versus those homozygous for the T allele. In a group of Li-Fraumeni syndrome and LFS-related p53-negative families, no difference was seen in the age of tumor onset, but there was a significantly higher percentage of SNP309 G/G homozygotes than in the general population. Ruijs et al. (2007) suggested that the MDM2 SNP309 G allele contributes to cancer susceptibility in LFS and LFS-related families.
Lessel-Kubisch Syndrome
In a 19-year-old Saudi Arabian man with a segmental progeroid syndrome, here designated Lessel-Kubisch syndrome (LSKB; 618681), Lessel et al. (2017) identified homozygosity for an antitermination mutation in the MDM2 gene (X498Qext5; 164785.0002). Functional analysis demonstrated that the mutation abrogated MDM2 activity, resulting in increased levels and stability of p53.
Associations Pending Confirmation
For discussion of a possible association between variation in the MDM2 gene and smoking-related accelerated decline in lung function, see 164785.0001.
Mendrysa et al. (2003) developed mice carrying a hypomorphic allele of Mdm2. These mice showed defects in multiple hematopoietic lineages, including mild anemia and reduced white blood cell counts, that were primarily due to decreased lymphocyte concentration. The spleen, thymus, and bone marrow of these mice contained significantly reduced lymphoid cell numbers. Lymphocytes from mutant mice also showed increased p53-dependent apoptosis, which occurred without increased p53 protein levels, and cultured mouse embryonic fibroblasts showed increased sensitivity to ionizing radiation. Mendrysa et al. (2003) noted that only a subset of tissues with activated p53 underwent apoptosis, indicating that factors other than Mdm2 determine the consequences of p53 activation.
The article by Buschmann et al. (2000) regarding sumoylation of MDM2 was retracted because of difficulties in reproducing the reported data.
Accelerated Tumor Formation, Susceptibility to
By screening 50 healthy volunteers, Bond et al. (2004) identified a SNP in the MDM2 promoter, -410T-G, which they called SNP309 (rs2279744) because of its position at the 309th nucleotide of intron 1. SNP309 was present at a relatively high frequency in both the heterozygous state (T/G, 40%) and the homozygous state (G/G, 12%). Bond et al. (2004) showed that SNP309 increased the affinity of the transcriptional activator Sp1 (189906), resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 (191170) pathway. They demonstrated that SNP309 was associated with accelerated tumor formation (614401) in both hereditary and sporadic cancers in humans. Bond et al. (2004) studied 88 individuals who were members of Li-Fraumeni syndrome (LFS1; 151623) families and had germline mutations in 1 allele of p53. The frequency of SNP309 in these individuals was similar to that found in the 50 normal volunteers. Of the 88 individuals in the Li-Fraumeni cohort, 66 were diagnosed with at least 1 cancer at a median age of 22 years old. Those either heterozygous or homozygous for SNP309 developed tumors on average 7 years earlier than those lacking SNP309. To determine whether SNP309 acted upon sporadic tumors as well as genetically altered individuals with a p53 defect, Bond et al. (2004) studied a group of patients who developed sporadic adult soft tissue sarcomas and had no known hereditary cancer predisposition and no known germline p53 mutation. Individuals homozygous for SNP309 were diagnosed on average 12 years earlier than those without SNP309, and the frequency of the SNP309 G allele was greatly increased in those who developed soft tissue sarcomas at a young age. These data demonstrated that SNP309 does not require the presence of an inactivating germline p53 mutation to associate with earlier soft tissue sarcoma formation.
Bougeard et al. (2006) studied the effect of the SNP309 polymorphism and the arg72-to-pro polymorphism of the p53 gene (191170.0005) on cancer risk in 61 French carriers of the p53 germline mutation. The mean age of tumor onset in MDM2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p less than 0.05). For the p53 codon 72 polymorphism, the mean age of tumor onset in arg allele carriers (21.8 years) was also different from that of pro/pro patients (34.4 years, p less than 0.05). Bougeard et al. (2006) also observed a cumulative effect of both polymorphisms because the mean ages of tumor onset in carriers of MDM2 G and p53 arg alleles (16.9 years) and those with the MDM2 T/T and p53 pro/pro genotypes (43 years) were clearly different (p less than 0.02). Therefore, the results confirmed the impact of the MDM2 SNP309 G allele on the age of tumor onset in germline p53 mutation carriers, and suggested that this effect may be amplified by the p53 arg72 allele. Polymorphisms affecting p53 degradation therefore represent one of the few examples of modifier genetic factors identified to that time in mendelian predispositions to cancer.
Using 14 different SNPs across the MDM2 gene from Caucasian, African American, and Ashkenazi Jewish population samples, Atwal et al. (2007) characterized the haplotype structure of the MDM2 gene. They found reduced variability of the deleterious SNP309 G allele haplotype and multiple common SNP309 T alleles in all 3 populations. These data suggested that the G allele haplotype underwent recent positive selection.
In 25 Dutch and 11 Finnish p53 mutation carriers, Ruijs et al. (2007) observed a significantly earlier age of tumor onset in SNP309 G allele carriers versus those homozygous for the T allele (mean difference, 16 years earlier; p = 0.005), confirming previously reported results. In 72 Dutch p53-negative LFS and LFS-related patients, no difference was seen in the age of tumor onset, but there was a significantly higher percentage of SNP309 G/G homozygotes than in the general population (p = 0.02). Ruijs et al. (2007) suggested that the MDM2 SNP309 G allele contributes to cancer susceptibility in LFS and LFS-related families.
Smoking-Related Accelerated Decline in Lung Function
In a study of 863 individuals with European grandparents from an unselected New Zealand birth cohort, Hancox et al. (2009) analyzed lung function (FEV1 and FEV1/FVC) between ages 18 and 32 in relation to cumulative history of cigarette smoking and the rs2279244 SNP, and found that the G allele was associated with accelerated smoking-related decline in lung function (see 608852) (FEV1, p = 0.004).
In a 19-year-old Saudi Arabian man with a segmental progeroid syndrome, here designated Lessel-Kubisch syndrome (LSKB; 618681), Lessel et al. (2017) identified homozygosity for a c.1492T-C transition in the MDM2 gene, resulting in a ter498-to-glu substitution predicted to extend the protein for 5 additional erroneous amino acids (X498Qext5). DNA was unavailable from his 2 deceased, reportedly affected sisters or his deceased first-cousin parents. Patient dermal fibroblasts and lymphoblastoid cell lines (LCLs) showed markedly elevated MDM2 and p53 (TP53; 191170) levels compared to control cells, suggesting a compromised MDM2-p53 negative feedback loop as the pathogenetic mechanism. Ectopically expressed mutant MDM2 was defective in its ability to degrade both ectopic and endogenous p53 in U2OS cells, and ectopic mutant MDM2 accumulated to markedly higher levels than wildtype MDM2 in U2OS or H1299 cells, indicating that its increased stability is an intrinsic property of the mutant protein itself. In cyclohexamide-treated patient fibroblasts, both MDM2 and p53 were significantly stabilized, and inhibition of the proteasome by MG132 confirmed the increased stability of p53 and MDM2. Further study indicated that mutant MDM2 is able to bind and repress transcriptional activity of basal P53, but that stress results in p53 hyperactivation. In contrast to other segmental progeroid syndromes, patient LCLs had no genomic instability but rather showed a certain level of protection against ionizing radiation and mitomycin C; however, patient fibroblasts demonstrated reduced replicative capacity, entering replicative senescence at passage 28, compared to passage 43 for controls. Zebrafish embryos deficient in Mdm2 displayed a severe apoptotic phenotype, which could be rescued by wildtype mdm2 mRNA but not mutant mdm2 mRNA bearing the 5-amino acid extension.
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