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MDM2 inhibits TP53. 1000 / 3877
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"184 Since this early report highlighting the structural bases of the p53/MDM2 interaction, very different classes of MDM2/MDMX (an MDM2 homolog that also inactivates p53) antagonists have been developed as potential anticancer agents, ranging from low-molecular-weight compounds to peptides."
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"However, upon cellular stress, p53 is phosphorylated resulting in the shutdown of Mdm2 mediated degradation and accumulation of transcriptionally active p53 which activates several targets including cell cycle inhibitors and pro apoptotic proteins resulting in apoptosis or proliferation arrest."
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"A number of previous observations confirm that wild-type p53 alleles are present in the vast majority of cases of newly diagnosed neuroblastoma, but that p53/MDM2/ARF responses to chemotherapy are repressed, in part due to unscheduled inhibition of p53 by MDM2 XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"Recently, studies from this group reported that Notch-1 signaling sensitizes tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced apoptosis in HCC cells by inhibiting Akt and HDM2 mediated p53 degradation and by up-regulating p53 dependent DR5 expression [XREF_BIBR]."
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"Recently, a single nucleotide polymorphism (SNP) in the intronic promoter region of the MDM2 gene (a T to G exchange at nucleotide 309) has been reported to increase expression levels of MDM2 leading to attenuated function of p53, and linked to the observed higher incidence of tumors in carriers with the homozygous G/G or heterozygous T/G genotype, respectively."
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"Our real-time PCR finding is consistent with recent reports by Bond et al. and Hong et al [XREF_BIBR, XREF_BIBR] that the MDM2 309GG genotype carriers had significantly higher MDM2 expression in NPC tissues than the TT and TG genotype carriers, suggesting the variant MDM2 genotype may cause attenuated TP53 function."
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"In line with the critical role for Mdm2 mediated degradation of p53 in favoring tumorigenesis, a specific Mdm2 inhibitor (MI-219) has been reported to synergize with oxaliplatin, which inhibits DNA synthesis, to exhibit superior anti-cancer effects in solid tumors types bearing wild-type p53 [XREF_BIBR]."
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"From oncogenic point of view extremely important appears to be that action of these two genes is interrelated : Protein product of TP53 gene -- p53 protein -- has the ability to activate (a number of genes including) MDM2 gene, resulting in an increased production of mdm2 protein, which in turn inhibits p53 protein activity and by reducing its suppressor properties may initiate the process of carcinogenesis, including EC as well [XREF_BIBR]."
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"In our previous studies [XREF_BIBR], we demonstrated that (a) the basal level of endogenous p53 protein is much higher in mouse Ube4b null MEFs than in parental wild-type MEFs; indicating Ube4b plays a critical role in regulating basal level of p53 in unstressed conditions; (b) overexpression of mouse Ube4b decreased the level of p53 in Mdm2 null MEFs, suggesting that the Ube4b dependent Mdm2 mediated p53 degradation is not absolute."
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"The difference in hepatic injury is likely unattributable to diminished DEN cytotoxity in p53 +/- rats as expression of CYP2E1, which is responsible for DEN bioactivation in hepatocytes, 14 did not differ between wild-type and p53 +/- rats, whereas the induction of p53 target gene, Mdm2 by DEN, was significantly suppressed in p53 +/- and p53 - / - rats (XREF_SUPPLEMENTARY."
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"Our finding that lenalidomide not only disrupts RPS14 association with MDM2, but also stabilizes MDM2 to promote p53 proteasomal degradation in del (5q) progenitors, suggests that strategies to induce or enhance MDM2 activity may restore effective erythropoiesis in disorders affecting integrity of ribosomal biogenesis."
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"The most extensively studied p53 activators are targeted against MDM2 – an E3 ubiquitin ligase that negatively regulates the activity and stability of p53. xref ; xref ; xref ; xref MDM2 inactivates p53 primarily by two different mechanisms: (1) physically sequestering the N-terminal trans-activation domain of p53 to suppress the expression of p53-regulated responsive genes; (2) channeling the tumor suppressor protein into the ubiquitin-proteasome pathway for degradation."
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"Recently, in mouse models carrying either the polymorphic MDM2 SNP309G or MDM2 SNP309T allele [XREF_BIBR], Post et al. found that MDM2 SNP309G/G cells exhibit elevated MDM2 levels, reduced p53 levels, and decreased p53 dependent apoptosis in response to DNA damage; importantly, those mice with two MDM2 SNP309G alleles have an attenuation of the p53 pathway resulting in a decreased latency to tumor formation and decreased survival."
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"XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR MDM2 inactivates p53 primarily by two different mechanisms : (1) physically sequestering the N-terminal trans-activation domain of p53 to suppress the expression of p53 regulated responsive genes; (2) channeling the tumor suppressor protein into the ubiquitin-proteasome pathway for degradation."
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"This is important as there has been experimental evidence that oscillations occur between p53 and MDM2 after cell stress;(2) the mechanism used to mathematically describe the degradation of p53 by MDM2 is accurate only for low concentrations of p53;(3) the concentration of p53 Ã is much higher than that of inactive p53 after the system reaching an equilibrium."
eidos
"In this way , p53 stimulates the expression of MDM2 , which in turn inhibits p53 activity through a negative feedback system developed at the level of protein degradation in the nuclear and cytoplasmic 26S proteasome and , through a positive feedback , promotes the mRNA translation of p53 through the interaction with it , striking a balance between p53 synthesis and degradation [ 37 ] ."
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"The cellular response to Mdm2 RING overexpression revealed that Mdm2 RING acted in a dominant negative fashion to suppress endogenous Mdm2 E3 ligase function and specifically in presence of a DNA-damaging signal prevented Mdm2-mediated inhibition of the p53 gene transcription activity.Under normal and stress conditions, stabilization of endogenous Mdm2 and MdmX as a result of MdmX RING overexpression was observed, whereas there was no effect on p53, phosphorylated p53, and Bax levels."
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"As speculated from the data on an rpl31 lacking yeast strain XREF_BIBR, RPL31 knockdown would impair the assembly of ribosomal large subunits, and free ribosomal proteins will inhibit the MDM2 mediated feedback inhibition of p53 in response to the same type of stresses caused by actinomycin D XREF_BIBR, XREF_BIBR."
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"The survival advantage conferred by MCUR1 mediated mitochondrial Ca 2+ uptake was majorly caused by elevated production of mitochondrial reactive oxygen species and subsequent AKT and MDM2- induced P53 degradation, which regulated the expression level of apoptosis related molecules and cell cycle related molecules."
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"The observation of more severe and earlier lens defect resulting from lack of MDM2 than that from lack of MDMX suggests that MDM2 and MDMX are able to suppress p53 by different ways, separately or synergistically, more than forming a complex, which is also indicated by the much stronger p53 signal induced by MDM2 deletion than that induced by MDMX deletion, as mentioned in the result section (XREF_FIG)."
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"In addition to them, parameters of processes forming a positive feedback loop in the p53 control system (Mdm2 and PTEN gene inactivation) and p53 degradation by Mdm2 were crucial for the model response.Substantial differences in the parameter rankings were observed for the ATM module."
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"Taken together, the current study provides mechanistic evidence that alcohol consumption induced let-7a suppression results in the upregulation of RB1, thereby promoting hepatic apoptosis through induction of pro apoptotic proteins (e.g., p73), and through, at least in part, preventing MDM2 mediated p53 degradation."
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"Since the function of cell cycle control genes including the cyclin dependent kinase inhibitors known as p15 (INK4b) and p16 (INK4a), as well as p14 (ARF) which blocks MDM-2 (an inhibitor of p53), the retinoblastoma (RB1) protein and the mismatch repair gene MGMT is critical for hematopoietic proliferation and differentiation, we performed methylation specific polymerase chain reaction (MSP) in low-density, non adherent bone marrow cells from 49 patients with MDS."
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"The identification of SUV39H1 as a p53 repressed methyltransferase in our screen is in agreement with recent reports showing that induction of p53 by various methods led to decreased RNA and protein levels of SUV39H1, whereas concomitant exogenous expression of MDM2 and SUV39H1 cooperatively inhibited p53 activity."
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"The hallmark of the study was the significant association of MDM2 expression with the p53 protein accumulation in 16/33 (49%) oral premalignant lesions (p = 0.001) and 39/65 (60%) malignant lesions (p = 0.021), suggesting an active role for MDM2 in binding and inactivating p53 in oral tumorigenesis."
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"Some of them play a significant role in p53 regulation; for example, the feedback loops involving p53, MDM2 and MDM4 (Mdm4 p53 binding protein homolog (mouse)), which include five interactions: p53 activates MDM2; MDM2 inhibits p53; MDM2 inhibits MDM4; MDM4 activates MDM2 and MDM4 inhibits MDM2 xref ."
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"The CDKN2 gene encodes two structurally different proteins : a cyclin dependent kinase inhibitor, p16, which regulates retinoblastoma protein (pRb)-dependent G1 arrest, and a cell cycle inhibitor, p14ARF, which blocks MDM2 induced p53 degradation resulting in an increase in p53 levels that leads to cell cycle arrest."
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"Novel approaches that have been tested in a preclinical setting or are currently in clinical development include adenovirus based p53 gene therapy, small molecules such as PRIMA that can restore the transcriptional transactivation function to mutant p53, and NUTLIN and RITA that interfere with MDM2 directed p53 degradation [XREF_BIBR, XREF_BIBR]."
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"Upon cellular stress, NPM1 moves from the nucleolus to the nucleoplasm where it binds MDM2, inhibiting MDM2 mediated degradation of TP53, leading to an increase in TP53 activity which results in cell cycle arrest or apoptosis.Due to such wide ranging and important cellular functions, it is not surprising that aberrant functioning of NPM1 has been found in a wide range of solid tumours such as prostate, ovarian, gastric and colon [33] ."
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"Because inhibition of p53 by MDM2 stems from their direct physical interaction, small-molecule inhibitors designed to bind to MDM2 and block the MDM2-p53 protein protein interaction (hereafter called MDM2 inhibitors), can lead to accumulation and activation of wild-type p53, thus releasing the tumor suppressor function of p53 [XREF_BIBR - XREF_BIBR]."
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"P53 is a tumor inhibitor, and its activation by reactive oxygen species leads to the autophagy and apoptosis of cancer cells; however, p53 is always inactivated in tumor cells due to the mutation or deletion of the TP53 gene or inhibited by overexpression of MDM2, leading to metastatic potential, while PD has been reported to target mutant p53 to suppress the progression of breast cancer."
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"Furthermore, we demonstrated that miR-339-5p can strongly suppress the expression of MDM2 and increase the levels and function of p53 protein; consistent with these observations, forced expression of miR-339-5p inhibits the progression of colorectal cancers in vitro and in vivo [XREF_BIBR]."
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"We examined survival duration over 10 years, relative to the individual expression of UBE2A (which stimulates p53 degradation by MDM2 ), MAGEA2 (which inhibits p53 acetylation ; prevents senescence induction and promotes proliferation ) and UTP14A (which binds p53 and promotes its degradation ) for each cancer, in a wt TP53 context."
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"Taken together, these studies present a strong case that in the embryo and in adult mice, MDM2 acts in a TP53-dependent manner to limit excessive TP53 overactivation and apoptosis in tissues, including in the endothelium.While the primary function of MDM2 might be to restrain TP53, additional evidence supports the idea that MDM2 is important for vascular homeostasis due to TP53-independent functions."
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"E1A triggers the accumulation of the p53 protein either by activating p53 transcription [XREF_BIBR] or stabilizing p53 via inducing the expression of p14 ARF tumor suppressor (referred to as p19 ARF in murine cells) which binds to MDM2 protein and subsequently blocks MDM2 induced p53 degradation and transactivational silencing [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Given that the inhibition of p53 by MDM2 protein relies on their direct binding with p53, small-molecule MDM2 inhibitors, such as Nutlin-3 that disrupts this interaction, have been utilized to induce WT p53-mediated cell-cycle arrest and apoptosis in various types of tumor cells [ xref ]."
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"For examples, the E3-E4 pair of parkin-CHIP ubiquitinates Pael-R (Pael receptor) and signals its degradation to relieve endoplasmic reticulum (ER) stress in neuronal cells, and the E3-E4 pair of mouse double minute 2 (Mdm2)-E4B induces p53 degradation and promotes the survival of cancer cells."
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"It is also interesting in our finding that consistent with enhanced binding of Mdm2-Rpl11, but not Mdm2-Rpl5, p53 induction triggered by Rps27l disruption is dependent of Rpl11, but independent of Rpl5, although both are key ribosomal proteins, released from nucleolus upon ribosomal stress, to inhibit Mdm2 mediated p53 degradation."
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"This is important as there has been experimen-tal evidence that oscillations occur between p53 and MDM2 after cell stress; (ii) the mechanism used to mathematically describe the degradation of p53 by MDM2 is accurate only for low concentrations of p53; and (iii) the concentration of p53 * is much higher than that of inactive p53 after the system reaches an equilibrium."
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"For example, a classic p53 regulator Mdm2, an E3 ubiquitin ligase, inactivates p53 by accelerating its nuclear export and degradation when cells are under a basal condition. xref Our findings suggest that UGT1A genes act as an important p53 regulator by maintaining p53 elevation after cellular stress."
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"Together, the above results demonstrate that p53 induction by MDM2 deletion occurs much earlier and is stronger than that by MDMX deletion in endocrine pancreas, which probably accounts for the distinct phenotypes observed in the mice with endocrine specific deletion of MDM2 or MDMX."
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"Our Rps27l acute depletion experiment conducted in both Trp53-wt and Trp53-null MEFs clearly showed a sequential change in the levels of Mdm2 (increase), Mdm4 (decrease) and p53 (increase), indicating that (1) Rps27l depletion induces p53 independent Mdm2 increase and (2) increased Mdm2 fails to degrade p53."
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"In sarcomas, malignant tumours resembling mesenchymal tissue, amplification of MDM2 (murine double minute 2) is relatively common (20%) in tumours having TP53 Wt, resulting in disabled p53 function because overexpressed MDM2 protein binds to and inactivates p53 [XREF_BIBR, XREF_BIBR]."
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"MDM2 is a known inhibitor of p53, but MDM2 also has over one hundred other interacting proteins whose link to p53 inhibition and cell growth controls are not well defined; nor is there an annotation of which of these over hundred MDM2 interactors are dominant or less significant which would clarify their importance as therapeutic targets in cancer XREF_BIBR."
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"However, deregulated p14 ARF levels may have a significant impact on the accelerated G1/S progression in SENP8 knockout cells, as p14 ARF plays a critical role as a tumor suppressor protein by blocking mouse double minute (MDM2)-induced degradation of p53, and inhibiting E2F transcriptional activity."
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"XREF_BIBR To date, more than 20 E3 ubiquitin ligases for p53 have been identified, including MDM2, RCHY1 (Pirh2), RFWD2 (COP1), STUB1 (CHIP), HUWE1 (ARF-BP1), Synoviolin, Cul1/4, RNF34 (CARP-1), RFFL (CARP-2), FBXO42 (JFK), and TOPORS, which promote p53 degradation through the proteasome degradation pathway."
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"Although stress signals have been shown to compromise MDM2 induced ubiquitination and proteolysis of p53 and thus activate p53 in normal cells, cancer cells employ oncogenic molecules, such as MDMX, which strengthen MDM2 mediated inhibition of p53 and thus induce cell resistance to p53 activation."
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"In HCT116 cells, 5-FU increased p21 mRNA and MDM2 but failed to accumulate p21, suggesting that MDM2 might antagonize p53 mediated growth inhibition through ubiquitination and destabilization of p21.33 In this context, MDM2 knockdown using chiMDM4 and chiMDM2 might disrupt these negative effects of MDM2 on p53- and p21 mediated growth inhibition and potentiate the antitumor activity of 5-FU."
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"It has been shown that circ-Foxo3 can promote MDM2 induced degradation of p53 by binding to MDM2 and p53; however, circ-Foxo3 contributes more to repression of MDM2 induced Foxo3 ubiquitination by binding to Foxo3 and thus increasing the expression of the downstream gene PUMA to induce apoptosis in breast carcinoma [XREF_BIBR, XREF_BIBR]."
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"P53 can be degraded by MDM2 via polyubiquitination and proteasome dependent pathways, however, p53 can also enhance MDM2 transcription through p53 specific response elements in the promoter region of MDM2, thus forming an autoregulatory feedback loop to control the balance of p53 and MDM2 in vivo [XREF_BIBR, XREF_BIBR]."
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"In the setting of radiation induced damage, AKT regulates cell cycle progression, in part, by direct phosphorylation of the Chk1 protein kinase, a key component of the DNA damage sensing and repair mechanism, or through phosphorylation of MDM2 modulating p53 degradation [XREF_BIBR, XREF_BIBR]."
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"In this way, p53 stimulates the expression of MDM2, which in turn inhibits p53 activity through a negative feedback system developed at the level of protein degradation in the nuclear and cytoplasmic 26S proteasome and, through a positive feedback, promotes the mRNA translation of p53 through the interaction with it, striking a balance between p53 synthesis and degradation [XREF_BIBR]."
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"Genetic disruption of MDM2 in adipocytes triggers canonical p53 mediated apoptotic and senescent programs, leading to age dependent lipodystrophy and its associated metabolic disorders including type 2 diabetes, non alcoholic fatty liver disease, hyperlipidemia and energy imbalance."
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"Overall, MDM2 and MDMX deletion models have suggested the following notions about MDM2- and MDMX mediated p53 regulation : (i) MDM2 is the master regulator of p53 and is necessary to prevent p53 dependent cell death at all stages following embryonic day 5; (ii) MDMX may serve to enhance MDM2 mediated p53 inhibition and/or degradation in a developmental and tissue specific manner."
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"First, when combined with the p53 neo allele, which expresses ~ 15% of wild type p53 levels, MEFs containing MDMX DeltaRING appear to display greater p53 activity with no difference in p53 stabilization compared to MEFs containing wild type MDMX, suggesting that MDMX does not necessarily contribute to MDM2 mediated p53 degradation."