No evidence text available
"For tumors that retain wild-type p53, therapeutic strategies aimed at removing the inhibitory activity of MDM2 on p53 are under development and to date have focused on drugs that prevent the binding of p53 to MDM2."
"In our recent paper we report that p53 reactivation by a small molecule inhibitor of p53-MDM2 interaction, Nutlin-3a, induces selective and massive apoptosis in PEL cells, and has striking anti-tumor activity in a mouse xenograft PEL model."
"A number of small molecules and peptides have been identified that impair the interaction of p53 with mdm2, an important negative regulator of p53 stability xref ."
No evidence text available
the interaction between MDM2 and p53 blocks the binding of p53 to
targeted DNAs and transports p53 from the nucleus to the cytoplasm,
rendering p53 ineffective as a transcriptional factor."
"However, unlike its setting in regulating MDM2–p53 interaction ( xref ), S7 did not interrupt the MDM2–GADD45α association in vivo ( xref F)."
"Nutlin-3a inhibits the interaction between MDM2 and p53, which stabilizes p53 and then selectively induces senescence in cancer cells."
"While on the one hand MDM2 binds to p53 and blocks its N-terminal transactivation domain, it induces p53's degradation via ubiquitin-proteasome machinery on the other hand [ xref ]."
"Extensive investigations have demonstrated that MDM2 protein–protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival."
"MDM2Δp53, a deletion mutant that lacks p53 binding domain fails to exert the inhibitory effect, demonstrating that the interaction of MDM2 and p53, but not its E3 ligase activity toward p53 plays key role in suppressing Axin-stimulated p53 activation."
"These findings support the hypothesis that inhibition of the HDM-2 and p53 interaction may be a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies."
"Besides, some studies have established that an allelic imbalance within the FHIT locus frequently coexists with p53 abnormalities.[ xref ] The interaction of FHIT with MDM2 could interfere with the association of MDM2 and p53 and subsequently interrupting MDM2-mediated p53 degradation.[ xref ]"
"ATM- or ATR mediated phosphorylation of MDM2 prevents the association between p53 and MDM2, and leads to stabilization of p53 [XREF_BIBR, XREF_BIBR]."
No evidence text available
"In contrast, in high-density cells, emetine induced RPS14 binding to the free MDM2-acidic domain and prevented virus-mediated interaction between MDM2-p53, resulting in stabilization of p53 and MDM2."
"For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53."
"Recent evidences suggest that radioresistance is due to tumour repopulation and involves several signalling pathways, including p53 and MDM2 interaction."
"Tat-αHDM2 inhibited the interaction of p53 and HDM2, resulting in the death of several human cancer cell lines including: melanoma, retinoblastoma, osteosarcoma and cervical carcinoma [ xref ]."
"Indeed, we show that PEPD and MDM2, the latter of which binds to p53 in a sequence (aa 18-26) adjacent to PRD (aa 64-89), compete for p53 binding."
"Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use."
"Carnosol (CAR), a natural inhibitor of MDM2 and p53 complex, has been attracted attention for its anti-cancer effects on several tumor types, including GBM."
"To determine whether p53 activation suppresses mTOR signaling, we then treated neuroblastoma cells with a specific first-generation inhibitor of MDM2-p53 interaction (Nutlin 3a), which induces robust p53 stabilization (Supplementary Fig. S1)."
"Asymmetric divisions can be measured by the distribution of Numb. xref Numb can directly interact with p53 and MDM2 and is thought to regulate p53 signaling by preventing MDM2-mediated ubiquitination. xref Interestingly, p53 knockout mice contain a higher percentage of cells that are capable of forming mammospheres in culture and repopulating the mammary gland in vivo , further supporting a role for p53 in maintaining the stem cell pool. xref "
"A key regulator is Mdm2, an E3 ubiquitin ligase, that binds and ubiquitinates p53 and directs its degradation via the proteosome."
"Further studies suggest that ribosomal proteins that can bind to HDM2 may regulate HDM2–p53 pathway in a cooperative way by forming a ribosomal proteins–HDM2–p53 complex ( xref , xref )."
"Other drugs – SAR405838 and RO5503781, also small-molecule inhibitors of the MDM2-TP53 interaction – are in clinical development for cancers other than lung."
"Other authors xref , xref , xref , xref stressed the role of delays in the p53/Mdm2 network, although recently it has been noticed xref , xref , xref that the use of explicit delays to explain p53 oscillations (and other dynamical features) may be avoided by including in the model the complexes formed by p53 and Mdm2."
"In agreement with our own work using CGM097 (XREF_FIG), targeted disruption of the MDM2 and p53 interaction by the small molecule MDM2 antagonists, such as nutlin-3 and RG7388, suppresses the proliferation of both chemoresistant and sensitive neuroblastoma cell lines with wild-type TP53."
"Its application for tumors in the brain has not yet been examined, even though the target, the MDM2-p53 interaction, is attractive for tumors that could occur in the brain, including glioblastoma (GBM) and brain metastases."
"Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53 bound MDM2 or MDMX."
"The interaction of p53 (1–160) with Mdm2 was abolished by the F19A mutation and by deletion of the transactivation domain (Additional file xref : Figure S8)."
"Although HdmX also binds to p53, HdmX does not induce p53 degradation."
"Our NMR data indicate that the three amino acids that are important for binding of p53 to Mdm2 and that are conserved in p63 are most likely not accessible in the inhibited dimeric conformation."
"The overexpression of MDM2 is a typical example of non-mutational p53 inactivation in NB cells, indicating that the inhibition of p53-MDM2 interactions is capable of restoring p53 tumor suppressor function."
"Strategies targeting p53 have been developed including gene therapy to restore p53 function, inhibition of p53-MDM2 interaction, restoration of mutant p53 to wild-type p53, targeting p53 family proteins, eliminating mutant p53, as well as p53-based vaccines."
"Additional studies on the transcriptional, posttranscriptional, and epigenetic aspects are necessary to understand the interactions between p53 and murine double minute 2 because we did not observe any numeric alterations by fluorescent in situ hybridization."
"This reduction in Mdm2 and p53 complex negatively impacts Mdm2 inhibition of p53 target gene transactivation as well as Mdm2 destabilization of p53."
"The region of HDM2 that binds to p53 was originally narrowed down to residues 19–102, whereas the minimal HDM2-binding domain of p53 was identified as a 15 residue sequence (amino acids 15–29) from the transactivation domain."
"Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment."
"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."
"In this article, overview on different therapeutic strategies that are exploited to restore the neoplasm therapeutic effect to p53 will be provided, including pharmacological rescue of mutant p53 and modulation of the p53-MDM2 interaction."
"HDMX is physically associated with HDM2 and drugs that block the interaction between HDM2 and p53 such as MI-319 also interfere to some extent with the ability of HDMX to suppress p53 transcriptional activity."
"Inhibition of MDM2 binding to p53 blocks ubiquitin mediated degradation of p53, leading to accumulation of both cytoplasmic and nuclear p53, with subsequent activation of downstream transcriptional targets such as p21 and induction of apoptotic stress responses."
"To achieve higher sensitivity and to confirm specificity, an MDM2 specific monoclonal antibody (2A10) was used to recognize both the free and p53 bound MDM2 proteins."
No evidence text available
"Treatment with cisplatin results in inter and intra-strand DNA crosslinks that activate the DNA damage checkpoint and disrupt the interaction between p53 and Mdm2."
"Upon cellular stress, DNA damage, or oncogenic activation, a decrease in MDM2 protein level and /or activity lead to the loss of p53-MDM2 interaction, p53 is stabilized and can act as a transcriptional activator of its target genes, promoting cell cycle arrest and apoptosis xref , xref ."
"Such mechanisms include enhanced Mdm2 degradation, post-translational modifications on p53 and Mdm2, altered binding to other proteins that modulate the p53-Mdm2 interaction and its consequences, and altered sub-cellular localization of p53 and Mdm2 (reviewed in ( xref ; xref ; xref ))."
"Importantly, use of NMR based screening allowed for determination of both compound affinity to Hdm2 and the ability of compounds to dissociate preformed p53 and Hdm2 complex."
"The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic alpha helix."
"Total five simulations were carried out for MDM2 and p53 complex, Bcl-XL and Bad, Bcl-XL and Bak, Bcl-XL and SN15 and Bcl-XL and SN15W23A, a SN15 point mutant peptide."
"Due to the importance of the Mdm2-p53 interaction, inhibition of this event with small molecules is regarded as having therapeutic potential."
"The exposure of cell stresses such as ionizing radiation, free radicals, hypoxia, and chemical reagents disrupts the p53 and Mdm2 complex and subsequently leads to the phosphorylation of p53."
"Conversely, in conditions where Mdm2 was prevented from interacting with p53, IGF-1R expression was drastically decreased along with cell viability. xref Within the same scenario, preventing p53–Mdm2 interaction, Nutlin-3 amplifies IGF-1R–Mdm2 association, unbalancing its signaling."
"Of note, 17AAG did not disrupt the interaction between MDM2 and p53 (XREF_FIG), indicating that it stabilized p53 through a mechanism different than Nutlin."
"However, the association between MDM2 and p53 was attenuated on OS, indicating that the enhanced p53-heterochromatin binding is unlikely derived from the MDM2 mediated scaffolding."
"The nutlins are the class of selective inhibitors of the p53-MDM2 interaction that are currently most advanced in their clinical development."
"For instance, 31 is a reasonable inhibitor of the p53 and hDM2 interaction in the FA screen, but does not score highly for induction of apoptosis or cell viability."
"A high through-put docking programme known as LIDAEUS was employed in an in silico screen of small-molecule databases, configured from the co-ordinates of the known p53 and HDM2 complex X and ray crystal structure."
"As observed for p53 binding to Taz2, mutation of Leu 22 to alanine also disrupts binding of p53 to MDM2."
"3 1-16) to study the interactions of p53 with MDM2 proteins, where the stochastic analysis was done using a Monte Carlo approach."
"What we have presented is a current version showing how the accumulated information on molecular interactions of p53 and Mdm2 can be organized in the form of a map."
"Nutlins were originally identified as potent small molecules that inhibit the interaction between p53 and MDM2, which promote p53 degradation XREF_BIBR, XREF_BIBR, XREF_BIBR."
"Murine double minute 2 (MDM2), a key negative regulator of p53 stability and activity, can bind to p53 and block p53 transcriptional activity [XREF_BIBR]."
"Indeed, deregulated SMO in C3H10T1/2 and MEFs promotes MDM2 mediated inhibition of p53 by enhancing the binding of MDM2 to p53, and abrogates p53 mediated growth arrest and apoptosis in response to DNA damage XREF_BIBR."
"It is known that Nutlin 1 is the small molecule compound that targets Mdm-2 and p53 interaction [ xref ]."
"However, more detailed studies of the mechanism of action of RITA are warranted since conflicting NMR structural studies later reported that RITA does not inhibit the p53–Mdm2 interaction ( xref )."
"Immunoprecipitation results showed that knockdown of PTEN enhanced the interaction between p53 and HDM2 (XREF_FIG)."
"Because p53 interacts with both MDM2 and CBP and p300 through its trans-activation domain, we examined the role of MDM2 in p53-coactivator interactions."
"Phosphorylation of p53 renders its main partner Mdm2 incapable of tightly binding p53, which is necessary to target p53 for degradation via the ubiquitin proteasome pathway."
"MDM2 and MDMX heteroligomers may also bind to p53 and suppress its transcriptional activity [XREF_BIBR]."
"Currently, from the pharmacological perspective, inhibitors of the p53-MDM2 interaction, such as Nutlin-3a, seem to be a promising approach to restoring p53 function in cancer."
"Therapies targeting the MDM2-p53 interaction are in development and considered to be promising (see reviews [ xref , xref ])."
"Mdm2 association with p53 targets its ubiquitination."
No evidence text available
"Nutlins are small molecules that inhibit MDM2 and p53 binding, leading to increased availability of p53."
"Particularly, Ser15, 20 and Thr18 are key sites for phosphorylation, which not only guide p53 for transcriptional binding on DNA target, but also disrupt the interaction of p53 with MDM2 [14,19] ."
No evidence text available
"They have no effect on the physical interaction between MDM2 and p53, suggesting that the mode of inhibition may be allosteric, perhaps by blocking a structural rearrangement of MDM2 necessary for p53 ubiquitination but not for MDM2 autoubiquitination XREF_BIBR, XREF_BIBR."
"Unphosphorylated p53-TAD binds to MDM2 with sub-micromolar affinity, which promotes polyubiquitination and degradation of p53 through MDM2’s E3 ubiquitin ligase activity[ xref , xref ]."
"These results suggest that the distribution of MDM2 reflects its nuclear-cytoplasmic shuttling ability; that interaction between p53 and MDM2 for tumor progression is not enhanced by point mutations at codon 17; and that the expression of MDM2 splice variants is a reason for the lack of its overexpression."
"The p53/MDM2 complex promotes p53 degradation by ubiquitylation and blocks the transactivation domain. xref Nutlin-3α can stabilize p53 levels and the transcriptional activity by inhibiting the MDM2–p53 interaction. xref The phosphorylation of p53 at serine 15 stimulates its transactivation. xref , xref Cyclic PFT-α, a cyclic analog of PFT-α, inhibits p53-dependent gene transcription. xref Surprisingly, in the current study, p53 and p-p53 levels decreased in CuONP-treated cells ( xref ), which implies that p53 did not have a prodeath function."
"Nutlin-3 inhibits the physical interaction between p53 and its inhibitor MDM2, and activates p53 responses in p53 wild-type cancer cells."
No evidence text available
"1 reactivated p53 transcriptional transactivation in cellulo, and also induced apoptosis and suppressed the growth of cancer cells, which we attribute, at least in part, to the disruption of the p53 and hDM2 interaction by 1."
"We tested a hypothesis that HDAC5 is a p53 down-stream target gene that on induction by p53 inactivates p53 by removal of acetyl group in p53 molecule, thus functioning as an auto-regulatory negative feedback loop in analogue to p53-murine double minute 2 interaction."
"While in normal lip mdm-2 and p21 were significantly correlated with p53, in AC only mdm-2 was associated with p53 expression."
"Indeed, several small molecule-PPI inhibitors have been developed, such as Nutlin-3 for HDM2-p53 interaction ( xref ), and ABT-737, a Bcl-2 family protein inhibitor ( xref )."
"MDM2 binds to p53 through its N-terminal domain and there are several phosphorylated residues in the domain."
"Our data suggested that AM-enhanced p53 nuclear accumulation and tetramerization might be related to inhibition of p53 and MDM2 interaction."
"In addition, MDM2 is able to bind p53, leading to the inhibition of its transcriptional activity and to its translocation from the nucleus into the cytoplasm XREF_BIBR."
"In a manner similar to other chaperones, Mdm2 binds partially unfolded p53 and, upon ATP binding, releases p53, which then assumes the most energetically favorable conformation."
"It still remains to be determined what function S20 has in the fine-tuning of the activation and signal transduction of p53, as phosphorylation of S20 did not have any direct impact on the binding of [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Although very little progress was made in the first few years after deriving the crystal structure of the MDM2 and p53 complex, lately, several classes of small-molecule inhibitors with distinct chemical structures and properties have been reported."
"Small-molecule drugs that inhibit the interaction of MDM2 and p53 and block p53 degradation are currently tested in clinical trials."
"TDP521252, TDP665759, PXN727, PXN822 and isoindolinones are other compounds currently under pre-clinical development that target MDM2 to increase p53 levels by inhibiting the MDM2-p53 interaction [ xref , xref , xref , xref ]."
"Because mdm-2 overexpression is observed in several types of human cancers and its physical association with p53 appears essential for down-regulating p53 activity the proportion of p53 bound to mdm-2 was examined in four types of cells with divergent growth properties : (1) Growth arrested cells (Al) expressing high levels of wild-type p53 activity; (2) Tumorigenic cells (3T3DM) expressing high levels of mdm-2; (3) Immortalized non tumorigenic cells (Swiss3T3 and Balb and c3T3); and (4) Normal murine fibroblasts."
"Cell-permeable beta-peptide inhibitors of p53 and hDM2 complexation."
"Several strategies are being developed and in particular targeting p53-MDM2 interaction has emerged as a promising approach, when dealing with cancers that retain wild-type p53 function."
"Similarly, a model of the bi-modal response of p53 to etoposide treatment suggested that the change in dynamics is driven by a stimulus-dependent interaction of phosphorylated Mdm2 with p53 mRNA [ xref ]."
"A related ‘alanine-scanning’ approach was applied to a fragment of p53 binding to deletion mutants of the oncoprotein Mdm2  ."
"MDM2 is a suppressor of both p53 and p73; however, while the interaction between p53 and MDM2 results in degradation of p53, MDM2 associates with, but does not degrade, p73 xref – xref ."
"Knock down of MDM2 using specific shRNA or chemical inhibition of MDM2-p53 interaction prevented protective changes triggered by GSK-3β inhibition in irradiated HT-22 neurons and restored radiation cytotoxicity."
"In parallel, the results question direct targeting of the p53-Mdm2 interaction by RITA and instead suggest that RITA primarily acts as a cross-linking drug whose activity is limited by mTOR-FancD2–mediated DNA repair."
"As one of E3 ubiquitin protein ligases, MDM2 interacts with the tumour suppressor p53 by mediating ubiquitination and degradation of p53."
No evidence text available
"Peptide P1 is a variant of a known inhibitor of the HIV-1 C-terminal capsid protein (C-CA) 27 and peptide P2 is a mutant of a peptide that disrupts p53 and MDM2 interaction based on the p53 protein."
"This suggested that restoring compromised wild-type p53 function by small molecule inhibitors of the p53-MDM2 interaction might be difficult in chemoresistant MDM2 overexpressing cancers."
"This binding is weaker than the main site of p53-Mdm-2 interaction, but can provide additional approaches for drug development."
"As expected, overexpression of HEXIM1 disrupts the interaction between HDM2 and p53 resulting in stabilization of p53 and activation of p53 downstream targets (such as PUMA and p21) in various cancer cell lines [XREF_BIBR]."
"[Interaction between p53 and MDM2 in human lung cancer cells]."
"Similar to Nutlin-3, MI-219 binds to MDM2 and interrupts the p53-MDM2 interaction, stabilizing p53."
"The levels of MDM2 and p53 are tightly regulated, as they act in a negative feedback loop where p53 induces MDM2 transcription in response to genotoxic stress, whereas MDM2 binds, inhibits and directs p53 for proteasomal degradation by ubiquitinylation [XREF_BIBR - XREF_BIBR]."
"MDM2 interacts with the transactivation domain of p53 inactivating its function ( xref , xref )."
"Aside from direct inhibition of mdm2 expression by antisense ( Bianco et al., 2005; Tortora et al., 2000; Zhang et al., 2004 ), several other approaches have sought to interfere directly with the p5[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"The phosphorylation of p53 might stabilize p53 protein through stabilizing the p53 and p300 complex and disassociating the p53 and Mdm2 complex [XREF_BIBR, XREF_BIBR]."
"Several strategies that aim to reinstate wt-p53 function, particularly gene transfer of wt-p53, inhibition of the MDM2-p53 interaction, and chemical restoration of wt-p53 activity, have been pursued."
"Another example of a small-molecule agent blocking a protein protein interaction is the molecule nutlin, which interferes with p53 and MDM2 interaction."
"To test the ability of ISA27 to disrupt the intracellular MDM2-p53 interaction, a co-immunoprecipitation assay was done."
"The addition of supplemental ZnCl 2 (32 muM) could negate the effect of zinc chelator TPEN, thereby restoring the MI-219-induced disassociation between MDM2 and p53."
"Issaeva et al. screened a chemical library and found the small molecule RITA (reactivation of p53 and induction of tumor cell apoptosis), which binds to p53 and inhibits the p53-MDM2 interaction both in vitro and in vivo ."
"These modifications render p53 resistant to inactivation by MDM2 (mouse double minute 2), an E3-ubiquitin ligase that binds p53 and targets it for degradation in the proteosome."
"Nutlins bind to the hydrophobic pocket of MDM2 in a manner similar to p53 binding, thereby interfering with the interaction between MDM2 and p53."
"Structural information on the HDM2-p53 complex was used to design our first class of peptoid inhibitors, and we provide here, in detail, the strategy to modify peptoids with the appropriate side chains that are effective inhibitors of HDM2-p53 binding."
"Computer modeling suggests that their side groups can mimic the side chains of Phe, Trp, and Leu residues in the helical domain of p53 and therefore prevent the binding of p53 to MDM2."
"These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction."
"Mdm2 interacts with p53 in yeast and induces a diminution of its transcriptional activity."
"Inhibition of MDM2-p53 interaction with 10 µM nutlin-3a abrogated this cytoprotective effect ( xref ), supporting the results obtained with MDM2-specific shRNA ( xref )."
"In 2004, Kodadek and co-workers reported a procedure for identifying bivalent ligands with high affinity and specificity for their target protein. xref A chalcone known to bind to the p53 binding domain of murine double minute 2 protein (MDM2, the mouse homolog of HDM2) with low affinity (K D = 220 μM) was selected for conjugation to peptoid decamers."
"Therefore, further studies are needed to elaborate whether butein blocked the interaction between p53 and MDM2 via directly binding to MDM2 or p53, or in an indirect way by inducing other modifications."
"Thus, blocking the interaction of p53 with MDM2 is a promising anticancer strategy to reactivate the p53 pathway."
"Moreover, PIMT destabilizes p53 by enhancing the p53–HDM2 interaction."
"Furthermore, the pharmacological disruption of MDM2-p53 interaction induced by nutlin-3a abrogates NMDA-PC-induced neuroprotection against ischemia."
"The results of such studies as well as efforts to probe the mechanism by which chlorofusin disrupts the interaction of p53 and MDM2 will be facilitated by the work summarized herein."
"MDM2 is a p53 binding protein and the interaction between MDM2 and p53 has been shown to block the biological activity of p53 by preventing essential transcription factors binding to the N-termina[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Consistent with this concept, expression of a constitutively active form of Akt-1, which phosphorylates MDM2 and promotes MDM2 binding to p53 [ xref ], prevented the I3C apoptotic response and restored MDM2–p53 protein interactions (data not shown)."
"In the present study, we found that SQ dissociated the MDM2 and p53 complex and directly induced MDM2 degradation through the ubiquitin dependent proteasome pathway in MCF-7 and MDA-MB-231cells."
"Given that binding of p53 to Mdm2 is required for the modification to take place, sumoylation was also abolished when we co-expressed Mdm2 with a mutant p53 which is impaired in binding to Mdm2 (p53W23S, see above) (XREF_FIG and XREF_SUPPLEMENTARY)."
"SAR405838 (MI-773), currently in phase-I clinical trials, is a novel, potent, and orally available MDM2 antagonist that blocks the interaction between MDM2 and p53."
"To directly assess the contribution of Hdm2 in regulating p53 expression and function, 786-MOCK cells were treated with nutlin-3, a small molecule inhibitor of Hdm2-p53 interaction."
"Nevertheless, more than 20 structurally-diverse small molecules that disrupt the interaction between p53 and its major repressor MDM2 at low micromolar levels or even nanomolar levels have been developed [ xref ]."
"We propose that stress-induced HDM2(ALT1) regulates HDM2 at two levels, RNA and protein, further modulating the p53-HDM2 interaction or interactions of HDM2 with other cell cycle regulatory proteins."
No evidence text available
"Considering that p53 is targeted by murine double minute (Mdm2) for ubiquitination and subsequent proteasomal degradation and knowing that this interaction is impaired by, for example, UV-treatment with concomitant stabilization of p53 we questioned the p53 and Mdm2 interaction in the presence of NO."
"Four compounds (9, 17, 32, and 62) showed no inhibition of the p53 and hDM2 interaction up to a concentration of 100mum."
"In addition, the ubiquitin-proteasomal system can regulate the level of apoptotic activity by affecting the Bcl-2 family, NF-kappaB family, p53 and MDM2 complex and others [XREF_BIBR, XREF_BIBR]."
"The MDM2 and p53 complex is an attractive target for therapeutic intervention in cancer cells with intact tumor suppressor p53, as it offers the possibility of releasing p53 by blocking the MDM2-p53 binding site with a small molecule antagonist to promote apoptosis."
"In this issue of Cancer Cell, Gajjar et al. provide important insight by demonstrating that the DNA damage- and ATM-dependent phosphorylation of Mdm2 on serine 395 promotes the interaction of Mdm2 with p53 mRNA."
"In response to agent inducing stress, MDM2 play a crucial role in the stabilisation and activation of p53 signalling by increasing expression of protein synthesis via disrupting the MDM2-p53 interaction, this explains as to why MDM2 is overexpressed, thus indicates an intact p53 downstream signalling [ xref ]."
"Biochemical experiments showed that these compounds can disrupt the MDM2 and p53 protein complex, releasing p53 from both the p53 and MDM2 and DNA bound p53 and MDM2 complexes."
"We used the dissociation constant of 212 nM for the p53-NFLuc and mdm2-CFLuc interaction that was previously obtained for the p53 and mdm2 interaction [ xref ]."
No evidence text available
"Thus, Roslin 2 or R2 compound can be a potential approach for increasing p53 activity, similar to small molecule compounds such as Nutlins [XREF_BIBR] or RITA [XREF_BIBR] that are known to disrupt p53 and Mdm-2 interactions."
"Crystal structures of the N-terminal domains of human and Xenopus laevis MDM2 in complex with short peptides from the N-terminal domain of p53 (residues 15-29) revealed the structural basis of the interaction between p53 and MDM2."
"Nutlin-3a, a small molecule inhibitor of the p53 and MDM2 interaction, which promotes p53 reactivation, kills PEL cells in culture and has potent anti-tumor activity in mice bearing PEL tumors [XREF_BIBR, XREF_BIBR]."
"Investigations of the mechanism revealed that activation of p53 was mainly attributed to the blockade of p53 binding to MDM2 and the suppression of MDM2 mediated p53 ubiquitination."
"As previously reported, inhibition of the MDM2-p53 interaction leads to activation of the p53 pathway xref , xref , xref ."
"Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction."
"Different stresses such as DNA damage, hypoxia, and oncogene activation upregulate and activate the p53 protein, mainly by inhibiting the interaction between p53 and the E3 ubiquitin ligase Mdm2 ( xref ; xref )."
No evidence text available
"The stronger binding of trans p53 (17-29) to MDM2 compared to cis may suggest a mechanism to help maintain minimal levels of p53 in unstressed cells and allow for rapid response to cellular stress."
No evidence text available
"The combination of fluorescent properties with inhibitory effect on the MDM2-p53 interaction could potentially be useful for real-time imaging as well as for the development of in vitro displacement assays for MDM2/p53."
"A third interaction between the MDM2 N terminus and the p53 C terminus was described in 2010, demonstrating that p53-MDM2 interaction is decreased upon deletion of this p53 region and that modifications of the p53 C terminus can regulate the interaction between p53 and MDM2."
"This also indicates that p53 and Hdm2 complexes are stabilized by PI, but destabilized or prevented from forming by Hdm2 antagonists."
"In the presence of 27-OHC, MDM2, and p53 interaction is enhanced, resulting in p53 inactivation and degradation."
"We first carried out pull-down assays using in vitro expressed proteins to investigate disruption of the HDM2-p53 interaction by Nutlin and the stapled peptides PM2 and MO11 ( xref ) [ xref ]."
"Whereas Nutlin‐3 specifically dissociates the p53–Hdm2 interaction, other compounds, such as RP73401, dissociate the PDE4A4 spots (PDE4A4 dislocators) without breaking the p53–Hdm2 interaction."
"One such interaction between MDM2 (HDM2) and p53, that silences the tumour suppression activities of p53, was found to be inhibited by the recently isolated natural product chlorofusin."
"XREF_BIBR, XREF_BIBR Activation of wtp53 can be achieved by MDM2 inhibitors which interact with the p53 binding pocket subsequently inhibiting p53 degradation, such as Nutlins XREF_BIBR, XREF_BIBR and MI-43, 18 or by small molecules directly binding p53 and thereby impeding p53 and MDM2 interaction such as the thiophene derivate RITA (reactivation of p53 and induction of tumor cell apoptosis)."
"Sequence specific 1H, 15N, and 13C assignment of the N-terminal domain of the human oncoprotein MDM2 that binds to p53."
"Acetylation of p53 can negatively regulate protein protein interactions, and unacetylated p53 binds more strongly to Mdm2 and Mdmx [XREF_BIBR]."
"Current strategies are focused on targeting Mdm2‐p53 interaction for p53‐activation‐based therapies."
"Recently, several small molecule antagonists of HDM2 have been developed which interfere with the interaction between p53 and HDM2, resulting in enhanced p53 stability."
"Pharmacological validation of inhibitor screening AlphaLISA using known inhibitors of the p53-MDM2 interaction."
"Initially discovered by high-throughput
screening at Hoffman-La Roche (HLR) in 2004, the Nutlins are cis -imidazoline small molecules that inhibit the MDM2-p53
protein–protein interaction (PPI). xref The Nutlins have been widely used to study the consequences of inducing
the activity of the tumor suppressor p53 when it is suppressed by
MDM2 in cancer cells. xref To date, HLR has
continued to pursue cancer drug development with the series. xref The most potent member (and enantiomer) in the
original Nutlin family, (−)-Nutlin-3 ( 1 , Chart xref ), or Nutlin-3a, is able to selectively disrupt
the binding of MDM2 and p53 by mimicking the side chains of key hydrophobic
p53 amino acid residues in the MDM2 binding motif. xref This orthosteric binding releases p53 from its heterodimer
complex with MDM2, leading to cell cycle arrest and apoptosis."
"We examine why MDM2 interacts preferentially with p53 and p73."
"Small molecule MDM2 inhibitors can block the binding of MDM2 and p53 by competitive binding to the region I of MDM2 protein, resulting in the increasing of p53 level and activation of p53 signaling pathway [ xref , xref ]."
"Mdm2, once produced, binds to p53 preventing it from acting as a transcription factor, and subsequently ubiquitinates it, which enhances its proteolytic breakdown [review in Oren et al.,]."
"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."
"Interaction between MDM2 and p53 represents a key step in the regulation of p53, as MDM2 promotes the degradation of p53."
"Shortly after the identification of Mdm2’s interaction with p53, mapping of the p53 and Mdm2 interaction domains determined that the N-terminus of Mdm2 bound to and inhibited the transactivation domain of p53 ( xref , xref )."
"XREF_BIBR Interestingly, no other protein protein interaction has attracted so much attention : over 20 different low molecular weight backbones have been described as antagonists of the p53 and mdm2 interaction in the past several years."
"To further analyze the interaction between Mdm2 and p53 in this model, we performed mice crosses to obtain mice that expressed Tg p53 in the absence ( −/− ) or presence ( +/− ) of Mdm2 ."
"As shown in table xref , there are three main categories of MDM2 inhibitors: inhibitors of MDM2-p53 interaction by targeting to MDM2, inhibitor of MDM2-p53 interaction by targeting to p53, and inhibitors of MDM2 E3 ubiquitin ligase."
"Nutlins prevent binding of the E3 ligase MDM2 to its substrate, the tumour suppressor p53 [ xref , xref – xref ]."
"However MDM2Deltap53, an MDM2 mutant lacking p53 binding domain, fails to exert the inhibitory effect, indicating that the inhibition may be based on the interaction between MDM2 and p53 (XREF_FIG)."
"In order to determine whether the stability of p53 in AML2 was conferred by sequestration by high levels of Mdm4, we sought to quantify the interactions between p53 and Mdm2, and p53 and Mdm4."
"VP4 impaired NME1-mediated inhibition of the p53-MDM2 interaction in a dose-dependent manner (Fig. xref )."
"Such phosphorylation might, for instance, weaken the
interaction between p53 and Mdm2 (S. Shieh, C. Prives), thereby
rescuing p53 from the inhibitory effects of Mdm2."
"Although the MDM2-p53 interaction has been the focus of considerable investigation, a range of different PPIs have been targeted with type I-III inhibitors [ xref – xref ]"
"TXNIP directly regulated p53 protein by interfering with p53- mouse double minute 2 (MDM2) interactions and increasing p53 transcriptional activity."
"Disruption of p53 and MDM2 Protein Protein Interactions."
"Since nucleic acids do not interfere with, or even slightly stimulate, the interaction of Hdm2 with p53, these results suggest that homooligomerization is required for Hdm2 to be active as an E3."
"Due to the important relationship between p53 and Mdm2, we determined whether SHP affected the interaction between Mdm2 and p53 using Co-IP and Western blots."
"We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction."
"Nutlin-3 has been shown to rapidly activate p53 in cancer cells with wildtype p53 [ xref , xref ] by inhibiting the interaction between HDM2 and p53, thus stabilizing p53."
"The MDM2-P53 interaction is not only necessary for early embryonic development ( xref , xref ), but also crucial for stem cell maintenance in adults ( xref )."
"With this approach, we visualize the p53-HDM2 interaction in living cells and directly monitor the disruption of this interaction by Nutlin 3, a drug developed to boost p53 activity in cancer therapy."
"In cancer cells, the tight control of the HDM2:p53 protein-protein interaction is disrupted, thereby minimizing the tumor-suppressive activities of HDM2 on p53 and promoting a cell growth advantage [ xref ]."
"Furthermore, an immunoprecipitation assay showed that the interaction between HDM2 and p53 was reduced."
"The interaction between p53 and MDM2 is mainly mediated by three hydrophobic residues Phe19, Trp23, and Leu26 of p53 and a small but deep hydrophobic cleft in MDM2."
"Such information on the kinetics of the MDM2-p53 interaction could help to understand the molecular mechanism underlying the inhibitory function exerted by MDM2, also in connection with the kinetics of other competitive or synergistic interactions within the p53 network."
"MDM2 can bind the N terminus of p53 and promote its ubiquitination and export from the nucleus to the cytoplasm, where p53 can then be degraded by cytoplasmic proteasomes."
"We have investigated whether disrupting the MDM2 and p53 complex in cells that overexpress MDM2 is sufficient to trigger p53 mediated cell death."
"The nutlins are the prototypical class of small molecules that block the MDM2-p53 interaction."
"MDM2 binds p53, which not only inhibits its ability to arrest the cell cycle and induce apoptosis but also promotes its transportation from the nucleus to the cytoplasm for ubiquitination and degradation by the ubiquitin-mediated proteasomal protein degradation pathway xref ."
"Up to now, many chemical compounds, such as peptide inhibitors PMI xref , P4 xref , pDI6W xref etc. and non-peptide inhibitors nutlins xref , isoindolinone xref , spiro-oxindoles (MI-63) xref xref and benzodiazepinedions derivatives xref , have been developed by mimicking the p53-MDM2 interaction."
"While many genes show the same behavior as CDKN1A (e.g., GDF15, DDB2, labeled green throughout XREF_FIG), another group shows decreased transcription in the presence of MDM2 bound p53 (e.g., PTP4A1, HES2, GJB5, labeled red throughout XREF_FIG)."
"The Mdm2 oncoprotein physically associates with p53 and antagonizes its tumor suppressor functions."
"As a consequence, Mdm2 cannot form complexes with p53, and p53 ubiquitination is impaired xref ."
"This interaction, which is needed for MDM2-mediated degradation of TP53, also is modulated by phosphorylation ( xref )."
"We tested whether nutlin‐3, an inhibitor of MDM2‐p53 interaction, could serve as a substitute for chiMDM2 to enhance the antitumor effect of chiMDM4 in 4 cell lines (NUGC‐4, SNU‐1, HCT116, and LoVo)."
"The activation of p53 by butein was mainly attributed to the blockade of the interaction between p53 and MDM2, and the suppression of MDM2-mediated p53 degradation."
"Furthermore, this phenotype was recapitulated in ex vivo assays measuring p53 transactivation function and the formation of p53-HDM2 complexes in the presence of Nutlin."
"Amino acid and peptidyl piperazine-4-phenyl derivatives as inhibitors of the interaction between MDM2 and p53 were disclosed by Zeneca in 2000. xref Compounds exemplified by 34 possess an IC 50 in the range from 0.03 to 200 μM. However no other patents or publications have been published since then based on those compounds."
"However, in the case of the P53 and HDM2 interaction, the P53 binding site on HDM2 is a cleft rather than a flat surface."
"Nutlins, newly discovered small-molecule inhibitors of the Hdm2-p53 interaction, offer a novel strategy for therapy of tumors with wild-type p53."
"Approaches are currently underway to target the p53 pathway and include gene therapy to restore p53 function, inhibition of interaction between p53 and MDM2, activating p53 in wild type tumors, [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Taken together, our results suggest that high sensitivity for cisplatin cytotoxicity and cisplatin induced apoptosis is related to a reduction in MDM2 and p53 complex formation and a change in p53 cellular localisation."
"Finally, the amount of MDM2 bound by p53 in PA28γ −/− MEF cells was higher than in wild-type MEF cells ( xref )."
"Consequent modifications of the p53 C-terminus further destabilize Mdm2 and p53 complex."
"Similarly, MDM2 and MDMX heterodimers bound to p53 interfere with transcriptional activation."
"The interaction of the tumor suppressor p53 with MDM2, the major E3 ubiquitin ligase driving p53 to proteasome for degradation, is of outstanding interest and this interaction is considered as one of the main targets for anticancer drug design aimed at impairing p53 down-regulation [ xref ]."
"A high level of Sp1, via its COOH-terminal domain, induces interaction between p53 and MDM2, resulting in degradation of p53 by MDM2-mediated ubiquitination [ xref ]."
"Nutlin-3 is a small molecule which binds to the p53 binding pocket of HDM2, thereby inhibiting wild type p53-HDM2 interaction, attenuating p53 degradation and activating cell cycle arrest/apoptosis mediated by the p53 network xref ."
No evidence text available
"Secondly, we examine the ability of each peptide to mimic the key Phe 19 -Trp 23 -Leu 26 pharmacophore formed in binding of p53 to MDM2."
"Furthermore, by directly inhibiting the mdm2-p53 interaction by using either ionizing radiation or the novel small molecule therapeutic Nutlin, p53 can be activated and cause tumor cell death, even in the presence of sustained Notch activity."
"Kap1 binds histone deacetylase 1 to the Mdm2 and p53 complex, causing the deacetylation of p53."
"MDM2 binds and ubiquitinates p53, facilitating it for proteasomal degradation XREF_BIBR, XREF_BIBR."
"After DNA damage, the p53 protein is phosphorylated, preventing the interaction of MDM2 with p53 and resulting in activation of p53 ( xref )."
"Our findings suggest that overexpression of p53 protein and MDM2 in papillary carcinoma of the thyroid is associated with the progression of the tumors, and that p53 may be a marker of the progression of PCT."
"The purpose of this study was to investigate whether alteration of p14 ARF , a key regulator of p53-MDM2 interaction, plays a role in deregulating the p53 pathway in a subgroup of CRCs exhibiting a restricted pattern of p53 overexpression significantly associated with MSI-H phenotype, low TP53 mutation, and MDM2 overexpression, and inversely correlated with p21 expression loss [ xref ]."
"In ELISA dissociation experiments, however, both Nutlin-3 and p53-TAD-I (1-42) peptide inhibited binding between p53 (FL) and Mdm2 (10-139) with IC 50 's of around 1 microM (XREF_FIG)."
"The structural information we obtained here provides important clues for designing small molecule inhibitors of the MDM2:p53 binding."
"These signals converge at the interaction of p53 with its negative regulatory partner, MDM2 (reviewed in [1,8] )."
"The binding of Mdm2 to p53 is essential for ubiquitination, but p53 's tertiary structure and/or C-terminal region may also be important for this reaction."
"Hence, if p53 TAD anchors additional binding sites for sigma and tau that are created upon DNA damage, it is possible that binding of sigma and tau to p53 TAD could competitively inhibit the binding of MDM2 to p53 TAD, resulting in increased p53 levels, similar to competitive binding of p300 and MDM2 to p53 TAD."
"Hdm2 binds p53 to inhibit its transactivation function and shuttles p53 from the nucleus to the cytoplasm to facilitate its degradation [XREF_BIBR - XREF_BIBR]."
"Similarly, whereas SRSF1-NRS was able to interact with RPL5 and MDM2, SRSF1-AAA, another mutant of SRSF1 that accumulates in the cytoplasm ( xref ), failed to interact with RPL5, yet weakly interacted with MDM2 and very marginally induced p53 protein ( xref )."
"Overexpression of p53 and MDM2 is associated with the pathogenesis and oncogenesis of ameloblastomas and KOT."
"However, the interaction between p53 and MDM2 as well as the poly-ubiquitination of p53 were attenuated after overexpressing miR-542-3p in HCT116 cells (XREF_FIG), suggesting that miR-542-3p may stabilize p53 by affecting other regulators of p53-MDM2 interaction."
"Recent studies indicate that MDM2 can bind p53 and promote its rapid degradation although the molecular basis for this degradation has not been clarified."
"The first molecule in this category is nutlin, which has been identified in several large in vitro biochemical screens as a molecule that inhibits interaction between p53 and MDM2 by occupying the p53 binding pocket."
"Another small molecule that inhibits p53 and MDM2 interaction is RITA (reactivation of p53 and induction of tumor cell apoptosis)."
"The compounds do not fit the currently accepted pharmacophore model of p53-MDM2 antagonists binding into the MDM2 pocket and therefore likely have a different mode-of-action."
"The interaction between Mdm2 and p53 was then assessed by co-immunoprecipitation analysis. xref illustrates that Mdm2 immunoprecipitated p53 in the absence of overexpression of caveolin-1."
"The protein nucleophosmin (NPM) competes for the binding of MDM2 with p53 and can stabilize ARF, increasing its concentration in the nucleolus and resulting in decreased p53 degradation XREF_BIBR."
"Phosphorylation by DNA-PK, that modifies serines 15 and 37, inhibits HDM2 binding to p53 but does not induce the DNA binding activity of p53."
"X-Ray crystallography reveals that in addition to the Phe19, Trp23, and Leu26 residues in p53, a fourth residue, Leu22, also appears to play an important role in the overall interaction between p53 and MDM2, a suggestion that finds support in results from mutation analysis [ xref , xref ] and alanine scanning of p53 peptides [ xref ]."
"We used recombinant IFN β (IFN-R) protein instead of the AdRGD-PG-IFN β vector and nutlin-3, a compound which inhibits the interaction between MDM2 and p53, xref instead of the AdRGD-PG-p19Arf vector."
"In 2011, Wu et al. showed that UBE4B acts as an E3/E4 ligase that physically interacts with p53 and MDM2 to promote the polyubiquitination and degradation of p53 in brain tumors, thus decreasing the apoptotic activity of p53 tumor suppressor [ xref ]."
"Yet other sentences describe p53 binding to the MDM2 promoter and still others describe p53 regulation of the MDM2 expression."
"To date, there are three identified regions of interaction between MDM2 and p53 (XREF_FIG)."
"Inhibition of MDM2-p53 binding could reactivate p53 in cancer cells with WT p53 and may offer an effective therapeutic approach for millions of cancer patients ( xref )."
"YY1, MDM-2 and p53 are known to form a ternary complex, which is necessary for MDM-2 to ubiquinate p53 [ xref ]."
"MDM2 may bind P53 and promote P53 degradation at baseline but stimulate P53 translation under stress XREF_BIBR."
"Consistent with this suggestion, the treatment of MCF7 cells with Nutlin leads to increased p53 protein levels through loss of Hdm2 binding to p53 and concurrent Hdm2 mediated degradation of HdmX [XREF_BIBR]."
"A high level of Sp1, via its COOH-terminal domain, induces interaction between p53 and MDM2, resulting in degradation of p53 by MDM2 mediated ubiquitination [XREF_BIBR]."
"Wild-type p53 can be induced by small organic molecules such as nutlin-3 inhibiting the p53 and MDM2 interaction."
"MDM2 protein binds to p53 protein and stimulates p53 degradation; hence MDM2 overexpression decreases apoptosis."
"Like NIR, the E3 ubiquitin ligase MDM2 can also bind and inhibit p53 at promoters."
"The protein protein interaction between the transcription factor p53 and the negative regulator Mdm2 is an important recent oncology target."
"Thus for example, nutlin-3 by inhibiting the interaction between MDM2 and p53, displays anti-proliferative and pro-apoptotic activity in various cancers, including mantle cell lymphoma [ xref ], pediatric ALL cells [ xref ], prostate and lung carcinoma [ xref , xref ], and chronic lymphocytic leukemia [ xref , xref ]."
"Mechanistically, miR-542-3p increased p53 protein stability by weakening interactions between p53 and its negative regulator MDM2."
"Efficient inhibition of Cdk2 by p21 Waf1/Cip1 requires Mdm2. xref The authors of that study showed that cells exhibited inefficient inhibition of Cdk2 when depleted with Mdm2-siRNA compared to that when treated with nutlin-3, a selective inhibitor of p53-Mdm2 interaction."
"Addition of MDM2(17-125) decreased the fluorescence intensity to an intermediate level, suggesting that competition for binding to p53(1-39) by MDM2(17-125) is reduced by phosphorylation of Ser 15 ."
"These findings suggest that as-APF inhibits MDM2 binding to p53, and leads to p53 accumulation."
"Thus, our present study provided an insight that means approaches directly targeting MDM2, rather than targeting the interaction between MDM2 and p53, would likely be a productive novel concept for the development of anticancer treatment of MYCN amplified refractory neuroblastoma."
"Nuclear FAK also functions as a scaffolding protein for p53 and Mdm2 complex and mediates p53 ubiquitination and degradation."
"The interaction of p53 and MDM2 is similar in this regard as it requires a site in the N-terminus of MDM2 as well as MDM2 's acidic domain region [XREF_BIBR]."
No evidence text available
"IKA treatment also increased p53 phosphorylation (Ser15) and decreased the interaction of p53-MDM2."
"While inhibiting Mdm2 interaction with p53 family members in p53 wild-type containing tumors is being clinically pursued ( xref ), evidence indicates that resistance develops through p53 inactivation ( xref – xref )."
"Reciprocally, p53 also could bind with PKM2 and MDM2."
"Because the interaction between MDM2 and p53 is a primary mechanism for inhibition of the p53 function in cancers retaining wild-type p53, targeting the MDM2-p53 interaction by small molecules to reactivate p53 has emerged as a promising new cancer therapeutic strategy, and is the focus of this review."
"In the case of the p53 and HDM2 interaction, the p53-binding site on HDM2 is a cleft rather than a flat surface."
"Many drugs specifically targeting MDM2–p53 interaction, MDMX–p53 interaction, or MDM2-mediated ubiquitination of p53 have been developed ( xref ; xref ; xref )."
"This may explain why only p53 mutation affects the response to MDM2 inhibitors whereas the MDM2 genetic alterations have no effect, since the inhibitors specifically target the p53 and MDM2 interaction."
"Recently, strategies of treatment based on the stabilization of p53 have been considered in p53 non-mutated cancers and aim at disrupting the interaction between MDM2 and p53 [ xref ]."
"For example, MDM2 binds to nuclear p53 and helps export it to the cytosol, where p53 is sequestered and targeted for degradation."
"Alternatively, MDM2 interacts with p53 and drives its sequestration in the cytoplasm."
"MDM2 directly binds with p53 and forms a protein complex, mediating p53 degradation via the ubiquitin–proteasome pathway. xref , xref Overexpression of MDM2 is an early event in CRC progression and is positively correlated with p53 loss. xref In vivo mouse models clearly demonstrated that the inactivation or loss of p53 stimulates tumorigenesis, whereas established tumors are disappeared or diminished after restoration of p53. xref These data indicate that recovery of wild-type p53 function is a valid therapeutic approach, and the specific targeting of MDM2/MDMX to reactivate p53 is a viable anticancer strategy. xref On the basis of this notion, structure-based drug design has led to the discovery of several MDM2 or MDMX antagonists that block the interactions between murine double minute (MDM) and p53, leading to p53 stabilization and activation for cancer treatment. xref "
"Naderi et al. [ xref ] proposed that elevated cAMP levels enhanced the binding of p53 to its negative regulator HDM2, which overrode the stabilization of the p53 protein induced by DNA damages."
"Inhibition of the MDM2–p53 interaction using either Nutlin-3 or MDM2 RNA interference resulted in hyperactivation of the p53 pathway and a strong induction of apoptosis in cisplatin-sensitive and -resistant TC cells."
"However, in response to DNA damage or other signals, p53 undergoes phosphorylation which disrupts the MDM2-p53 interaction, resulting in increased p53 levels and activity ( Xu, 2003; Bode and Dong, 20[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Some of these mechanisms include directly re-expressing p53 in tumors by adenoviral delivery systems, blocking formation of Mdm2-p53 complexes (e.g., nutlins), reactivating mutant forms of p53 (e.g., via small peptides) or inhibiting the p53 deacetylases (e.g., tenovins) [ xref , xref ]."
"Therefore, potent and selective small-molecule inhibitors of the p53-MDM2 interaction have been designed with the intention to treat p53 wild-type tumors [ xref ]."
"Certain chalcones were also found to interfere with the p53–MDM2 interaction (Stoll et al., xref )."
"Blocking the MDM2-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control."
"To verify the EB148 covalent mechanism of action, kinetic dissociation of the p53 and MDM2 complex was evaluated in cell lysates and in whole cells."
"Furthermore MDM2 gene is a direct transcriptional target of p53, thereby p53 and MDM2 form a negative feedback loop where p53 regulates the expression of MDM2, that in turn blocks p53 functions and promotes its degradation."
"MK-8242 (SCH-900242) is an orally bioavailable and potent small molecule inhibitor of the MDM2-p53 interaction."
"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."
"Also of note, MI-63 and nutlin do differ in their structures, and while both bind residues Phe 19, Trp 23, and Leu 26 of the p53 and HDM -2 interacting domain, MI-63 also captures a fourth residue, Leu 22, which may play an important role in the interaction between HDM-2 and p53."
"In addition, in contrast to nutlin-3, RITA also did not inhibit the MDM2 and p53 interaction as shown by immunoprecipitation in GIST48B (XREF_FIG)."
"To assess the ability of PhR to inhibit p53 binding to MDM2 and MDMX, we incubated with PA-1 cells with PhR at 40 muM for 4 h and determined the levels of MDM2 and MDMX associated with p53 by immunoprecipitation (IP) from cell lysates followed by western blotting."
"These cis-imidazoline compounds compete with MDM2 for p53 binding, thus preventing the formation of the p53 and MDM2 complex and the negative regulation of p53 [XREF_BIBR]."
"On the basis of this finding, inhibiting the MDM2-p53 interaction can be a potentially important target for cancer therapy."
"As a scaffold, STIP is likely to function in concert with and depend on USP7 to mediate complex assembly with Mdm2 or p53, enabling USP7 to stabilize both proteins."
"MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction."
"As discussed by Uversky, interaction between Mdm2 and p53 involves a disorder-to-order transition upon binding which would thermodynamically favor blocking by small molecule competitors ( xref )."
"In conclusion, the data acquired from A549 cells indicated that L2 exhibited high antiproliferation activity by disrupting MDM2-p53 interaction, and that the mechanism was derived from the activation of p53 and the p53 pathway."
"In this report we demonstrate that the RBR E3 ubiquitin ligase RNF31 associates with the MDM2 and p53 complex."
"It is promoted through the binding of MDM2 to p53 mRNA as well as by circumventing MDM2-mediated RPL26 (ribosomal protein L26) degradation [73, 74]."
"In the present study, we investigated the interaction between endogenous MDM-2 and P53 following UV-induced DNA damage in an MDM-2 overexpression cell line."
"Specifically, Mdm2 (murine double-minute 2 or human hMdm2) binds to p53 and targets p53 for proteasomal degradation."
"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."
"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 xref ."
"Mdm2 and p53 bind to each other with higher affinity than to SHP, whereas TR3 has a higher p53 binding affinity and can sequestrate p53 from Mdm2."
"ATM indirectly regulates MDM2 mediated degradation of p53 through phosphorylation of Chk2 which then phosphorylates p53 at Ser 20 to prevent the formation of the MDM2 and p53 complex."
"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."
"Moreover, DNA damaging reagents and nutlin-3, an inhibitor of MDM2 and p53 interaction, increased APE1 ubiquitination in the presence of p53."
"Therefore, it is possible that these three SNPs in MDM4 or other untyped functional ones in linkage with them may promote expression of one of the shorter isoforms of MDM4 with more efficient binding to p53 or MDM2, thereby attenuating the p53 tumor suppressor pathway and leading to tumorigenesis in humans."
"In addition, the investigation of the molecular mechanism underlying the improved tumor cytotoxicity of prenylchalcone 2a revealed that prenylation could be a determinant factor for the enhancement [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"The p53-MDM-2 interaction has been extensively studied and small molecules have been created that disrupt their binding [ xref ]."
"Binding of p53 to Mdm2 and Hsp70 was not dependent on CCT interaction."
"Evidence supporting a role for abnormal cell proliferation in RSA includes the increased risk of abortion associated with polymorphisms of the cell cycle-related genes TP53 and MDM2 ( Pietrowski e[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"In the recent years, a number of peptide inhibitors have been reported. xref To overcome the pharmacokinetic shortcomings of peptides, the discovery of high potency non-peptidic small molecule inhibitors of the MDM2-p53 interaction has been pursued."
"The MDM2-p53 interaction was initially thought to result solely from the mutual binding of MDM2 and p53 via their N-terminal domains XREF_BIBR."
"Based on the findings of Haupt et al.  and Kubbutat et al.  , the current model of p53-MDM2 interactions now predicts that mutant p53 fails to stimulate transcription of MDM2 and that subseque[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Interestingly, the elevated levels of MDM2 do not reduce the levels of p53 in non-stressed cells and the blockage of p53 binding to MDM2, using inhibitors of MDM2, promotes apoptosis xref ."
"Nutlin-3a is a small molecule that activates the p53 pathway by disrupting p53–MDM2 interaction."
"The posttranslational modification of p53, such as phosphorylation, acetylation, methylation and deubiquination, affects the interaction between p53 and MDM2, and thus regulates p53 protein stability."
No evidence text available
"HEK293 cells were used to investigate the function of RNF31 on the p53 and MDM2 complex."
"The highly conserved Ser15 conveniently flanks the transactivation domain of p53 and is in close proximity to MDM2 in the p53 and MDM2 complex 24."
"The RB-MDM2 interaction does not prevent MDM2 from inhibiting p53 dependent transcription, but the RB and MDM2 complex still binds to p53."
"In ER+ breast cancer, the activity p53 is frequently silenced either by mutational inactivation and/or by the amplification of MDM2 that binds to p53 and represses its stability and transcriptional activity xref ."
"We tested this question using a small molecular p53 activator Nutlin-3a, which disassociates the binding of MDM2 to p53 [ xref ]."
"Many of the initial reporters for E3 ligase activity were incorporated into a high throughput screening assay in order to evaluate the effectiveness of inhibitors against the binding of p53 and Mdm2 (or Hdm2 in humans), a major mechanism of p53 inactivation in tumors."
"In this assay, the wt-p53 15 mer peptide inhibited the p53-MDM2 interaction at an IC 50 value of 4 μM, which was consistent with literature precedence. xref Two of the functionalized trisaccharides ( 1c–1d ) showed weak inhibitory activity against the p53-MDM2 interaction, while compounds 1a and 1b were inactive."
"Targeting the MDM2-p53 Interaction."
"Furthermore, activated MDM2 binds to TP53, acting as its agonist through an autoregulatory feedback loop mechanism; thereby, it may regulate and sustain TP53 level in both cell lines."
"To test whether inhibiting the interaction between Mdm2 with p53 could prevent anoikis in these cells, we pretreated the cells with Nutlin and then subjected them to the anoikis condition and thereafter quantified cell death using an ELISA assay."
"Interactions between p53 and MDM4 and MDM2 were examined by immunoprecipitation, as described above."
"Structure-based optimization of Spiro-oxindoles (including SAR405838) were designed to capture bind the hydrophobic protein–protein binding site between p53 and MDM2."
"In this study, the VISM surface area is similar to the solvent accessible surface area (SAS), and they are highly correlated with each other with R 2 = 0.922, as shown in Figure XREF_FIG d. B P53 and MDM2 Complex."
"In vitro experiments revealed phosphorylation of Ser15, a target of both ATM and ATR, inhibits the p53-Mdm2 interaction ( xref ) and coincides with p53 activation ( xref )."
"Subsequent work [19 ,20 ] has shown that, in fact, phosphorylation of another residue, Ser20, is important for p53 stabilization because this modification interferes with p53's association with its [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"To investigate whether this abrogation of HDM2-p53 interaction is at least in part due to inhibition of HDM2 by ribosomal proteins, we performed additional CoIP experiments."
"It has been shown that in vitro EBV transformed LCLs expressing wild-type p53 are sensitive to Nutlin-3a mediated growth suppression, which exclusively targets p53-Mdm2 interaction and thereby increasing p53 stability and apoptosis (Forte and Luftig, xref )."
"Wild-type p53 is normally expressed at low levels and inactive due to MDM2, an E3 ligase that binds p53 and promotes its degradation."
"In these instances blocking the interaction between p53 and HDM2 is hypothesized to stabilize p53 leading to pathway activation and growth arrest and/or apoptosis in cancer."
"Altogether, these data are consistent with our in vivo data demonstrating age related decrease in the sensitivity of SCs to the disruption of Mdm2 and p53 interaction."
phosphorylation of p53 by DNA-PK at Ser15 and Ser37 can inhibit the
binding of p53 to Mdm2."
"It is known that Mdm2‐mediated degradation of p53 is dependent on the direct interaction of these two proteins, so we examined whether disruption of the interaction between p53 and Mdm2 by using inhibitor nutlin‐3 could result in p53 stabilization in HCV cell culture."
"Most MDM2 inhibitors under development target MDM2-p53 binding and have little or no effect on cancers without functional p53, including pancreatic cancer."
"In particular, phosphorylation at Ser15 impairs MDM2 binding to p53, promoting both the accumulation and activation of p53 in response to DNA damage XREF_BIBR."
"Stress (DNA damage) induced phosphorylations, particularly those in the p53 N-terminus, inhibit the binding between p53 and MDM2 and thus stabilize p53 and cause its levels to increase."
"These results suggest that DBC1 regulates p53 by affecting the MDM2-p53 interaction."
"Often the same interaction was categorized as an example of both linear motif mediated binding and of disordered binding regions, such as the binding of p53 to MDM2 and the N-terminal region of p27 binding to the cyclin A and CDK2 complex."
"In response to DNA damaging agents, posttranslational modifications such as the phosphorylation of Ser 15 [XREF_BIBR, XREF_BIBR], Thr 18 [XREF_BIBR], and Ser 20 [XREF_BIBR] weaken the binding between p53 and MDM2."
"These results suggest that PIMT and its methylation of p53 are required for p53 destabilization through the enhancement of the interaction between HDM2 and p53."
"X-ray crystallographic studies of the p53 and Mdm2 complex reveal that the Mdm2 binding region of p53 forms a helical structure that binds into a deep groove on the surface of Mdm2 (see XREF_FIG) [XREF_BIBR]."
"The interaction between p53 and mdm2 is attested by the coincidence of their kinetic plots (Figs. 1A, D, E, H) with the maximum of cell accumulation during the S and G2/M phases."
"MDM2-bound p53 inhibits p53-mediated transcription by preventing p53 from contacting transcriptional coactivators such as p300 and CBP and subsequently allows for p53 export from the nucleus to the cytoplasm via the ubiquitination proteasome system xref ."
"Based on the crystallographic structure of the p53 and HDM2 peptide complex, small p53 peptides that mimic the region of p53 sufficient for HDM2 binding and small-molecule HDM2 antagonists have been shown to disrupt the p53 and HDM2 interaction in vitro and in vivo."
"Forced expression of the wt or the K1 forms of Mdm2 in these cells led to a dose-dependent decrease in the levels of p53 protein."
"So, nutlin-3 binds to HDM2 thereby inhibiting the interaction between HDM2 and p53 and resulting in an accumulation of p53 and activation of the p53 signaling pathway [XREF_BIBR, XREF_BIBR]."
"p53 can bind to MDM2, which interacts with its activation domain and prevents it from activating downstream genes."
"Hdm2 and p53 form an autoregulatory feedback loop, where p53 activates transcription of its own negative regulator."
"Thus, the inhibition of MDM2-p53 interactions presents an appealing therapeutic strategy for the treatment of glioma."
"To identify proteins other than p53 that associate with Mdm2, we chose an unbiased approach by immunoprecipitating endogenous Mdm2 from HeLa cells and performing mass spectrometry on the associated proteins."
"Towards that end, efforts have evolved to produce compounds that disrupt MDM2-p53 binding, thereby liberating p53 from its negative inhibitor and enabling elevated p53 activity."
"Similar attenuation was induced when p53 stabilization was induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the DNA damaged cells, half-lives of Mdm2 and p53 were decreased by statins, indicating a more rapid formation of p53 and Mdm2 complexes and facilitated p53 degradation."
"On one hand, induced MDM2 binds to p53 and RPS27L and promotes their ubiquitination and degradation."
"This decreased MDM2–p53 interaction was concomitant with decrease in p53 ubiquitination, suggesting that CK2-I increases p53 levels by preventing ubiquitin-mediated p53 degradation ( xref )."
"Using siRNA technology to interrupt p53-MDM2 interactions may therefore have therapeutic implications for controlling excessive osteoclastic activity."
No evidence text available
"Cellular stresses, including DNA damage, can disrupt the binding of MDM2 to p53 and increase p53 protein expression."
No evidence text available
"As MDM2 has also been identified as a USP7 target protein, it is intriguing to consider whether the binding of p53 to MDM2 might be affected by ABRO1 and whether ABRO1 might thus influence the ubiquitination and degradation of p53."
transactivation domain of p53 binds to MDM2, the key residue L26 occupies
the left region in the figure, W23 occupies the middle, and F19 occupies
"The Wang laboratory has recently developed a new class of small molecule inhibitors of the MDM2-p53 interaction."
"The co-crystallization of p53 peptide and Mdm-2 protein identified the 109 amino-acid region of amino-terminal domain of Mdm-2 bound to p53 peptide and detected that Phe 19, Tro23, and Leu 26 were deeply inserted inside the hydrophobic Mdm-2 cleft ( xref )."
"We calculated the binding constant for the Mdm2–p53-CTD complex to be in the low micromolar range, which is similar to the affinity of peptides from the Mdm2 acidic region for p53 core domain (in the range of 10–100 µM xref – xref ) but much weaker than the interaction of Mdm2 with the p53 N-terminus (nanomolar range)."
"Often the same interaction was categorized as an example of both linear motif mediated binding and of disordered binding regions, such as the binding of p53 to MDM2 and the N-terminal region of p27 binding to the cyclin A-CDK2 complex."
No evidence text available
"MDM2 is also activated by p53 itself; therefore, the inhibition of the MDM2-p53 interaction leads to the malignant transformation  ."
"Furthermore, human p53 and the various chimaeric proteins were generally less effective in inhibiting growth of mouse cells compared to mouse p53, suggesting that mouse p53 is more potent than human p53 in suppressing growth, partly due to enhanced binding of MDM2 to human p53."
"The results further demonstrate that loss of PTEN in ACHN cells activated the Akt/HDM2 signaling pathway and promoted the interaction between p53 and HDM2, which led to degradation of p53 and resulted in block of apoptosis induced by etoposide."
"Similarly, the small molecule Nutlin-3a binds Mdm2 in its p53-binding domain and thereby disrupts Mdm2–p53 interaction [ xref ]."
"In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation."
"Yoon et al. evaluated the association of MDM2 and p53 polymorphisms with the early onset of HCC in Korean patients with chronic hepatitis B virus (HBV) infection."
"Given that MDM2 is a crucial negative regulator of p53 and a major suppressor of p53 function in most p53 wild-type tumors, blocking the interaction between p53 and MDM2 is expected to stabilize p53 and activate the p53 pathway, leading to growth arrest and/or apoptosis in cancer."
"An Epstein-Barr virus (EBV) viral protein, Epstein-Barr nuclear antigen 1 (EBNA1), also binds the same region of HAUSP as that bound by the MDM2 and p53 peptides, competitively blocking these cellular interactions xref , xref ."
"Small molecule inhibitors of the MDM2-p53 interaction have been developed that only disrupt the protein-protein interaction and leave the intrinsic MDM2 ligase activity intact (Gessier et al., 2015)."
No evidence text available
"To confirm the microarray data, we performed real-time qPCR analysis using the isogenic p53 +/+ and p53 −/− HCT116 cells treated with Nutlin 3, an mdm2-antagonist that specifically blocks p53-mdm2 interactions and rapidly induces endogenous p53 protein accumulation."
"MDM2 binds to p53 by interaction through the amino terminus binding pocket domain, the central acidic domain, and the C-terminal xref ."
"13 Interestingly, wild-type PMI grafted cyclotides were about three times more effective disrupting the p53 and Hdm2 complex than the selective Hdm2-inhibitor Nutlin-3."
"Currently, two different approaches are being used: a molecule that directly activate p53 by blocking protein-protein interactions and compounds that trigger indirectly the stimulation of TP53 system xref such as Nutlin-3, a small molecule antagonist of MDM-2 that disrupts the MDM2-p53 interaction resulting in p53 stabilization and activation of p53 function xref ."
"In clear cell carcinomas without TP53 mutations, high MDM2 expression was significantly associated with poor progression-free survival (PFS) ( P = 0.0002 by log-rank test, Figure xref ), as was advanced stage ( P = 0.0002 by log-rank test, xref ), but not age ( xref )."
"This result indicates that p53 physically interacts with MDM2 in cellular extracts, which is consistent with previous studies XREF_BIBR - XREF_BIBR."
"Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2 (K (d) values of 36 and 7 nm, respectively)."
"We further use this approach to develop a cell-permeable vector that releases a highly specific peptide disrupting the p53 and HDM2 interaction."
"The binding of Mdm2 to p53 is required for targeting p53 for degradation."
No evidence text available
"Because the PIMT-mediated methylation of p53 could directly regulate the interaction between HDM2 and p53, PIMT might act as a regulator for the maintenance of p53 steady-state levels, and the interaction of p53 and HDM2 could be regulated through the PIMT-mediated methylation of isoaspartyl residues."
"As p53‐MDM2 forms a negative feedback loop, enhancement of the antitumor effect of 5‐FUbyMDM4/MDM2double knockdown could be attributed to blocking of the feedback mechanism in addition to direct suppression of these p53 antagonists."
"Central to the activation process, by whichever route, is the destabilization of the p53-MDM2 interaction."
"The results in xref indicate strong repression of the HDM2-p53 interaction by both Nutlin and the stapled peptides."
"The interaction of MDM2 with p53 was disrupted by neuronal treatment with nutlin-3a."
"Inhibiting the MDM2 and p53 interaction to reactivate p53 function is therefore a promising strategy for cancer and GBM therapy."
"XREF_BIBR Interestingly, deletion of Glu17 alone from 17-26 p53 was reported to have little impact on p53 binding to MDM2, XREF_BIBR; XREF_BIBR whereas a 13- and 6-fold decrease in binding affinity for MDM2 and MDMX, respectively, was noted in our work."
"To avoid this issue, we instead explored the use of Nutlin-3 and its derivative RG7112, both of which are inhibitors of the interaction between p53 and MDM2, a p53 E3 ubiquitin ligase."
"Therefore, restoration of p53 activity by inhibiting the p53–MDM2 interaction represents an appealing therapeutic strategy for tumors with wt p53."
"This strongly suggests that HDM2 binds and inactivates p53 that could be pathogenic for MHPCs, by a different mechanism than point mutation."
"Overall, these results strongly suggest that the functional interaction between p53 and MDM2 is at least in part dependent on the same amino acids in the p53 N-ter domain as in mammalian cells but does not lead to a strong reduction in p53 protein stability."
"Therefore, it is of great interest to understand the interaction between P53 and its main negative regulator MDM2, as it may lead towards a therapeutic approach in paediatric patients with malignancies that do not have TP53 mutations and who have poor prognoses [ xref ]."
"One of the better-understood negative regulators of p53 function is MDM2, which binds to p53 and leads to ubiquitination and subsequent proteasomal degradation of p53 protein."
"Consequently, small molecules that impair or disrupt the p53 and MDM2 interaction result in the accumulation of transcriptionally active wild-type p53."
No evidence text available
"Thus, MDM2 interacts with p53 and RUNX3 through separate regions."
"Nonetheless, it is important to note that p53 directly interacts with MDM2, a transcriptional repressor in its own right."
"Additionally, neither was found to inhibit the formation of the HDM2 and HDMX heterodimer, nor did they inhibit the formation of the p53 and HDM2 complex [XREF_BIBR]."
"A previous study demonstrated that DNAJC7 participates in the p53 and MDM2 negative feedback pathway, dissociating MDM2 and p53 by inhibiting the formation of p53 and MDM2 complex to improve the stability and activity of p53 protein; thus plays a role in inhibition of human carcinogenesis [XREF_BIBR]; thus, polyglutamylated DNAJC7 would lose its function in regulation of p53 stability and activity and subsequently, RCC will occur."
"We used the small molecule nutlin, which blocks the interaction between p53 and its major negative regulator Mdm2, thereby preventing p53 degradation and inducing its activity [ xref ]."
"Formation propensity of C-HBs in the MDM2 and p53 complex."
"Our work, consistent with other reports, suggests that the p53 tetramer interacts with at least two sites on mdm2."
"These targeted alterations were specifically designed to inhibit binding of stress induced p53 to the Mdm2 promoter and thus abrogate the p53-Mdm2 feedback loop."
"On the other hand, a negative circuit is comprised of an odd number of negative interactions, such as the interaction between p53 and Mdm2, that leads to a periodic behavior or homeostasis."
"Interestingly, suppression of p53 expression in CNE2 cells was associated with significant down-regulation of p21WAF1/CIP1 expression and decreased HDM2 protein level in both steady state and genotoxic stress induced by ionizing radiation (IR)."
"MDM2 inhibitors, which block the specific interaction between MDM2 and p53, can thus generate high levels of intracellular p53 and trigger apoptosis."
No evidence text available
No evidence text available
"A recent study showed that REGγ facilitates the interaction of the E3 ubiquitin ligase MDM2 with p53, thus promoting the polyubiquitin-dependent degradation of p53 (Zhang and Zhang, xref )."
"P53 and HDM2 form an oscillating feedback loop."
"First, MDM2 binds to the same region of p53 as
do components of the transcription factor TFIID and thus, the ability
of p53 to transactivate target genes is diminished."
"The interaction between MDM2 and p53 regulates baseline protein levels and activity of p53 through an autoregulatory feedback loop [XREF_BIBR, XREF_BIBR]."
"For the two enantiomers of compound 5s obtained by chiral separation, we found only R-5s could inhibit p53-MDM2 interaction and release p53 to suppress tumor proliferation."
"To address this issue, we have used the cis-imidazoline compound Nutlin-3, an inhibitor of MDM2 and p53 interaction, which represents a potent and selective non genotoxic activator of the p53 pathway both in in vivo and in vitro experimental settings."
"For instance, the inhibitor of the p53-MDM2 interaction, MK-8242, was investigated in 47 patients with p53-wild-type solid tumours [ xref ]."
"HDM2 has been shown to bind to p53 through an N-terminal domain, and we confirmed that p53 could form a complex with wild-type HDM2, an HDM2 protein carrying a point mutation in the C-terminal RING fi[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Additionally, mirror-image phage-display (MIPD) techniques together with native chemical ligation have provided proteolytically more-resistant d -peptide inhibitors of the p53–MDM2 interaction."
"Recent efforts in anti-cancer drug design have focused on the identification of small molecules that disrupt the Mdm2-p53 interaction, in hopes of re-engaging the p53 pathway."
"The activity of compound EB148 in inhibiting p53 and MDM2 complex was maintained unchanged after sample dilution."
"The augmentation of DHCR24 by HCV suppresses p53 activity by blocking nuclear p53 acetylation and increasing the interaction between p53 and HDM2 (p53-specific E3 ligase) in the cytoplasm, which may be mediated by inhibition of p53 degradation."
"The latter inhibition required the formation of complexes between the Mdm2 protein and p53, and operated only on SST-dependent apoptosis but not SST-independent apoptosis."
"Also, these data suggest the existence of other proteins than mdm2 that may associate with p53."
"Structurally, the N-terminal domain of MDM2 binds a short 15-residue α-helical peptide of p53 [ xref ]."
"After publication of the crystal structure of p53 bound to MDM2, several efforts were made to design more potent peptide derivatives and small molecules to target this interaction."
"MDM2 binds p53, sequestering p53 in the cytosol and targeting it for degradation."
"As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G(1) phase cell-cycle arrest and apoptosis."
"The protein-protein interaction (PPI) of the tumor suppressor p53 and its negative regulator MDM2 consists of the most intense studied PPI with a group of small molecular weight antagonists described and many more disclosed in patent literature."
"These stapled peptides are protease-resistant, cell-permeable, metabolically stable, bind multidomain proteins with high affinity [ xref ], and were able to inhibit the p53-Mdm2 interaction [ xref ]."
"What is not understood well is the process of binding of p53 and MDM2 to each other, mediated by these conformational states: is it pre-organization prior to binding or is it reorganization after binding (or induced fit)."
"To decipher the structural basis of D-peptide inhibition of the p53-MDM2 interaction, we determined the co-crystal structure of D PMI-α and synthetic 25–109 MDM2 at 2.4 Å resolution ( Table S1 and Figure S3 )."
"This fragment of hMdm2 contains the region necessary for binding to p53 and binding of Mdm2 to p53 is thought to be sufficient to inactivate the transcriptional activity of p53 ( xref )."
"In order to predict the effect of an Mdm2 inhibitor that blocks the interaction between p53 and Mdm2, for example Nutlin, the binding rate of Mdm2 and p53,
, was reduced from [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"Siva1 was originally identified as a protein associated with the cytoplasmic tail of CD27 conveying an apoptotic signal. xref Ectopically expressed Siva1 also binds to Bcl-XL and inhibits Bcl-XL-mediated protection against UV radiation-induced apoptosis. xref Siva1 is induced by p53, xref and is also reported to participate in p53-dependent apoptosis in cerebella granule neurons. xref In this study, we show that Siva1 is a crucial regulator for the p53-Hdm2 interaction."
"Following activation, MDM2 binds and ubiquitinates p53, leading to its translocation to the cytosol and proteasomal degradation XREF_BIBR."
"The phosphorylation of this serine when DNA damage is detected weakens the interaction between p53 and MDM2, thereby stabilising p53 ( xref – xref )."
"Because p53 and Mdm2 form an autoregulatory negative feedback loop in which p53 transactivates and Mdm2 targets p53 for degradation, stabilization of p53 in response to genotoxic or other stress can [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"We used biophysical methods to determine the thermodynamic and kinetic-binding parameters for the interaction between MDM2 and the human p53 wild-type peptide (PMD1, aa 15–29; see Figure 1(a)
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"Yoon [ xref ] evaluated the association of mdm2 and p53 polymorphisms with the early onset of HCC in Korean patients with chronic HBV infection, and found that both the mdm2 SNP309 and the p53 codon 72R > P polymorphism were associated with the development of HCC."
"By using Nutlin-3a, an inhibitor of the interaction between Mdm2 and p53, we were able to partially reconstitute p53 transactivation and apoptosis in transgenic cells."
"Stress responsive kinases ATM and ATR are rapidly activated after DNA damage and phosphorylate p53 protein at different sites, including Ser15, leading to the disruption of the interaction between p53 and HDM2 with resultant p53 stabilization and activation. xref To determine whether depletion of LZAP reduced p-p53 (Ser15) level, CRISPR constructs targeting LZAP were stably transfected into U2OS cells prior to zeocin treatment."
"We found that treatment with 27-OHC increased MDM2 and p53 binding."
"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, pres[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"MDM2 and MDMX bind to p53 at their N-terminal domains to inhibit its transactivation."
"MI-63 targets the p53–MDM2 interaction, blocking the inhibition of the tumour suppressor and protein ubiquitination ( xref )."
"Angiogenin expression results in the phosphorylation of p53, increased p53-Mdm2 interaction and ubiquitination of p53."
"First, the Arg72 variant retains a higher potential to localize itself to mitochondria; hence, this cellular activity might provide an opportunity to enhance interaction between TP53 and MDM2."
"Taking in consideration that p53 Trp23 side chain (indole group) seems to be critical for p53-MDM2 interaction, by burying deep inside p53 hydrophobic pocket and establishing a hydrogen bond (NH) to the MDM2 backbone (carbonyl), the oxindole moiety was believed to perfectly mimic this residue."