IndraLab

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MDM2 bound to TP53 inhibits TP53. 114 / 114
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"For this reason, inhibition of the interaction between MDM2 and p53 to reactivate endogenous p53 activity offers the opportunity for therapeutic intervention, particularly in GBMs."
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"They inhibit p53 via distinct mechanisms, with iASPP binding p53's C-terminus and inhibiting p53's transcriptional activity [ 25 , 26 ], while MDM2 binds p53's N-terminus and degrades p53 protein [ 16[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Mdm2 binds to p53 in a region of its transactivation domain and blocks the ability of p53 to activate transcription (reviewed in [106,107])."
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"It is well established that p53-MDM2 forms a negative auto-regulatory feedback loop in which p53 transactivates MDM2, whereas induced MDM2 binds to p53 and promotes p53 degradation."
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"P53 activates the transcription of Mdm2, which binds p53 (40), ubiquitinates it, and thus initiates the proteasomal degradation of p53 both in the nucleus and cytosol (41)."
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"MDM2 interacts with p53, inducing its inactivation by blocking the arrest of p53 in cell cycle stage G1, thereby promoting the cell cycle."
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"The interaction between Mdm2 and p53 is essential for Mdm2 to block the p53 response."
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"Although we cannot rule out the possibility that the physical interaction between Mdm2 and p53 still inhibits p53 function to a certain extent, or toward a specific set of target genes, our study has [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"After p53 is phosphorylated at Ser15 which is located within the α-helix of MDM2-p53 interaction, the interaction between MDM2 and p53 is blocked, allowing the stable accumulation of p53 protein [ 37 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Thus, the MDM2/p53 interaction hampers p53 transcriptional regulatory activity and accelerates degradation of p53 within the proteasome [7]."
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"MDM2 can bind directly to p53 and promote the degradation of p53 protein (Momand et al., 1992; Oliner et al., 1992); this mechanism forms a circuit for negative regulation of p53."
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"UBX0101 is an inhibitor of the interaction between MDM2 and p53 which allows p53 to facilitate the induction of apoptosis [12,39]."
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"P53 protein levels are regulated by the MDM2 protein which binds p53 at the amino-terminal region to promote ubiquitin-dependent degradation of p53 (Haupt et al ., 1997; Prives, 1998) ."
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"Small molecule inhibitors of the interaction between HDM-2 and p53 such as nutlin restore p53 function in tumor cells with wtp53."
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"The disruption of the interaction between Mdm2 and p53 increases the stability of p53 and is responsible for the increasing of p53 to different steady states."
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"RITA was shown to disrupt the interaction between p53 and MDM2, and was able to reactivate p53 in tumours that have aberrant MDM2 expression."
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"RITA is known to disrupt the p53 and MDM2 complex and hereby reduces degradation of wild-type p53 and reactivates its transcriptional function XREF_BIBR, XREF_BIBR."
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"Genomic stress causes inhibition of binding of Mdm2 to p53, which allows p53 to accumulate and cause cell cycle arrest or apoptosis.47,48 Hypothetically, absence or dysregulation of p53, RB, Mdm2, or p16 may allow genetically damaged cells to proliferate."
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"The MDM2–p53 complex also inhibits p53 mediated transactivation [26] ."
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"MDM2 directly binds to and forms a complex with p53, inhibiting p53 transactivation23."
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"MDM2 binds to p53 blocking its trans-activation domain and inducing p53 degradation.Treatment of cancer cells with MDM2 antagonists should induce transcriptional activation of p53 downstream genes and[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"A homolog of Mdm2, MdmX (or Mdm4), can similarly bind p53 and inhibit p53 dependent transactivation although unlike Mdm2 it lacks E3 ubiquitin ligase activity [XREF_BIBR]."
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"These data build a compelling case in favor of MDM2 as the mediator of p53 degradation.Mere complex formation between MDM2 and p53 is not sufficient to mediate p53 degradation."
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"MDM2 binds and blocks the N-terminal trans -activation domain of p53, causing the accumulation of p53 in these cells before ubiquitination."
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"Ribavirin stimulated the expression of the p53 dependent gene Mdm2, which can bind to p53 and inhibit the activation of p53 by targeting p53 protein for degradation through the ubiquitin dependent proteolytic pathway XREF_BIBR."
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"In this process, MDM2 binds directly to p53 and mediates the ubiquitination dependent degradation of p53."
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"By dephosphorylation of MDM2 and making its stability, Wip1 can enhance the interaction between MDM2 and p53, to promote the degradation of p53 protein [XREF_BIBR - XREF_BIBR]."
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"Mdm2 binds to p53 and then induces p53 degradation."
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"For instance, p48 EBP1 physically associates with MDM2 (also known as HDM2) and enhances the interaction between MDM2 and p53, promoting p53 degradation in glioblastoma cells of patients with poor clinical outcome (4)."
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"Three amino acids of p53 (Phelg, Trp23 and Leu26) are buried deep into the Mdm2 pocke09,2 Interaction between Mdm2 and p53 has previously been shown to block the bio- logical activity of p53, presumab[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Under normal conditions Mdm2 is tightly bound to p53 thereby blocking the N-terminal transactivation domain of p53, which allows p53 to undergo proteosomal degradation by ubiquitin dependent mechanism[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Inhibition of p53 and Mdm2 interactions by small molecule (nutlin-3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway."
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"Small molecule inhibitors of the MDM2 and p53 interaction have been identified, such as the Nutlins XREF_BIBR, which were the first generation of agents directly targeting this pathway, and bind in MDM2 's p53 binding pocket in the N-terminal region to induce p53 accumulation."
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"Elevated Mdm2 protein levels induced by Ras activation may bind those mutated forms of p53 and abolish remaining p53 function."
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"Mdm2 then binds the amino terminus of p53, thereby preventing p53 from interacting with the transcriptional machinery [9,10]."
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"MDM2 binds directly to p53 and represses its transcriptional activity, promoting p53 degradation."
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"MDM2 binds directly to p53, acting as a major negative regulator by repressing its transcriptional activity, and promotes p53 proteasomal degradation (19)."
37326394
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"MDM2 constantly binds to p53, thereby enabling the degradation of p53 by proteasomes [94,95]."
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"Our findings are in agreement with a report showing that CMA degrades mutant p53 in a lysosome dependent manner.17 We showed that inhibition of p53 and Mdm2 interaction using nutlin-3 or silencing Mdm2 did not prevent degradation of p53 in an HCV infected culture."
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"Disruption of the MDM2 and p53 interaction leads to increased p53 levels and restored p53 transcriptional activity, indicating restoration of the genome integrity check and therapeutic potential for MDM2 and p53 binding antagonists."
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"XREF_BIBR, XREF_BIBR, XREF_BIBR Except for cancer selected p53 mutations, the p53 activity is mainly inhibited by p53 binding proteins Mdm2 and MdmX ((MDM4), mouse double minute 4) in normal and cancer cells."
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"Phosphorylation of p53 at serine 15 attenuates MDM2 binding to p53 and thus promotes p53 stability 55."
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"This oncoprotein MDM2 binds p53 and negatively regulates the p53 activity via the direct inhibition of the p53 transcriptional activity and enhancement of p53 degradation via the ubiquitin–proteasome pathway."
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"Binding of MDM2 to p53 inhibits its transcriptional activity and targets p53 for ubiquitin-dependent proteolysis [2,3] ."
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"As a result of the NOC2L association with MDM2, NOC2L facilitates MDM2-mediated P53 repression by sustaining the stability of MDM2 itself and the MDM2-P53 complex, which further represses the P53-mediated transcriptional activation significantly [8]."
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"When the membrane caveolae of Ewing’s sarcoma cells are restored by the reintroduction of CAVIN1/PTRF, the MDM2/p53 complex is disrupted, resulting in p53 activation and induction of apoptosis [40]."
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"In turn, MDM2 binds to p53, which (a) blocks its N-terminal transactivation domain and (b) targets p53 for degradation via the ubiquitin-proteasome system following ubiquitinylation through its E3 ligase activity."
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"It was known prior to these reports that MDM2 could bind p53 and prevent p53 dependent transcriptional activation of target genes, that tumor cells that had elevated MDM2 also contained wild-type p53 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The E3 ubiquitin ligase MDM2 directly binds to p53 and promotes its nuclear export and proteasomal degradation, thus suppressing p53’s transcriptional activity [222]."
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"Early studies of the p53/MDM2 interaction showed that MDM2 binds p53 within its transcriptional activation domain and may act simply to block access of this region of p53 to other components of the tr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Mdm2 binds to p53 and is thought to repress p53 activity via two main mechanisms: by promoting degradation and blocking p53 transcriptional activation [12,13,17] ."
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"Therefore, the disruption of the MDM2 and p53 complex by small molecules such as nutlin-3a and the administration of the active p53 protein can effectively restore the apoptotic activity of the p53 protein in tumor cells."
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"Binding of MDM2 to p53 inhibits the transcriptional activity of p53 and targets it for proteasomal degradation [XREF_BIBR]."
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"MDM2 binds p53 directly through N-terminal transactivation domain to inhibit p53 transactivation."
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"The similarity between the ZCP-MDM2 interaction and the P53-MDM2 interaction suggests that ZCP blocks the formation of the MDM2 and P53 complex, causing P53 release."
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"It is reported that MDM2 can bind to p53 and block the p53 signaling pathway, and could also promote the degradation of p53; when p53 is activated, in turn, it also inhibits the transcriptional expression of MDM2."
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"Acting as an ubiquitin (Ub) protein ligase (E3), MDM2 (also called HDM2) can bind and ubiquitinate TP53 and promote rapid degradation of TP53 through the ubiquitin proteolysis pathway, which keeps TP53 at low levels in the absence of stress signals."
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"Small-molecule MDM2 antagonists that disrupt the interaction between p53 and MDM2 to activate the p53 pathway have shown initial signs of antitumor efficacy in patients with solid and hematologic malignancies."
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"In fact, it is known that Mdm2 binds most of the cellular p53, which both inhibits the ability of p53 to activate transcription and targets p53 for proteolytic degradation, thus maintaining low levels of p53 under normal conditions."
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"The critical negative regulator MDM2, which is often amplified in human cancer, directly binds to p53 and inhibits p53 transcriptional activation [8,9] ."
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"ARF can bind to MDM2 and promote MDM2 degradation , and MDM2 can form a complex with p53 and inhibit p53-mediated activation ."
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"102 In cells containing wild-type p53 and subjected to various stimuli, p53 normally transcribes the MDM2 gene to produce MDM2 protein, and in turn, the binding of MDM2 to p53 directly inhibits p53 function.102 Notably, MDM2 expression is abnormally upregulated in different cancer types."
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"Binding of MDM2 to p53 blocks the transcriptional activity of p53 and promotes its proteosome-mediated degradation."
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"Mdm2, an important negative regulator of the p53 tumor suppressor, binds to p53 and inhibits p53 mediated transactivation."
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"Surprisingly, the protein product of mdm2 binds p53 and inhibits p53 mediated transcriptional activation (Momand et al., 1992; Oliner et al., 1993; Zauberman et al., 1993)."
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"Mdm2 binds the transactivation domain of p53 and inhibits the ability of p53 to activate transcription."
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"HDM2 oncoprotein physically associated with p53 and inhibits wild-type p53 transactivation function."
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"EZH2 was verified to bind to MDM2, and MDM2 could bind p53 to promote p53 degradation, which then influenced CRC progression [33, 34]."
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"XREF_BIBR, XREF_BIBR As proteasomal degradation is not compromised in E/R positive leukemic cell lines (data not shown), we tested whether Nutlin-3, a small molecule that disrupts the MDM2 and p53 interaction, can reactivate p53 signaling."
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"Binding of Mdm2 to p53 inhibits the transcriptional activity of p53 and targets it for proteasomal degradation [15] ."
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"Inhibition of MDM2 binding to p53 prevents its degradation and activates p53 to function in the cell."
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"In the basal setting, Mdm2 binds p53 and promotes p53 degradation."
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"Pharmacological targeting of the pivotal Mdm2 and p53 interaction with natural compounds, small molecules, and even stapled (helix linked) peptides, has been extensively investigated in an effort to restore the tumor suppressor activity of wild-type p53."
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"Nutlin-3, a specific inhibitor of the MDM2 and p53 interaction, is able to relieve the ensuing p53 attenuation, which leads to cell cycle arrest and enhanced apoptosis in the affected cells."
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"On the one hand, MDM2 binds to p53 to prevent the transcriptional activation of p53 and promote p53 degradation through ubiquitination."
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"First, Mdm2 binds p53 19 and inhibits the transactivation function of p53 20,21."
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"By binding to p53, MDM2 inactivates the anti-tumor function of p53 and prevents it from intervening in the cell cycle (36)."
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"MDM2 may bind P53 and promote P53 degradation at baseline but stimulate P53 translation under stress XREF_BIBR."
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"Mdm2 binds to the tumor suppressor p53 and inhibits transcriptional activation of p53 target genes [45]."
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"The p53 protein increases MDM2 levels by upregulating the expression of the MDM2 gene, which then binds to p53 and causes p53 degradation as a negative regulator (Shangary and Wang, 2008)."
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"Nutlin-3, a small molecule MDM2 antagonist blocking interaction between MDM2 and p53, activates p53 resulting in cell growth arrest or apoptosis in various cancer cells."
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"The binding of MDM2 to p53 inactivates p53 and removes growth regulation by this protein, in a manner similar to that seen in virally induced cancers6,8."
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"circFoxo3 binds to MDM2, which is associated with p53, to induce p53 degradation."
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"MDM2 binds to p53, inactivates p53 transcription function, inhibits p53 acetylation, and promotes p53 degradation."
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"MDM2 inhibitors commonly disrupt the binding between MDM2 and p53, thereby activating wild-type p53."
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"Mdm2, an E3 ubiquitin ligase that binds to p53 and targets it for destruction, is overexpressed in many cancer types, impairing the ability of p53 to perform its intended role."
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"Phosphorylation of p53 on Ser 15 reduces binding of the mdm2 oncogene product to p53 in vitro [88] , and binding of mdm2 to p53 promotes rapid degradation of p53 by targeting it for proteolytic degrad[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"MDM2 binds to p53 at its DNA-binding domain which directly inhibits p53-mediated transactivation [95]."
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"MDM2 directly binds to and forms a complex with p53, inhibiting the transactivation of p53."
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"MDM2 binding to p53 inhibits p53 dependent apoptosis by suppressing transcriptional activation of p53 in response to DNA damage, exporting p53 out of the nuclease and targeting p53 for proteasomal degradation due to E3 ligase activity of MDM2."
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"The first small-molecule inhibitor of p53 and mDM2 interaction, 4, 5-dihydroimidazoline (nutlin, Roche), was demonstrated to bind to mDM2 and induce p53 dependent cell cycle arrest at low micromolar levels in vitro [XREF_BIBR]."
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"MDM2 binding to p53 TADs inhibits p53 activity by preventing it from regulating the target genes [60,61]."
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"MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation."
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"Interestingly, the binding between MDM2 and p53 can negatively regulate the transrepression function of p53 (Chen et al. 1995)."
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"In addition, HDM2 binding to p53 blocks its transactivation domain preventing p53 transcriptional activation of its target genes."
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"Concomitantly, Mdm2 binding to p53 is reduced, which results in p53 accumulation in the nucleus and, consequently, NCC apoptosis and craniofacial anomalies."
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"In unstressed cells, p53 activity is negatively regulated by MDM2 (Mouse Double Minute 2), which binds to p53 and promotes its proteasomal degradation [5,6,7,8]."
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"Very recently, we identified that p48 Ebp1 physically associates with HDM2 and enhances the interaction between HDM2 and p53, promoting p53 degradation in human glioma cells with poor clinical outcome[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"MDM2 directly binds to p53 and promotes the ubiquitination and proteasomal degradation of p53 [106,107]."
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"In addition, binding of Mdm2 to p53 can directly inhibit the transcriptional activity of p53 through a number of mechanisms."
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"P14 prevents the formation of the MDM2-p53 complex, thus inhibiting the degradation of p53 induced by MDM2."
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"Milademetan is an oral small molecule inhibitor of the MDM2-p53 complex that reactivates p53."
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"Both DNA-PKcs and ATM can phosphorylate p53 at serine 15, which inhibits the MDM2 binding to p53 and promotes both nuclear accumulation and activation of p53 in response to DNA damage."
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"For example, MDM2 can directly bind to p53 to inhibit its transcriptional activity; quickly enhance the ubiquitination and degradation of p53 through ubiquitin-E3 ligase; and promote p53 degradation by blocking p53 's transport from the nucleus to the cytoplasm XREF_BIBR XREF_BIBR."
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"The direct binding of Mdm2 to p53 inhibits the transcriptional activation function of p53 [XREF_BIBR]."
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"The interaction between Mdm2 and p53 directly inhibits p53 transcription activity and blocks p53 dependent activation of downstream effectors [5]."
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"Once cells are stimulated, the binding between MDM2 and p53 is disrupted, resulting in p53 protein accumulation, which enables cells to respond to stimulus."
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"MDM2 binds to p53, enhancing the degradation of p53 through the ubiquitination pathway 57-60, as well as concealing the activation domain of p53 (Ref."
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"Indeed, they were designed to inhibit the interaction between the MDM2 and p53, which promotes the degradation of p53."
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"This may lead to impairment of MDM2 binding to p53, a plausible mechanism for p53 induction because it prevents degradation of p53 ( Shieh et al., 1997; Unger et al., 1999 ; for a review see Bode and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"However, in response to cellular stress (eg, DNA damage, hypoxia, oncogenic activation), the interaction between MDM2 and P53 is disrupted, which leads to stabilization of P53."
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"Embryonic lethality of Mdm2 C462A mice is rescued by p53 loss indicating that Mdm2 binding to p53 is not sufficient to inhibit p53 in vivo."
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"It was reported that p53 pathway could be activated by blocking the interaction between MDM2 and p53, which induced cell cycle arrest, apoptosis and growth inhibition of p53 wild-type tumor xenograft [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"We assume in these patients that MDM2 formed a complex with wild-type TP53 and inhibited the ability of TP53 to activate transcription of its target gene (s)."
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