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Statements
TP53 binds MDM2. 1000 / 12695
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"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 ]"
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"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."
sparser
"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 ."
sparser
"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 ))."
sparser
"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."
sparser
"Table A1: The parameters used in the module of DSBs generation and repair process
Table A2: The parameters used in the module of ATM activation process
Table A3: The parameters used in the module of P53-MDM2 feedback regulatory loop
Fig. 1: The integrated model scheme of P53 gene regulatory networks under radiotherapy."
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"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."
sparser
"The main therapeutic methods are to restore the function of p53 and to interfere with the p53–MDM2 axis. xref By reviewing recent studies on PI3K/Akt pathway and p53 pathway in NPC, we have summarized some potential targets that can affect the PI3K/Akt pathway and p53 pathway, which will be conducive to the selection of targeted therapeutic targets for NPC in future basic studies."
sparser
"In the case of FXR overexpression, SHP is upregulated and plays an important role in increasing MDM2 expression through binding with MDM2 to inhibit MDM2-p53 binding and ubiquitination by forming the SHP-MDM2 complex in the nucleus; this slows down MDM2 degradation and increases the stability of the MDM2 protein."
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"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."
sparser
"Although de novo USP7 germline mutations have been found to cause neurological disorders by disrupting its regulation of MAGE-L2-TRIM27 xref , USP7 is best known to regulate the MDM2-TP53 axis via deubiquitination xref , affecting several downstream pathophysiological processes such as DNA repair, immune response, and cancer."
sparser
"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."
sparser
"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 ]."
sparser
"Among compounds that restore wild-type function of p53 there are agents such as CP-31398 (stabilize the DNA-binding core domain and induce conformational changes) ( xref ), PETIC (sensitize the p53 mutant to proteasome-mediated degradation and restore p53 WT conformation) ( xref ), RITA (reactivate p53 in mutant p53 cancers by inhibiting the p53-HDM2 interaction) ( xref ), and COTI-2 (restore WT p53 activity by targeting and binding to misfolded p53 mutant) ( xref )."
sparser
"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 ]."
sparser
"However, when treated with Nutlin-3, an MDM2 antagonist that inhibits MDM2-p53 interaction resulting in p53 activation, there was no induction of either MDM2 or p21 (indicators of p53 activation) in NIH-OVCAR3 compared to a p53 wild type (WT) cell line, confirming functional loss of p53 caused by the mutations ( xref )."
sparser
"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 ]."
sparser
"Further, MDM2 mediates the nuclear export of p53. xref Moreover, when p53 is ubiquitinated by MDM2, it cannot be acetylated by p300/CBP, and, therefore, rapid proteasome-mediated degradation takes place. xref As MDM2 is transcriptionally induced in a p53-dependent manner, the two proteins make an elegant feedback loop (Fig. xref ). xref When modifications occur on MDM2, the direct interaction between p53 and MDM2 is broken, such as during a DNA damage event in which MDM2 is phosphorylated at serine 395. xref "
sparser
"Transient and oscillatory activation of p53 was found to be compatible with DNA repair and proliferation, while sustained p53 levels, obtained by chemical manipulation of the p53-Mdm2 feedback loop using an Mdm2 inhibitor, led to terminal fates such as apoptosis and senescence xref ."
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"Therefore, we demonstrate here the probable binding (unbinding) pathway of transactivation domain 1 of p53 during the formation (dissociation) of the p53 and MDM2 complex in terms of free energy as a function of reaction coordinate from the potential of mean force (PMF) study using two different force fields : ff99SB and ff99SB-ILDN."
sparser
"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 ."
sparser
"The p53-Mdm2 network model describes the interactions between the tumor suppressor protein p53 with its main negative regulator, the ubiquitin ligase Mdm2, with the three variables P , Mn , and Mc , which stand for proteins p53, nuclear Mdm2, and cytoplasmic Mdm2, respectively [ xref ]."
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"Similarly, high-quality one-bead-one-b-peptide libraries suitable for on-bead screening have been reported by Schepartz and used to identify inhibitors of the p53/MDM2 interaction with IC 50 values in the low mM range following simple tandem mass spectrometry (MS/MS) decoding method.Complementary to chemical methods to generate nonnatural oligomers and corresponding libraries, several biotechnological approaches are gaining increasing attention in the context of nonnatural oligomers and foldamers."
| DOI
sparser
"CircFoxo3 was shown to bind CDK2 and p21, which simultaneously facilitated p21-mediated suppression of CDK2 activity and prevented CDK2 from binding cyclin E, arresting cell cycle progression in the G1 phase. xref CircFoxo3 was also shown to bind p53 and MDM2 to form a complex that facilitated MDM2-induced p53 ubiquitination and relieved MDM2-induced Foxo3 ubiquitination, leading to increased PUMA expression and tumor cell apoptosis. xref These studies and others xref , xref suggest that circRNAs frequently interact with proteins."
sparser
"The p53-MDM2 interaction is a relevant pharmacological target for anti-cancer therapeutics xref – xref and an important model for the study of protein-protein binding due to the abundance of structural information. xref – xref MDM2 has a highly concave and hydrophobic binding pocket that undergoes dewetting fluctuations prior to the binding of p53, as seen in explicit solvent molecular dynamics (MD) simulations and level-set VISM calculations. xref , xref , xref Here, we first calculate the solvation free energy of this protein complex and obtain the potential of mean force with respect to some separation distance of the two molecules."
sparser
"Ischemic preconditioning was shown to activate Mdm2 and enhance phospho-Mdm2-p53 binding in a PI3K-dependent manner, xref but whether helium specifically causes phosphorylation of Mdm2 or produces a similar phospho-Mdm2-p53 interaction was not specifically examined in the current investigation."
sparser
"Interestingly, the interaction was restored by deleting a non-conserved flanking region of Ci-p53 BOX-I. As the p53 mRNA–MDM2 interaction is present in C. intestinalis , this suggests that the p53 mRNA–MDM2 interaction preceded the p53–MDM2 protein–protein interaction and that the latter evolved by elimination of the BOX-I flanking region."
sparser
"In this sense, numerous tumor suppressor approaches are related to p53-MDM2/MDMX, namely preventing the formation of p53-MDM2 complexes, preventing the p53 protein ubiquitination degradation and modifying p53 transcriptional active region to stabilize the p53 protein [ xref , xref , xref , xref ]."
sparser
"Phosphorylation of p53 is a known modification and it has been demonstrated that phosphorylation of p53 at Ser 15 by the serine/threonine protein kinase ATM (ataxia telangiectasia mutated) and the p38 MAP (microtubule-associated protein) kinase (She et al. xref ) or at Ser 20 by ATM blocks the p53 MDM2 interaction and hence p53 ubiquitination (Elias et al. xref )."
sparser
"To further validate the regulatory role of p53 on PDE4D, we also treated HCT116 p53+/+ and HCT116 p53-/- cells with 10 μM Nutlin-3 (Nut), which disrupts MDM2-p53 interaction and therefore activates p53 ( xref ), and 5 nM Actinomycin D (ActD), which causes ribosomal stress-mediated p53 activation ( xref ), and found PDE4D was reduced by both of these two drugs only in p53 positive, but not p53 negative, cells ( xref )."
sparser
"The large increase in sites after Nutlin compared with DXR treatment was unexpected and suggests that Nutlin treatment leads to changes in chromatin architecture or nucleosome occupancy that are not anticipated for a drug selected for its specific effect on the interaction between p53 and MDM2 ( xref )."
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"The detrimental effect of the phosphorylation of p53 Thr18 (Lee et al., 2007), p53 Ser20 (ElSawy et al., 2015), MDM2 Ser17 (Dastidar et al., 2011), and MDMX Tyr99 (Chan et al., 2017) on p53 binding to MDM2 or MDMX have also been extensively studied in MD and Brownian dynamics (BD) simulations.Nussinov and coworkers (Tuncbag et al., 2009) provided a temporal dimension to the PPI network of the p53 hub protein based on its DBD interactions."
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"MDM2, which is a RING-finger type E3 ubiquitin protein ligase, bound to NH 2 -terminal transactivation domain of p53, ubiquitylated COOH-terminal 6 Lys residues (Lys 370, Lys 372, Lys 373, Lys 381, Lys 382, and Lys 386), and thereby targeting p53 for proteasome dependent degradation [XREF_BIBR]."
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"However, a full implementation of such approach is computationally intractable for various reasons, including (a) the lack of crystal structures of the p53 and MDM2 complex with the lid present (in either truncated or complete form); and (b) the inherent uncertainty in computing peptide binding free energies in the presence of long and highly variable lid construct."
sparser
"The important functional domains of MDM2 include the N-terminus domain, which binds to both the N- and C-terminus regions of p53 [ xref , xref , xref ], and the C-terminus domain, which contains a RING finger motif that carries out the E3 ligase function and a central zinc finger/acidic domain that serves as an allosteric binding site that modulates p53-MDM2 interaction [ xref , xref ]."
sparser
"In those assays, Staplin-2 (MO11), a modified version of Staplin with a chlorinated tryptophan ( xref ; xref ), can disrupt the interactions of placozoa p53 with either placozoa Mdm or human Mdm2, while Staplin can only disrupt the interaction between placozoa p53 and human Mdm2 but not between placozoa p53 and placozoa Mdm."
sparser
"Abundant evidence suggests that the de-ubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) plays a critical role in stabilizing p53, even in the presence of excess MDM2, and that it activates p53-dependent cell arrest and apoptosis. xref , xref HAUSP was also shown to form a complex with MDM2 and p53."
sparser
"In combination with the previously reported results that the Bcl-2 inhibitor BH3I blocked the interaction between p53 and MDM2 xref , the Bcl-X L /Nutlin-3 complex structure sheds lights on structure-based design of a multi-targeting anticancer agent that can simultaneously inhibit MDM2 and Bcl-X L proteins."
sparser
"In addition, capsaicin can induce apoptosis by indirectly inhibiting the ubiquitin–proteasome system, leading to the accumulation of target substrates normally targeted by the proteasome, such as p53, Bax, and p27. xref By inhibiting the interaction between p53 and MDM2, capsaicin has been reported to stabilize the p53 protein and enhance the transcriptional activity of its encoding gene in human colon cancer cells. xref In the present study, we report that TRIB3 is a potent target of capsaicin and its upregulation might play a critical role in the capsaicin-mediated apoptosis of different human cancer cells."
sparser
"Among these, chlorofusin (Fig. 3, compound 14) , a fungal metabolite isolated from Fusarium sp., was found to have the highest (14) and chalcone (AM114) (15) , which specifically interfere with the HDM2-p53 or HDM2-proteasome interactions ( Refs 88, 89, 90, 91, 92, 93) , and thalidomide (16) inhibitory activity towards HDM2 (Ref."
sparser
"For instance, phosphorylation of Ser15, Thr18, Ser20 and Ser37 stabilizes p53 by disrupting interaction between p53 and MDM2 [ xref ], whereas phosphorylations at the p53 C-terminus such as Ser315 and Ser392 are reported to regulate the oligomerization state and sequence-specific DNA-binding ability of p53 [ xref ]."
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"To this end, we show that three different quaternary structures with the subunit dissociation constant K (d) approximately 0.5-20 microM, the antibody variable domain (Fv), the IL-8 dimer, and the p53 and MDM2 complex, can not be displayed on the yeast surface as a noncovalent complex."
sparser
"Ovarian tumor domain-containing Ub aldehyde-binding protein 1 (Otub1), DUB from the OTU-domain containing protease family, directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. xref However, Otub1 decreases p53 ubiquitination, stabilizing and activating p53 in cells via inhibition of UbcH5, a cognate ubiquitin-conjugating enzyme of MDM2. xref Thus, Otub1 mediates p53 ubiquitination in cells independently of its de-ubiquitinating enzymatic activity. xref , xref , xref , xref Furthermore, Otub1 plays a crucial role in the stability and activity of p53 after DNA damage, because Otub1 can inhibit DNA damage-induced chromatin ubiquitination and slow down DNA repair. xref In conclusion, Otub1 regulates the p53-MDM2 loop as a potential inhibitor of the E2 enzyme."
sparser
"To further confirm that the enrichment of red fluorescence signal was due to the cognate interaction between MDM2 and p53, we treated the cells co-expressing GFP-Nup98N-MDM2 and mCherry-p53 with Mi-773, a potent inhibitor specifically targeting the MDM2/p53 interaction (Wang et al., 2014)."
sparser
"Using Brownian dynamics simulations, we show that the preferential binding of the MDM2 protein to the geometrical isomers of Nutlin-3, an effective anticancer lead that works by inhibiting the interaction between the proteins p53 and MDM2, can be explained by kinetic arguments related to the formation of the MDM2:Nutlin-3 encounter complex."
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"More small molecules have been identified in the second category, including Nutlin, Rita, MI-219, and Tenovins, to activate wild type p53 in cancer cells and to kill them by either directly inhibiting the interaction between MDM2 and p53 or indirectly inducing p53 acetylation XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR."
sparser
"For example Spirotryptostatin A and B, 1 and 2 inhibits tubulin polymerization and induces cell cycle inhibition of cancer cells at G2/M phase and spirooxindole MI-5, 3 , demonstrated novel type of inhibition of p53-MDM2 protein-protein interaction that is critical for modulating tumor suppressing ability of the p53-proteins ( xref ) xref xref xref ."
sparser
"Colon carcinoma RKO cells were selected for these experiments due to their wide use in prior p53 studies. xref Colon carcinoma RKO cells were treated with the MDM2 inhibitor (±)-Nutlin-3 ( xref ) to block the interaction of MDM2 and p53. xref – xref Because MDM2 promotes p53 degradation under normal cell conditions ( xref , lane 1), the disruption of MDM2/p53 interactions stabilized p53 for cellular accumulation ( xref , lanes 2 and 3). xref "
sparser
"Similarly, agents that activate the p53 tumour-suppression pathway, including Nutlin and HLI98, small molecules that block the p53-Mdm2 interaction ( xref ), and inhibit the E3 ubiquitin ligase activity of Mdm2, respectively, ( xref ) are currently being tested for their potential use in cancer therapy."
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"Comparing to a small molecule RITA, originally reported to display antitumor activity by inhibiting the p53 and MDM2 interactions 9, exo-PpIX inhibits proliferation and induces apoptosis in B-cell chronic lymphocytic leukemia cells (B-CLL) more efficiently and without affecting healthy blood cells 8."
sparser
"As a representative GBM cell line, we used U87MG cells, which is an appropriate model to study the interaction between the AKT/mTOR and MDM2-p53 pathways because of the following characteristics: i) U87MG cells maintain a wild type status of p53, and ii) U87MG cells are deficient for the tumour suppressor phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K/AKT pathway; moreover, PTEN deficiency leads to MDM2 nuclear accumulation, thus inhibiting p53 functions xref ."
sparser
"Again, the affinity of binding of ubiquitinated p53 and Mdm2 may be a contributory factor to the differential sensitivity to free polyubiquitin, or the ubiquitin receptor proteins may differ in their ability to bind the unanchored polyubiquitin that accumulates after USP5 knockdown."
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"Our results show that the hydrophobic cluster that forms in p63 " slows " down folding but yet eventually does lead to a conformation that is suitable for sequestration by MDM2; this may partly be responsible for the experimental demonstrations of weak interaction between p63 and MDM2 (relative to the interactions between MDM2 and p53 and p73)."
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"The disruption of protein protein interactions, which are signaling hubs that link and transmit oncogenic signals across various molecular networks, offer a potentially effective means of halting oncogenic signaling (e. g. inhibition of p53 and MDM2 interaction by Nutlins) [XREF_BIBR, XREF_BIBR]."
sparser
"Association of RNF31 with the p53/MDM2 complex was confirmed in HEK293 cells after the introduction of RNF31, p53 and MDM2 ( xref ). xref shows that RNF31 still interacts with p53 in the presence of Nutlin-3 (compare lanes 7 and 3), which blocks the interaction between p53 and MDM2 (compare lanes 8 and 4), whereas the RNF31 association with MDM2 was partially blocked by Nutlin-3."
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"While there are numerous studies demonstrating the potential for small molecules capable of inhibiting Hdm2 and p53 interactions there are extremely few reported small molecules which have been shown to be capable of inhibiting HdmX and p53 and none that have demonstrated both cell and animal efficacy."
sparser
"Strong control over the system response is distributed among the p53-Mdm2 interactions (k 45 ), activation of the nuclear p53 (k 11 ) and ensuing transcriptional activation of PUMA (k 20 ), translocation/retranslocation of Bax between the mitochondria and the cytosol (k 24 ± ), Bax activation (k 30 ) and caspase-3 regulation (k 38 + andk 42 )."
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"Therefore, it was reasoned that pharmaceutical agents targeting the Mdm2 and p53 interaction in transformed cells retaining wild-type TP53 status may be a promising new approach to cancer therapy, which is considered particularly important in the context of hematological malignancies, where the frequency of TP53 mutations is relatively low (in comparison with solid tumors), while Mdm2 is frequently amplified and overexpressed."
sparser
"Considering the p53-dependent manner, MDM2 directly binds
to p53, forms a complex with it, and then inhibits transactivation
of p53. xref Moreover, it has also been found
that there are two other sites of interaction between p53 and MDM2:
one is between the acidic domain of MDM2 and the DNA binding domain
of p53, xref − xref and the other is between the N-terminal domain (NTD)
of MDM2 and the C-terminal domain of p53. xref An extensive amount of data has confirmed that MDM2 plays the central
role in the p53 pathway."
sparser
"The obtained results led to the identification of a hit compound, prenylchalcone 2e, which behaved as potential inhibitor of the MDM2-p53 interaction in yeast, and showed improved cytotoxicity against human tumor cells expressing wild-type p53, including liver hepatocellular carcinoma HepG2, breast adenocarcinoma MCF-7, and malignant melanoma A375 cells."
sparser
"Following on earlier hints that reducing synthesis of RPS3a in tumor cells ( xref ) or increasing S29 ( xref ) would lead to apoptosis, it has now been shown that a constituent of the small ribosomal subunit, S7, can interact with the MDM2-p53 complex, again protecting p53 so that its effective concentration rises ( xref )."
sparser
"Many groups have succeeded in developing diverse stabilized helices and helix mimetics to target the interaction between p53 and HDM2, including terphenyl-based helical mimetics by Yin et al. [ xref ], hydrocarbon stabilized helical peptide by Bernal et al. [ xref ], β -hairpin protein epitope mimetics by Fasan et al. [ xref ], helical β -peptide inhibitors by Kritzer et al. [ xref ] and Murray and Gellman [ xref ], and oligobenzamide proteomimetic inhibitors by Plante et al. [ xref ]."
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"20 Thus, further structural simplification led to the identification of spiro-pyrrolidinyl MI-888 (5) as a potent nonpeptide inhibitor of p53 and MDM2 interaction (K i = 0.44 nM), which was reported to achieve rapid, complete, and long lasting tumor regression in two types of xenograft models of human cancer, with oral administration."
sparser
"The tumor suppressor p53 is the most frequently mutated gene in human cancers, and mediates cell-cycle arrest and apoptosis in RCC. xref – xref p53 Transactivation is inhibited by MDM2, a nuclear protein induced by p53, and MDM2 also mediates p53 stabilization and degradation in p53-mediated apoptosis. xref – xref A large percentage of human tumors have amplified MDM2, leading to p53 loss and tumorigenesis. xref These observations implicate the importance of p53 and MDM2 feedback-loop interactions in regulating cancer development."
sparser
"These include the nutlins, which interfere with the interaction between TP53 and its suppressor HDM2, and ABT-737 (and its derivatives ABT-263 and ABT-199), which serves as a BH3 mimetic to prevent the interaction between the pro-survival members of the Bcl-2 family such as Bcl-2 itself, Bcl-x L and Bcl-w, and the pro-apoptotic Bcl-2 members such as Bax and Bak ( xref , xref )."
sparser
"In addition, Pengbo Cao et al. xref also found a possible mechanism of HBV-related HCC development without cirrhosis because of MDM2–p53 axis dysfunctions; the expression of small nucleolar RNAH/ACA box 18-like 5 (SNORA18L5) in hepatocytes can be upregulated by HBV, which promotes p53 ubiquitination and degradation by preventing RPL5 and RPL11 (ribosomal proteins) to escape into the nucleoplasm to bind MDM2."
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"The protein protein interaction (PPI) of the transcription factor p53 and its negative regulator MDM2 has emerged as a novel non genotoxic target for anticancer drugs, and AML seems to be an appropriate disease to test this new approach due to the presence of wild type p53 and overexpression of MDM2 in the majority of AML cases."
sparser
"Western blot study showed that the S-5s could inhibit NF-κB activation only, while the R-5s could inhibit both p53-MDM2 interaction and induce the inhibition of NF-κB activation with the in vitro antiproliferative result indicating poor selectivity over cancer cell lines (H1299 and Saos-2) with deleted p53."
sparser
"Hence, the above-mentioned evidence seems proposed that the normal proliferation and apoptosis of infected hepatocytes can be disrupted via HCV-induced apoptosis-related protein inactivation by interfering with MDM2–p53 axis; moreover, the abnormal differentiation hepatocytes cannot be killed because of T-cell exhaustion by HCV-mediated p53 dysfunction."
sparser
"As a result of the elucidation of the crystal structure of the MDM2-p53 complex, especially the identification of the three crucial amino acids in p53 (Phe19, Trp23, and Leu26) required for the binding of these two proteins, hundreds of peptides, synthetic compounds, and natural products have been designed, synthesized, or screened for their ability to target the MDM2-p53 interaction, preventing MDM2 binding to p53, stabilizing 53 protein and activating p53 functions."
sparser
"Several strategies have been suggested: (1) Wee-1 kinase inhibitors together with DNA damaging agents, (2) inhibitors of the p53-MDM2 interaction, which result in p53 stabilization, and (3) vascular endothelial growth factor receptor (VEGFR)/VEGF-targeting agents in patients with TP53 mutations [ xref ]."
sparser
"One candidate of this series is currently being tested in clinical trials.[ xref ] Moreover, ATSP-peptides bind to mutated forms of MDM2 that are not accessible for small-molecule p53–MDM2 inhibitors of the Nutlin family (Figure xref ).[ xref , xref ] Nutlins are class D peptidomimetics capable of inhibiting the p53–MDM2 interaction.[ xref ] High-throughput screening of synthetic chemical libraries provided lead structures that were further developed into the Nutlins."
sparser
"The combination of p53-activating agents, particularly inhibitors of the p53 interaction with MDM2 (e.g., nutlin-3a), with BRAF and MEK inhibitors, might therefore represent an appealing therapeutic strategy, potentially overcoming therapeutic resistance and improving disease-free survival of melanoma patients [ xref , xref ]."
| PMC
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"In those assays, Staplin-2 (MO11), a modified version of Staplin with a chlorinated tryptophan, can disrupt the interactions of placozoa p53 with either placozoa Mdm or human Mdm2, while Staplin can only disrupt the interaction between placozoa p53 and human Mdm2 but not between placozoa p53 and placozoa Mdm."
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"A co-crystal structure of the SAR405838 : MDM2 complex shows that in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53 and MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity."
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"In this latter case, the use of the small molecule RITA (reactivation of p53 and induction of tumor cell apoptosis) that inhibits MDM2 and p53 interaction and induces expression of p53 target genes and massive apoptosis in various tumor cells lines [XREF_BIBR], can be useful to counteract HIPK2 degradation and to reactivate p53 apoptotic function [XREF_BIBR]."
sparser
"The supporting evidence for this alternative model stems from biochemical studies of several MDM2 mutants, where the phospho-mimetic mutation S17D was found to increase the stability of the p53-binding domain of MDM2, enhance the p53-MDM2 interaction, and promote MDM2-mediated ubiquitination of p53 in vitro xref , xref ."
sparser
"Although it is known that the MDM2–p53 interaction is controlled by an autoregulatory loop ( xref ; xref , xref ; xref ) and that the MDM2-mediated degradation of p53 is dependent upon the cellular level of MDM2 ( xref ), the mechanisms regulating this interaction appear to be complex and are poorly understood."
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"Detection of such pre-existing pathways in the populations of cancer cells can help in selecting appropriate drug treatment that either kill the cancer cells along or potentiate the response to Mdm2 and p53 binding inhibitors as it is demonstrated previously for various cancer cell lines [XREF_BIBR]."
sparser
"We have previously demonstrated the efficiency of TP53 activation (Nutlin) in combination with MYC (JQ1) inhibition in the treatment of MPNs. xref , xref Nutlin inhibits the interaction between HDM2 and TP53 leading to the stabilization of TP53. xref JQ1 is a BET bromodomain inhibitor, which reduces transcription by disruption of chromatin-dependent signaling xref with MYC as a primary target. xref CBL0137 inhibits NF- κ b, activates TP53, and has been reported to regulate MYC expression. xref , xref CBL0137 is an inhibitor of the facilitates chromatin transcription complex (FACT) xref of which the component SSRP1 displays 2.7 ± 0.4 and 3.0 ± 0.4-fold increases at the transcriptome level in NS and NS/JMML cells when compared to wild-type CD33 cells. xref We, therefore, investigated the utility of these drugs to preferentially affect NS/JMML cells."
sparser
"Currently, the majority of MDM2 inhibitors have been developed to inhibit the MDM2–p53 interaction, releasing p53 from MDM2-mediated degradation and activating the transcription of p53 target genes. xref Several MDM2–p53 binding inhibitors have shown potent efficacy against human cancers harboring wild-type p53, and are undergoing further evaluation in clinical trials, for example, RG7112, xref HDM201, xref AMG 232, xref and NVP-CGM097. xref However, due to frequent mutation and deletion of p53 in advanced breast cancer, especially advanced TNBC, the MDM2–p53 binding inhibitors often show limited efficacy. xref Many MDM2 inhibitors have also been developed to block the E3 ligase activity of MDM2, activating the wild-type p53, such as HLI98C xref and MEL23. xref JNJ-26854165 (serdemetan), a novel inhibitor of the MDM2 E3 ligase activity, has been evaluated in a phase I trial performed in patients with advanced solid tumors, including seven patients with advanced breast cancer. xref A dose-and exposure-dependent p53 induction was observed in some of the patients."
sparser
"These post-translational modifications interfere with the formation of the p53-Mdm2 complex resulting in p53 stabilization, increased p53 protein levels and transcriptional activity, and activation of cell cycle arrest, senescence, DNA repair and apoptosis [ xref , xref , xref ]."
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"Interestingly enough, in most of the targeted IDPs, binding of the molecules does not induce a folding of the polypeptide chain of the disordered protein; in fact, protein-folding-upon-binding only occurs when the molecule is a peptide [as in the AF4-AF9 system or in the MDM2 and p53 complex]."
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"In this paper, we reported that LSH acted as a novel positive regulator of p53 by preventing MDM2 binding to p53 and promoting p53 deubiquitinase and stabilization in an MDM2-dependent manner.Therefore, the p53 and MDM2 regulatory loop is not a simple loop but a sophisticated regulatory network that includes a number of regulators and reactors."
sparser
"MDM2 regulates p53 primarily in two ways: (i) MDM2 binds directly to p53, thereby “masking” p53’s transactivation domain from access to the basal transcriptional machinery ( xref ), and (ii) MDM2 acts as an E3 ubiquitin ligase for p53, mediating the conjugation of ubiquitins to p53 and subsequent proteasomal degradation ( xref ; xref ; xref )."
reach
"Using the well established protein protein interaction of p53 and Mdm2 as a positive control and nLuciferase and cLuciferase as a negative control, we investigated the interactions of K-RAS with K-RAS, K-RAS with K-RASG12D, K-RAS with DIRAS3, and K-RAS with DeltaNT DIRAS3 (XREF_FIG)."
sparser
"Experiments with Nutlin-3 and other inhibitors performed in vivo confirmed the “proof of concept” that small-molecule inhibitors of the p53–Mdm2 interaction are able to induce either the cell-cycle arrest or apoptosis in tumor cells, while not affecting healthy cells.[ xref – xref ]"
sparser
"Increased transcriptional activity downstream of TP53 was further investigated at the protein level after treatment with two different PARP inhibitors (talazoparib and niraparib) and an MDM2-TP53 wild-type interaction inhibitor (idasanutlin) as a positive control ( xref a and Supplementary Fig. S4 and S5)."
sparser
"While the real p53 signaling pathway is very complex, modelling studies [ xref ] revealed that the flexibility of p53 activity is rooted in the core p53-Mdm2 negative feedback loop in the pathway: the transcription factor p53 activates the expression of Mdm2, and Mdm2 in turn inhibits p53 by either turning down its transcription or triggering its degradation."
sparser
"Other than PRIMA-1 MET (also called APR-246), a small-molecule mutp53 re-activator, most p53-targeting drugs in active clinical development/trials are small molecules that stabilize WT p53 by interrupting p53-MDM2 interaction or inhibiting MDM2’s ubiquitin ligase activity ( xref )."
sparser
"Furthermore, it was reported that the phosphorylation of WNV capsid protein by protein kinase C enhanced its binding and nucleus co-localization with the HDM2 protein, which then blocked the formation of the HDM2 and p53 complex, thereby causing the stabilization of p53 and the subsequent induction of its target apoptotic protein, Bax [ xref , xref ]."
sparser
"Despite some gaps in the phylogenetic tree and the complicating matter of low sequence coverage of some genomes, the overall picture that emerges is that the p53-MDM2 regulatory axis can be traced back to early metazoans and has since then tightly co-evolved, or disappeared in distinct lineages including C. elegans and D. melanogaster [ xref , xref ]."
sparser
"Effective suppression of MDM2-p53 interaction should promote p53 signaling, and consistent with this expected pharmacodynamic effect on the p53 transcriptional target p21, daily SAR405838 dosing for 4 days in orthotopic GBM108-VEGFA resulted in an 11.3-fold increase in the fraction of p21-positve nuclei ( xref , p21-positive nuclei: 3.2 ± 0.2% with placebo versus 34.8 ± 3.9% with SAR405838 treatment; p=0.0002)."
sparser
"The MDM2 E3 ubiquitin ligase belongs to a category of enzymes that regulate protein level by attaching ubiquitin, a small protein, to their substrates. xref – xref An important example of an E3 ubiquitin ligase enzyme is MDM2, a protein composed of 491 amino acid residues that interact specifically with polypeptides and aids in the final step of attachment of ubiquitin passed along from the E1 and E2 conjugating enzymes. xref The region of MDM2 that performs the E3 ubiquitin ligase function is the really interesting new gene (RING) domain, located at the C-terminal end of the protein. xref , xref The best-known ubiquitination target of MDM2 is the p53 transcription factor that can act as a tumor suppressor protein when stress signals allow for the disruption of the p53-MDM2 complex. xref – xref MDM2 down-regulates p53 by binding to the protein and directing it for proteolysis by the proteasome. xref , xref - xref Structural analysis of MDM2 homodimers, and heterodimers with its related RING domain protein MDMX, make it clear that the C-terminus of MDM2 can offer differential regulatory activities under different circumstances. xref This suggests that alternative spliced forms of MDM2 that retain their C-termini might possess biochemical functions for cellular regulation."
sparser
"Focused study of the interaction between Mdm2 and p53 at physiological levels has provided additional insight into both p53 and Mdm2 regulation, which will allow for more effective application of therapeutics targeting this pathway, as well as additional targets for the development of effective drugs."
sparser
"Secondary structure motifs involve the peptide adopting a determined secondary structure (e.g., alpha helix or beta strand) such as in the p53-MDM2 interaction ( xref ) or the BH3-Bcl-2 interaction ( xref ), whereas tertiary structure represents discontinuous binding sites such as the XIAP-Smac interaction ( xref )."
sparser
"Treatment of
H-Ras V12-expressing cells in the same manner did not lead to further p53
stabilization nor enhanced p21 induction, presumably indicating that the
MDM2-p53 interaction is already maximally disrupted in these cells and also
suggesting that NPM-ALK induces expression of p53 whilst simultaneously enabling
its degradation (p53 expression levels are much higher in the NPM-ALK expressing
cells suggesting that it induces transcription of this protein)."
reach
"Regarding the different approaches to reactivate p53, whenever this protein is found as awild type in tumors and the p53-regulatory pathways are defective, the approach to its reactivation is the use of small molecules or peptides to inhibit the N-terminal interaction between p53 and MDM2 or MDM4."
sparser
"In the hopes of reactivating damaged apoptotic cascades and inducing cell death, several proteins in the apoptotic pathway have been targeted by small molecules. xref ; xref ; xref Indeed, small molecules that disrupt the p53—MDM-2 interaction, xref ; xref bind to Bcl-2, xref promote apoptosome formation, xref or inhibit XIAP xref ; xref have shown potential in cell culture and/or pre-clinical models of cancer."
sparser
"Nutlin-3 was originally developed as an anti-cancer agent and was shown to be effective against OS xenografts. xref , xref The small molecule inhibitor targets the MDM2-p53 interaction, and displaces p53 from the MDM2 binding pocket thereby releasing it from inhibition and proteasomal degradation. xref Nutlin-3 activity leads to the induction of downstream p53 targets, cell cycle arrest, and apoptosis; although p53-independent nutlin-3 effects have also been noted. xref – xref Nutlin-3 and several second generation analogs have been shown to regress human tumors (including osteosarcoma) in preclinical studies. xref – xref "
sparser
"As expected, based on the mechanism of activity of MDM2 inhibitors, evidence from the aforementioned clinical studies suggests that the expression levels of MDM2 in tumor cells could serve as predictive and early response biomarker for the treatment of patients with MDM2-p53 targeted therapies [ xref ]."
sparser
"Nevertheless, only a limited number of small-molecule p53-MDM2 inhibitors with superior pharmacokinetic profile have advanced into clinical trials [ xref ] Among these, small molecules 1 – 7 ( xref ) have shown good pharmacokinetic profile, as well as effective anticancer activity by oral administration in animal models [ xref , xref , xref ] and in clinical trials [ xref , xref , xref , xref , xref , xref , xref ]."
sparser
"In this review, we will introduce a battery of MDM2 inhibitors, and then describe how some of these inhibitors are used to build-up several MDM2-recruiting PROTAC degraders ( xref ) for 1) the disruptors of the MDM2-p53 binding to stabilize p53, and 2) acting as E3 ligand component of PROTAC for degradation of other targeted oncogenic proteins ( xref )."
reach
"Therefore, the objective of the present study was to evaluate the in vitro effect of treatment with Nutlin-3, a small molecule inhibitor of the MDM2 and p53 interaction, on the expression of the suppressor of cytokine signaling 1 in primary acute myeloid leukemia cells and in myeloid cell lines with differential p53 status."
sparser
"Furthermore, activation of p53 by a cis-imidazoline analog, Nutlin-3a, a stabilizer of p53 and an inhibitor of the mouse double minute 2 homolog (Mdm2)–p53 interaction, reversed experimental PH by a reduction of proliferation of pulmonary artery smooth muscle cells (PASMCs) [ xref ]."
sparser
"Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs."
sparser
"In agreement with these concepts, small molecules “Nutlins” have been discovered that inhibited the p53-Mdm2 interaction by mimicking the inducible α-helix in p53 (residues 13–29) that binds to Mdm2.259,260 Although X-ray crystallographic studies of the p53-Mdm2 complex revealed that the Mdm2 binding region of p53 forms an α-helical structure that binds into a deep groove on the surface of Mdm2,267 NMR studies showed that the unbound N-terminal region of p53 lacks fixed structure, although it does possess an amphipathic helix part of the time."
reach
"Viewed as a proof of principle model for therapeutic development, our findings support an approach that would inhibit MDM2 E3 activity without preventing MDM2 and p53 binding as a promising avenue for development of compounds to activate p53 in tumors with reduced on-target toxicities."
sparser
"Chlorofusin ( 1 , xref ) was isolated from the fungal strain Microdochium caespitosum and found to disrupt the MDM2-p53 interaction by directly binding to the N -terminal domain of MDM2 xref (IC 50 = 4.6 μ M, K D = 4.7 μ M). xref Thus, chlorofusin represents an exciting lead for antineoplastic intervention that acts by a rare disruption of a protein-protein interaction, although the structural details of the inhibitory MDM2 binding have yet to be established. xref On the basis of extensive spectroscopic and degradation studies, the chlorofusin structure was proposed to be composed of a densely functionalized, azaphilone-derived chromophore linked through the terminal amine of ornithine to a 27-membered cyclic peptide composed of nine amino acid residues. xref Two of the cyclic peptide amino acids possess a nonstandard or modified side chain, and four possess the d -configuration."
sparser
"Although the physiological significance of the Seg1/Mdm2 interaction remains to be clarified, there was an excellent correspondence between sensitivity of the p53-Mdm2 interaction to small-molecule inhibitors in the Y2H assay and their stable association in the in vitro binding assay."
reach
"The sustained inhibition of MDM2 and p53 complex formation may account for the different kinetic pattern in the regulation of p53 gene targets induced by the reversible versus the long lasting compound and may explain the differences in the long-term pro apoptotic effects elicited by EB148."
sparser
"Next, we treated shh-EGFP cells with Nutlin-3a, the active enantiomer of Nutlin-3, which disrupts the interaction between p53 and Mdm2, preventing proteasome-mediated p53 degradation. xref Nutlin-3a and p53 shRNA alter p53 activity in opposite ways. sh Trp53 reduces p53 activity by blocking p53 expression, while Nutlin-3a activates p53, by stabilizing the p53 protein."
reach
"The system, given by van Leeuwen et al. [XREF_BIBR] with the small transient stress stimulus S (t) = 0, has the form (27) P.I = sp+ jaPA-dpPI-kcPIM+ jcC, M. = sm0+ sm1PI+ sm2PAPI+ PA+K m+ ku+ jcC-dm+ kcPIM, C. = kcPIM-jc+ kuC, P.A =-ja+ dpPA, where P I represents the concentration of the p53 tumor suppressor, M (mdm2) is the concentration of the p53 's main negative regulator, C is the concentration of the p53 and mdm2 complex, P A is the concentration of an active form of p53 that is resistant against mdm2 mediated degradation, s * (* = p, m0, m1) are de novo synthesis rates, k * (* = a, c, u) are production rates, j * (* = a, c) are reverse reactions (e.g., dephosphorylation), d p is the degradation rate of active p53, and K m is the saturation coefficient."
sparser
"Numerous mechanisms of blocking apoptosis have been reportedly employed by the Chlamydia spp.: (1) the prevention of cytochrome c release from the mitochondria by Chlamydia -dependent anti-apoptotic factors; (2) the murine double minute 2 (MDM2)-dependent proteasomal degradation of cellular p53, mediated by the activation of the classical MDM2–p53 interaction axis ( xref ); (3) the sequestration of the BCL-2-associated agonist of cell death (BAD) to the inclusion membrane via 14-3-3β-binding, and of pro-apoptotic protein kinase Cδ (PKCδ) on the inclusion vacuole through binding to diacylglycerol-enriched membranes away from its conventional target sites ( xref ; xref ); and (4) the upregulation of the expression of genes that encode anti-apoptotic inhibitors of apoptosis protein (IAP) homologues, BAG family molecular chaperone regulator 1 (BAG1), and BCL-2 family member MCL-1 ( xref ; xref ). xref compared host cell apoptotic responses to infection using 17 different chlamydial serovars and strains (including A–K, L1, L3, Ba, and C. muridarum ), all of which exhibited clear anti-apoptotic activity, the extent of which varied between serovars."
sparser
"Examples of these compounds include Navitoclax (ABT-263) [ xref ], which inhibits BCL2-BAX interactions; Nutlin-3 [ xref ], which blocks MDM2-TP53 interactions; PRI-724 [ xref ], which interferes with β-catenin-CBP interactions; and JQ-1 [ xref ] and I-BET726 [ xref ], which prevent BRD4 binding to acetylated histones."
reach
"Nutlin-3 is a small molecule able to specifically target the p53 and MDM2 interaction, leading to the increment of p53 protein levels, transcriptional activation of the p53 molecular targets and, subsequently, to the promotion of cell-cycle arrest and apoptosis induction in a variety of tumor cells [XREF_BIBR - XREF_BIBR]."
reach
"Though there was initial excitement in targeting the Hdm2 and p53 interaction as a therapeutic strategy, this initial excitement over selective Hdm2 inhibitors, has been dampened by observations that HdmX which also inhibits p53 activity, is overexpressed in a relatively large percentage of cancers."
sparser
"We present an analysis of how molecules based on the 1,4-benzodiazepine-2,5-dione scaffold serve to mimic the side-chains presented by the hydrophobic face of two turns of an alpha-helix derived from the tumor suppressor protein p53, and thus antagonize the HDM2-p53 protein-protein binding interaction."
sparser
"MDM2 directly binds to p53, resulting in the p53 transactivation inactivity. xref – xref Moreover, MDM2 also acts as an ubiquitin protein ligase and controls p53 by targeting it for proteasomal degradation. xref – xref Therefore, overexpression of MDM2 and inactivation of p53 were associated with oncogenesis."
reach
"MDM2 heterodimerizes with MDMX to enhance P53 ubiquitination and degradation.Some compounds inhibit MDM2 interaction with P53, such as small molecules [328] that act as MDM2 antagonists, inhibit E3 ubiquitination of P53, or stabilize P53 and restore its conformation and DNA-binding ability [329,330]."
sparser
"Activation of P53 stimulates MDM2 expression; conversely, E3 ubiquitin‐protein ligase MDM2 mediates p53 constant degradation through a ubiquitin‐dependent proteasome pathway. xref , xref Increasing evidence shows that the MDM2‐p53 feedback loop can also be regulated by RPs. xref , xref , xref , xref RPL34 belongs to the L34E family of RPs, located in the long arm 2 region 5 of human chromosome 4 and contains two exons, encoding 117 amino acids."
sparser
"We believe that the referred SAR and drug-likeness considerations discussed in this review for chalcones with p53–MDM2 inhibitory effect can pave the way for rational design of new p53–MDM2 inhibitors, leading to accelerate the discovery of more efficient anti-cancer drug candidates in the near future."
sparser
"Many different scaffolds can mimic short α-helices, such as the one formed at the N-terminus of p53 that is bound by HDM2; however, short α-helices can also be mimicked effectively by small organic molecules (such as the nutlins) [ xref ], which suggests that foldamer approaches to this type of target must achieve outstanding performance to have a practical impact."
reach
"Herein, we report design of a novel class of small molecule alpha-helix mimetics, development of a facile solid-phase synthetic pathway, and a subsequent high-throughput screen, which led to the identification of potent inhibitors that disrupt the interaction between p53 and MDMX and MDM2."
reach
"As shown in XREF_FIG, treatment of Nutlin-3 produced a substantial decrease in the amount of p53 bound to MDM2 in both control and co-transfected cell lysates, suggesting that Nutlin-3 was indeed able to disrupt the binding of p53 and MDM2, and consequently the loss of p53 in complex with MDM2 caused a reduction in the hOC promoter activity."
sparser
"We also detected Nutlin-3-induced phosphorylation of p53 at Ser15, as well as at two other key serine residues; Ser20 and Ser37 (Figure xref ), indicating that Nutlin-3 does not only disrupt the interaction between MDM2 and p53, but could also play a role in activating DDR pathways resulting in p53 phosphorylation, and subsequent activation of downstream target proteins involved in for example, cell cycle checkpoint control."
sparser
"The tumor suppressor p53 protects cells from transformation and tumorigenesis by activating the transcriptional expression of many genes whose protein products induce cell growth arrest, apoptosis or senescence in response to stress signals. xref MDM2 negatively regulates p53 by inhibiting its transcriptional activity and promoting its ubiquitination and degradation. xref – xref Mdm2 itself is a transcriptional target of p53 and deletion of p53 gene completely rescues the lethality of mdm2 knockout mice. xref , xref Thus, MDM2 forms an autoregulatory feedback loop with p53 to regulate cellular homeostasis. xref Cytotoxic and genotoxic stressors induce modifications of both p53 and MDM2 proteins, which uncouple the MDM2–p53 interaction to stabilize and activate p53. xref , xref Moreover, MDM2 is able to interact with other proteins independent of p53, thereby contributing to cellular responses to different stimuli. xref "
sparser
"For example, Ji et al. chemically engineered a cyclotide that antagonized an intracellular interaction of the tumor suppressor p53 and the oncoprotein Hdm2 both in vitro and in vivo . xref However, it has been known for a long time that cell penetrating peptides can remain trapped in endosomes during endocytosis, leading to their lysosomal degradation and limited ability to reach their target sites and to convey biological activity. xref Whether and how cyclotides escape endosomes remains to be determined, but the work of Ji et al. demonstrates that grafted cyclotides are active in the cytoplasm. xref Furthermore, Huang and colleagues have optimized the cell penetrating properties of cyclotides in order to foster their intracellular uptake. xref It is thus of interest to explore if the capacity of cyclotides to penetrate cell membranes can be leveraged in the future to engineer and develop cyclotide-based peptide ligands able to target GPCRs beyond barriers and reach areas such as the central nervous system ( xref )."
sparser
"Because the extract mixtures usually contain a number of the unknown secondary metabolites, they may offer a good opportunity to identify the novel candidate for anticancer medicine as exemplified in the discovery of chlorofusin by screening the microbial extracts to find the inhibitors of the p53–MDM2 interaction [ xref ]."
sparser
"It is known that the MDM2 protein directly interacts with p53[ xref xref ] and regulates p53 function by binding to its transcription domain, adding ubiquitine to assist its degradation and binding to p53 to help its nuclear export.[ xref xref ] Besides, a couple of studies disclosed p53 and FHIT interaction[ xref xref ] and their possible correlation.[ xref ] Based upon our results, the interaction site of FHIT with MDM2 and p53 are different with overlapping parts."
sparser
"Treatment with the compound Nutlin-3, which blocks the interaction between MDM2 and p53, and thereby stabilizes p53, causes cell cycle arrest and apoptosis. xref , xref Consistently, Nutlin-3 was effective in several cancers when combined with chemotherapy. xref , xref , xref We found that RNF31 depletion could arrest the cell cycle and enhance cisplatin-induced cell death, providing insight into the molecular mechanism for the regulation of p53 signaling in breast cancer cells."
sparser
"Instead, in a previous study on the roles of post-translational modifications of MDM2 in the regulation of the MDM2–p53 interaction [ xref ], it was proposed that simultaneous phosphorylation of S17 on the intrinsically disordered N-terminal lid of MDM2 (residues 1 – 24), and T18 and S20 of p53 brings negatively charged residues from both molecules into close proximity, resulting in the disruption of the MDM2–p53 interaction."