Mdm2 in evolution.
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ABSTRACT:
SUBMITTER: Lane DP
PROVIDER: S-EPMC3494368 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
While the presence, in the invertebrates, of genes related in sequence and function to the vertebrate p53 family has been known since the discovery of the fly Drosophila melanogaster Dmp53 and the worm Caenorhabditis elegans cep-1 gene, the failure to discover homologs of the essential vertebrate negative regulator of p53 Mdm2 in these species led to the false assumption that Mdm2 was only present in vertebrates. Very recently, clear homologs of Mdm2 have been discovered in a wide range of inver ...[more]
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Project description:MDM2 and MDM4 are proto-oncoproteins that bind to and inhibit members of the p53 protein family, p53, p73 and possibly p63. p53 is a mammalian tumor suppressor and p63 and p73 are critical for development. With the sequencing of genomes from multiple organisms there is mounting evidence for a consensus scenario of p53 gene family evolution. A single p53/p63/p73 gene is in invertebrates and required for maintenance of germline DNA. Gene duplication occurred in an ancestor in common with cartilaginous fishes, giving rise to a separate p53 gene and at least one ancestral p63/p73 gene. In bony vertebrates, all three p53 gene family paralogs, p53, p63, and p73 are distinct genes. This raises the question of how MDM2 and MDM4 genes evolved. We show evidence that MDM2 and MDM4 arose from a gene duplication event prior to the emergence of bony vertebrates more than 440 millionyears ago. Comparative genome studies indicate that invertebrate organisms have only one MDM homolog. In jawed vertebrates, the p53-binding domains of MDM2 and MDM4 proteins evolved at a high rate, approaching the evolution rate of the MDM2-binding domain of p53. However, the MDM2-binding domain of p73 exhibits markedly stronger conservation suggesting novel p53-independent functions. The most conserved domain within all MDM2 family members is the RING domain of the MDM2 ortholog which is responsible for ubiquitination of p53 and heterodimerization with MDM4. We suggest a model where oligomerization is an ancient function of MDM and ubiquitination activity was acquired later near the MDM gene duplication event coinciding with the time of the emergence of p53 as a distinct gene.
| S-EPMC3162079 | biostudies-literature
Project description:BackgroundThe p53 signalling pathway, which controls cell fate, has been extensively studied due to its prominent role in tumor development. The pathway includes the tumor supressor protein p53, its vertebrate paralogs p63 and p73, and their negative regulators MDM2 and MDM4. The p53/p63/p73-MDM system is ancient and can be traced in all extant animal phyla. Despite this, correct phylogenetic trees including both vertebrate and invertebrate species of the p53/p63/p73 and MDM families have not been published.ResultsHere, we have examined the evolution of the p53/p63/p73 protein family with particular focus on the p53/p63/p73 transactivation domain (TAD) and its co-evolution with the p53/p63/p73-binding domain (p53/p63/p73BD) of MDM2. We found that the TAD and p53/p63/p73BD share a strong evolutionary connection. If one of the domains of the protein is lost in a phylum, then it seems very likely to be followed by loss of function by the other domain as well, and due to the loss of function it is likely to eventually disappear. By focusing our phylogenetic analysis to p53/p63/p73 and MDM proteins from phyla that retain the interaction domains TAD and p53/p63/p73BD, we built phylogenetic trees of p53/p63/p73 and MDM based on both vertebrate and invertebrate species. The trees follow species evolution and contain a total number of 183 and 98 species for p53/p63/p73 and MDM, respectively. We also demonstrate that the p53/p63/p73 and MDM families result from whole genome duplications.ConclusionsThe signaling pathway of the TAD and p53/p63/p73BD in p53/p63/p73 and MDM, respectively, dates back to early metazoan time and has since then tightly co-evolved, or disappeared in distinct lineages.
| S-EPMC5543598 | biostudies-literature
Project description:Mouse double minute (Mdm) genes span an evolutionary timeframe from the ancient eukaryotic placozoa Trichoplax adhaerens to Homo sapiens, implying a significant and possibly conserved cellular role throughout history. Maintenance of DNA integrity and response to DNA damage involve many key regulatory pathways, including precise control over the tumour suppressor protein p53. In most vertebrates, degradation of p53 through proteasomal targeting is primarily mediated by heterodimers of Mdm2 and the Mdm2-related protein Mdm4 (also known as MdmX). Both Mdm2 and Mdm4 have p53-binding regions, acidic domains, zinc fingers, and C-terminal RING domains that are conserved throughout evolution. Vertebrates typically have both Mdm2 and Mdm4 genes, while analyses of sequenced genomes of invertebrate species have identified single Mdm genes, suggesting that a duplication event occurred prior to emergence of jawless vertebrates about 550-440 million years ago. The functional relationship between Mdm and p53 in T. adhaerens, an organism that has existed for 1 billion years, implies that these two proteins have evolved together to maintain a conserved and regulated function.
| S-EPMC6372010 | biostudies-literature
Project description:Mdm2 and Mdmx are oncoproteins that have essential yet nonredundant roles in development and function as part of a multicomponent ubiquitinating complex that targets p53 for proteasomal degradation. However, in response to DNA damage, Mdm2 and Mdmx are phosphorylated and protect p53 through various mechanisms. It has been predicted that Mdm2-Mdmx complex formation modulates Mdm2 ligase activity, yet the mechanism that promotes formation of Mdm2-Mdmx complexes is unknown. Here, we show that optimal Mdm2-Mdmx complex formation requires c-Abl phosphorylation of Mdm2 both in vitro and in vivo. In addition, Abl phosphorylation of Mdm2 is required for efficient ubiquitination of Mdmx in vitro, and eliminating c-Abl signaling, using c-Abl(-/-) knock-out murine embryonic fibroblasts, led to a decrease in Mdmx ubiquitination. Further, p53 levels are not induced as efficiently in c-Abl(-/-) murine embryonic fibroblasts following DNA damage. Overall, these results define a direct link between genotoxic stress-activated c-Abl kinase signaling and Mdm2-Mdmx complex formation. Our results add an important regulatory mechanism for the activation of p53 in response to DNA damage.
| S-EPMC3012977 | biostudies-literature
Project description:BackgroundMDM2 is a negative regulator of p53 and is upregulated in numerous human cancers. While different MDM2 splice variants have been observed in both normal tissues and malignant cells, their functions are poorly understood.MethodsWe evaluated the effect of MDM2 splice variants by overexpression in MCF-7 cells and analyses of expression of downstream genes (qPCR and Western blot), subcellular localization (immunofluorescence), cell cycle assays (Nucleocounter3000), apoptosis analysis (Annexin V detection), and induction of senescence (β-galactosidase analysis).ResultsIn a screen for MDM2 splice variants in MCF-7 breast cancer cells, extended with data from healthy leukocytes, we found P2-MDM2-10 and MDM2-Δ5 to be the splice variants expressed at highest levels. Contrasting MDM2 full-length protein, we found normal tissue expression levels of P2-MDM2-10 and MDM2-Δ5 to be highest in individuals harboring the promoter SNP309TT genotype. While we detected no protein product coded for by MDM2-Δ5, the P2-MDM2-10 variant generated a protein markedly more stable than MDM2-FL. Both splice variants were significantly upregulated in stressed cells (P=4.3 × 10-4 and P=7.1 × 10-4, respectively). Notably, chemotherapy treatment and overexpression of P2-MDM2-10 or MDM2-Δ5 both lead to increased mRNA levels of the endogenous MDM2-FL (P=.039 and P=.070, respectively) but also the proapoptotic gene PUMA (P=.010 and P=.033, respectively), accompanied by induction of apoptosis and repression of senescence.ConclusionWe found P2-MDM2-10 and MDM2-Δ5 to have distinct biological functions in breast cancer cells.General significanceAlternative splicing may influence the oncogenic effects of the MDM2 gene.
| S-EPMC5576977 | biostudies-literature
Project description:The protein-protein interaction (PPI) between p53 and its negative regulator MDM2 comprises one of the most important and intensely studied PPI's involved in preventing the initiation of cancer. The interaction between p53 and MDM2 is conformation-based and is tightly regulated on multiple levels. Due to the Angstrom level structural insight there is a reasonable understanding of the structural requirements needed for a molecule to bind to MDM2 and successfully inhibit the p53/MDM2 interaction. The current review summarizes the binding characteristics of the different disclosed small molecules for inhibition of MDM2 with a co-crystal structure. Synthetic access to these compounds as well as their derivatives are described in detail.
| S-EPMC3719986 | biostudies-literature
Project description:The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that plays a prominent role in p53 suppression by promoting its polyubiquitination and proteasomal degradation. In its active form, MDM2 forms homodimers as well as heterodimers with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through their respective C-terminal RING (really interesting new gene) domains. In this study, using multiple MDM2 mutants, we show evidence suggesting that MDM2 homo- and heterodimerization occur through distinct mechanisms because MDM2 RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with WT MDM2. Intriguingly, deletion of a portion of the MDM2 central acidic domain selectively inhibits interaction with MDM2 while leaving intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an MDM2 C-terminal deletion mutant reveals that the C-terminal residues of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model in which MDM2-MDMX heterodimerization requires the extreme C terminus and proper RING domain structure of MDM2, whereas MDM2 homodimerization requires the extreme C terminus and the central acidic domain of MDM2, suggesting that MDM2 homo- and heterodimers utilize distinct MDM2 domains. Our study is the first to report mutations capable of separating MDM2 homo- and heterodimerization.
| S-EPMC4432308 | biostudies-literature
Project description:Retinoblastoma (Rb) is the most common intra-ocular malignancy in children. The association of rs2279744, and rs937283 in MDM2 gene, and p21 rs1801270 polymorphism and RB development have been demonstrated. To provide a comprehensive assessment of and to clarify associations between the 3 SNPs (MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270) and the risk of RB, we performed a meta-analysis of all the eligible case-control studies. We searched English databases include PubMed, Embase, Google Scholar, and Cochrane Library, using an upper date limit of January 1, 2018. The association between MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270 polymorphisms and the risk of RB were estimated by calculating a pooled OR and 95% CI under a homozygote comparison, heterozygote comparison, dominant model, and recessive model. The statistical power analysis was performed using G*Power. Our meta-analysis showed a significant association between RB susceptibility and MDM2 rs2279744 recessive model (OR?=?1.427, 95%CI: 1.107-1.840, P?=?.006, I?=?0%). Moreover, a significant link was observed between RB risk and MDM2 rs937283 homozygote comparison (OR?=?0.471, 95%CI: 0.259-0.858, P?=?.014, I?=?0%) and recessive model (OR?=?0.587, 95%CI: 0.410-0.840, P?=?.004, I?=?0%). However, no significant relationship between the p21 rs1801270 polymorphism and RB susceptibility was detected in any of the 4 models (P?>?.05). In conclusion, we found that significant association between the MDM2 rs2279744 polymorphism and increased RB risk, while MDM2 rs937283 polymorphism was associated with significantly decreased RB risk. However, as to the P21 rs1801270 polymorphism, a statistically significant association was not identified for RB.
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Project description:The interaction between the transcription factor p53 and the ubiquitin ligase MDM2 results in the degradation of p53 and is well-studied in cancer biology and drug development. Available sequence data suggest that both p53 and MDM2-family proteins are present across the animal kingdom. However, the interacting regions are missing in some animal groups, and it is not clear whether MDM2 interacts with, and regulates p53 in all species. We used phylogenetic analyses and biophysical measurements to examine the evolution of affinity between the interacting protein regions: a conserved 12-residue intrinsically disordered binding motif in the p53 transactivation domain (TAD) and the folded SWIB domain of MDM2. The affinity varied significantly across the animal kingdom. The p53TAD/MDM2 interaction among jawed vertebrates displayed high affinity, in particular for chicken and human proteins (KD around 0.1 μM). The affinity of the bay mussel p53TAD/MDM2 complex was lower (KD = 15 μM) and those from a placozoan, an arthropod, and a jawless vertebrate were very low or non-detectable (KD > 100 μM). Binding experiments with reconstructed ancestral p53TAD/MDM2 variants suggested that a micromolar affinity interaction was present in the ancestral bilaterian animal and was later enhanced in tetrapods while lost in other linages. The different evolutionary trajectories of p53TAD/MDM2 affinity during speciation demonstrate high plasticity of motif-mediated interactions and the potential for rapid adaptation of p53 regulation during times of change. Neutral drift in unconstrained disordered regions may underlie the plasticity and explain the observed low sequence conservation in TADs such as p53TAD.
| S-EPMC10303687 | biostudies-literature
Project description:MDM2 is an oncoprotein that blocks p53 tumor suppressor-mediated transcriptional transactivation, escorts p53 from the cell nucleus to the cytoplasm, and polyubiquitylates p53. Polyubiquitylated p53 is rapidly degraded in the cytoplasm by the 26S proteasome. MDM2 is abnormally upregulated in several types of cancers, especially those of mesenchymal origin. MDM4 is a homolog of MDM2 that also inhibits p53 by blocking p53-mediated transactivation. MDM4 is required for MDM2-mediated polyubiquitylated of p53 and is abnormally upregulated in several cancer types. MDM2 and MDM4 genes have been detected in all vertebrates to date and only a single gene homolog, named MDM, has been detected in some invertebrates. MDM2, MDM4, and MDM have similar gene structures, suggesting that MDM2 and MDM4 arose through a duplication event more than 440 million years ago. All members of this small MDM2 gene family contain a single really interesting new gene (RING) domain (with the possible exception of lancelet MDM) which places them in the RING-domain superfamily. Similar to MDM2, the vast majority of proteins with RING domains are E3 ubiquitin ligases. Other RING domain E3 ubiquitin ligases that target p53 are COP1, Pirh2, and MSL2. In this report, we present evidence that COP1, Pirh2, and MSL2 evolved independently of MDM2 and MDM4. We also show, through structure homology models of invertebrate MDM RING domains, that MDM2 is more evolutionarily conserved than MDM4.
| S-EPMC4221809 | biostudies-literature