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MDM2 inhibits TP53. 1000 / 5310
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"However, since Mdm2 regulates p53 activity in proliferative and terminally differentiated stages of the same cell type [XREF_BIBR, XREF_BIBR], and this regulation has been demonstrated even in quiescent cells [XREF_BIBR], Mdm2 probably inhibits p53 in any spatial and functional compartment of the lens in which they may interact."
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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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"However, in light of previous reports revealing a physical interaction of EZH2 and the p53 antagonist MDM2 [75] and recent findings suggesting EZH2 as a specific and important inducer of the translation of the p53 mutant protein in prostate cancer [76], non-canonical EZH2 functions might additionally contribute to the increased protein turnover of p53wt in EZH2-proficient PDAC."
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"In nearly half of cancer cells, the overexpression of Mdm2 or MdmX proteins inhibits p53 activity, resulting in persistently low levels of p53 protein.Therefore, for cancers with an overexpression of Mdm2/MdmX, developing effective inhibitors that target Mdm2/MdmX to release p53 and restore its normal tumor-suppressive function could provide new approaches to overcoming the challenges of cancer prevention and treatment."
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"Therefore, p53 becomes an ideal target for cancer gene therapy.In non stressed cells p53 protein is present at very low cellular concentrations, because it interacts with the hdm2 protein, the human analogue of the murine mdm2 (mouse double minute 2), which acts as an ubiquitin ligase (3, 4) and promotes p53 degradation (5, 6)."
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"37 The modest induction of p53 in response to MDM2 and/or MDM4 depletion contrasted with the dramatic induction of p53 and p53 mediated cell death in response to Nutlin-3a, 20 most likely because residual MDM2 mediates p53 degradation after MDM2 knockdown whereas Nutlin-3a effectively blocks MDM2 mediated p53 degradation."
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"We propose a model in which these miRNAs are : 1) regulators of the auto-regulatory loop, increasing the window of time between p53 apoptotic action and p53 degradation by MDM2; and 2) at the same time targeting the IGF axis, antagonizing the MDM2 ubiquitin ligase function on IGF-1R (XREF_FIG)."
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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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"The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter."
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"These findings and the present results indicate that PUMA plays a dominant role over other BH3-only members of the BCL2 family in p53-dependent stem cell apoptosis.The present results also revealed that survivin was not only a downstream mediator of p53-dependent apoptotic glioma stem cell death induced by the inhibition of MDM2, but was also a unique vulnerability of glioma stem cells, similar to MDM2."
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"Mouse genetic studies demonstrate that disruption of either MDM2 or MDM4 RING domains causes p53-dependent embryonic lethality [14–16], establishing that RING-RING mediated MDM2-MDM4 heterodimer formation is crucial for p53 regulation in vivo.MDM2-MDM4 heterodimers can negatively regulate p53 function by two distinct mechanisms: masking p53 transcriptional transactivation through direct p53 binding or promoting p53 degradation through their E3 ligase activity."
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"The importance of the acetylation status of p53 (and thus the role of direct HDAC-p53 interactions) is controversial [XREF_BIBR], however there is evidence that acetylation of p53 is enhanced in the setting of cellular stress [XREF_BIBR], is required to interrupt Mdm-2 mediated repression of p53, [XREF_BIBR, XREF_BIBR] increases the affinity of p53 for DNA [XREF_BIBR], reduces ubiquitin mediated degradation of the transcription factor [XREF_BIBR], and can enhance expression of p21 Waf1 and Cip1 [XREF_BIBR]."
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"Upon induction by p53, Mdm2 inactivates p53 through at least two main mechanisms: (a) binding to p53 at its transactivation domain and blocking its transactivation activity, and (b) serving as an E3 ubiquitin ligase to promote a rapid degradation of p53 ( xref ; xref ; xref ; xref ; xref )."
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"We found only one example of a mutation in an IDR binding pocket: Levine and coworkers have previously described mutations in the p53-binding groove of Mdm2 and found that single mutations in Mdm2 (residues G58 and V75) abrogate binding of p53 – a result similar to described above for HIF-1α CTAD and TAZ1."
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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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"While both idasanutlin and FX1-5303 act along the USP7/MDM2/p53 pathway to block p53 degradation, direct MDM2 inhibition with idasanutlin led to much larger and more sustained increases in p53 activity compared to the upstream inhibition of USP7 with FX1-5303.This effect cannot be easily attributed to a difference in potency of these compounds, since both idasanutlin and FX1-5303 inhibit the cell viability of MM1.S cells equipotently (Figure S4B)."
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"The principal mechanism that links nucleolar disruption with p53 activation and mammalian cell cycle arrest utilizes MDM2 (murine and/or human double minute 2), the ubiquitin E3 ligase that negatively regulates p53 by marking it for ubiquitin mediated proteasomal degradation (see XREF_FIG)."
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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_BIBR]."
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"Moreover, some groups reported that p19ARF can associate with MDM2 (a p53 ubiquitin protein ligase) or inhibit the E3-ligase activity of MDM2 to prevent MDM2 induced p53 degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] suggesting that these proteins -- p19ARF, MDM2 and p53 -- exist in a common regulatory pathway."
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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 diversity is achieved in part because Hdm2 uses multiple mechanisms to inactivate p53; it targets p53 for ubiquitination and degradation by the proteosome [6-8], shuttles it out of the nucleus and into the cytoplasm [9, 10], prevents its interaction with transcriptional coactivators [11], and contains an intrinsic transcriptional repressor activity [12]."
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"Proteins coded by these three genes are all well known to play an important role in cell cycle regulation and apoptosis; thus p16 INKa and p15 ARF regulate cell cycle progression at the G1/S-phase checkpoint by inhibiting cyclin-cdk complexes, whereas p14 ARF regulates apoptosis through a blockade of MDM2 mediated degradation of p53 [XREF_BIBR]."
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"For example, the oncogene MDM2 is critical for p53 subcellular distribution [13] and can degrade p53 rapidly [14], and human herpesvirus proteins are able to repress p53 transcriptional activity [15], finally inducing malignant transformation.Dysfunction of p53 occurs also when the p53 gene itself is mutated; this knowledge, which was achieved more than a decade ago [16], is regarded as one of the basic scientific keys that facilitates understanding of the development of malignancies."
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"Artificial inhibition of p53 using p53 siRNA, p53 dominant negative forms and p53 antagonist MDM2 can recover cell viability and HDR frequency ; however, it remains uncertain whether such forced suppression of physiological p53 activation is free from long-term genome instability and unexpected side effects."
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"This is supported by findings showing that telethonin promotes Mdm2 mediated degradation of the pro apoptotic transcription factor p53 in the nuclear compartment upon biomechanical stress.8 The ubiquitin-proteasome system (UPS), together with autophagy, controls skeletal muscle proteolysis and protein mass."
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"Proposed Model of the Mechanism whereby Hdm2 Recruits CtBP Proteins to Negatively Regulate p53 Dependent Transcription (A) Recombinant human p53, Hdm2, and GST-hCtBP2 (1-110) were mixed as indicated and subjected to either GST pull-down analysis or immunoprecipitation with mAb 2A9 to Hdm2."
eidos
"The signaling pathways described to play a role in neuroblastoma cells are ( 1 ) PI3K / AKT / mTOR pathway - - promotes NB cell survival and chemoresistance ; ( 2 ) Wnt signaling , which is involved in drug resistance , stemness , and increases MYCN levels ; ( 3 ) p53-MDM2 pathway , where MDM2 inhibits p53 activity , promotes angiogenesis , increases MYCN translation , and promotes drug resistance ."
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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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"14
MDM2 overexpression can downregulate P53 activity and promote P53 degradation through the proteasome pathway, which in turn leads to tumor suppressor P53 pathway inactivation, allowing cells to pass through the cell cycle in the presence of DNA damage, which in turn initiates tumorigenesis."
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"We have recently demonstrated that inhibitors of the MDM2 dependent degradation of p53 exert anti-cancer effects also in the cells carrying these mutations [XREF_BIBR], suggesting that in the absence of the transcriptional activity, the mitochondrial apoptotic pathway induced by p53 is still active [XREF_BIBR]."
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"Comparedto normal splenic B cells, it has previously been shown that mdm-2 mRNA is increased in 30% of CLL patients, and overexpression at the RNA appears to correlate
with protein expression as assessed by immunohistochemistry of the CLL cells.[331As mdm-2 inactivates p53, it would be expected that those patients overexpressing mdm-2 mRNA might be drug resistant.[129131 However, althoughwe found a twenty-fold variation in mdm-2 mRNA levels in our patients, we found no correlation between expression and resistance to any of the drugs."
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"An earlier study on WI-38 fibroblasts reported that Nutlin3a, a small molecule that stabilizes p53 by interfering with MDM2-mediated degradation of p53, stimulates p53 transcriptional activity when cells are in a senescent state, but not to the same extent as when they are cycling ."
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"4 These small molecules have received much attention from academia and industry in the past decade, since the function of wild-type (WT) p53 is inactivated by overexpression 5 or amplification 6 of MDM2, even though the p53 gene is either deleted or mutated in approximately 50% of all human cancers."
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"26
Single nucleotide polymorphisms in the promoter region of MDM2, as well as amplified MDM2 gene, have been observed in various malignant tumors, including breast cancer, lung cancer, esophageal cancer, colon cancer, and various sarcomas,
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and antagonists of MDM2/MDMX can reactivate the p53 pathway and enhance the apoptosis of RB cells,
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while the high expression of MDMX and MDM2 subsequently inhibits the p53 pathway during tumor development."
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"* Ongoing clinical trials are examining treatment strategies using FAK inhibitors in combination with chemotherapy, targeted therapy, or checkpoint inhibitors to increase efficacy.This box summarizes key points contained in the article.of FAK acts as a scaffold for MDM2 and p53 and promotes MDM2 mediated p53 degradation by ubiquitination, thus inhibiting apoptosis and promoting cancer cell survival [19]."
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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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"Subsequently, it was found to interact with p53 and to inhibit its function through two main mechanisms : first, the direct binding of Mdm2 to the N-terminal domain of p53 inhibits the transcriptional activation function of p53; second, Mdm2 possesses E3 ubiquitin activity that targets p53 for degradation through the 26S proteasome."
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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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"Our results are in consistence with recent reports that MDM2 may negatively regulate genomic stability independent of p53 by directly binding to Nbs1 of the MRN complex to impair MRN complex mediated ATM activation and subsequent DNA damage response in other model systems XREF_BIBR - XREF_BIBR, XREF_BIBR."
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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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"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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"Under normal conditions, MDM2 promotes the degradation of p53 via protein-protein interactions while following genotoxic stress, the stress sensor ATM kinase is activated by double-stranded DNA breaks and phosphorylates MDM2(S395) inducing a conformational change which dramatically increases the affinity of MDM2 for the p53 mRNA [6–14]."
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"Recently discovered is that MDM2 has been found to disrupt the function of p53 via blocking p53 transcriptional activity and p53 protein degradation; such inconsistent activity of MDM2 for suppression of p53 expression is related to the higher progression of various types of malignancies, especially brain cancer [20,21,22]."
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"The present results revealed that tanshinone IIA combined with imatinib not only synergistically inhibited MDM2 protein expression but also inhibited the phosphorylation of MDM2 (ser166) by synergistically inhibiting the phosphorylation of AKT (Ser473), thereby more effectively inhibiting MDM2-induced degradation of P53 and thus activating the P53 signaling pathway more effectively."
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"Thus, HDM-2 limits the ability of p53 to stimulate the apoptosis of transformed cells.PNC-27 was originally designed by our research group to block the binding of p53 to HDM-2 in the nuclei of cancer cells as a “decoy” peptide, i.e., the peptide would cross the cancer cell and nuclear membranes using its penetratin sequence and bind to HDM-2 in place of the full p53 protein, hopefully enhancing p53-induced apoptosis of the cancer cells [13]."
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"Since errant activation of p53 could have disastrous consequences for multicellular organisms, it is tightly regulated primarily through its interaction with the ubiquitin E3 ligase MDM2 (mouse double minute 2), which suppresses p53 transcriptional activity and promotes its proteasomal degradation."
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"Consistent with the ability of Ski to inactivate p53, overexpressing Ski desensitized cells to genotoxic drugs and Nutlin-3, a small-molecule antagonist of Mdm2 that stabilizes p53 and activates the p53 pathway, whereas knocking down Ski increased the cellular sensitivity to these agents."
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"As described above, MDM2 and MDMX are two physiological inhibitors of p53 and work together as a complex and/or independently to control p53 level and activity by directly blocking p53 's transactivational activity and promoting its ubiquitination dependent proteasomal degradation, in a spatial-temporally specific manner."
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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 order to analyze DNA damage caused by NPRL2 ectopic expression, we used three cell lines with different status of p53: 1) HEK293 cells expressing constitutively active p53; 2) H1299 non-small lung cancer cells, in which p53 is deleted xref and 3) U2OS osteosarcoma cells, where p53 is inhibited by MDM2."
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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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"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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"MDM2 inhibits p53 by: ( i ) ubiquitinating p53 to promote its proteasomal degradation; xref ( ii ) binding to the N‐terminal activation domain of p53, masking its ability to activate transcription; xref and ( iii ) participating in the nuclear export of p53. xref In turn, p53 regulates MDM2 expression at the level of transcription as part of an autoregulatory feedback loop. xref "
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"Chronic catecholamine stimulation of the beta 2 AR results in the accumulation of chromosomal DNA damage in both somatic and germ cells via beta-arrestin1-dependent mechanisms that include : PI3K and AKT activation, AKT mediated phosphorylation and activation of the E3 ubiquitin ligase Mdm2, Mdm2 mediated ubiquitination and proteasomal degradation of p53."
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"w xy represents the suppression of Mdm2 by ATM, w yz represents the suppression of p53 by Mdm2, w zy represents the transcriptional activation of Mdm2 by p53, w y represents the stability of Mdm2 (1-w y represents Mdm2 degradation), and w z represents the stability of p53 (1-w z represents p53 degradation)."
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"Within the p53-Mdm2 negative feedback loop, post-translational suppression of p53 by Mdm2 achieves a better trade-off between steady-state and transient errors than transcriptional suppression, which potentially explains why the former has been experimentally observed in the cell."
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"Sustained activation of AKT makes tumor cells insensitive to antiproliferative
signals by inducing the nuclear entry of Mdm2, which leads to the
inhibition of p53-regulated processes, and by inducing cytoplasmic
localization of p21Cip/Waf1 and p27Kip, which promotes cell proliferation."