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MDM2 activates TP53. 1000 / 1698
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"Therefore, although we can not completely rule out possible involvement of Mdm4 for p53 regulation and/or p73 for suppression of T cell proliferation in this study, Mdm2 mediated p53 regulation appears to be of predominant importance for controlling antigen specific T cell proliferation."
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"In our research, the nuclear localization of MDM2 when HepG2 cells were treated with PB showed no significant difference compared to the control (XREF_SUPPLEMENTARY), but the expression of p-MDM2 decreased obviously, which suggested the p53 stability was mainly mediated by phosphorylation of MDM2 at Ser 186."
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"In normal cells, MDM2 is a transcriptional target of p53 creating a negative feedback loop that maintains p53 at low levels, but during stress, p53 escapes interaction with MDM2 and accumulates in the nucleus to initiate transcription of target genes capable of inducing senescence."
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"However, these p53 activating agents often exhibit dose limiting adverse effects, which are most-commonly related to gastrointestinal and hematological disorders, and could be caused, at least in part, by elevated MDM2 expression subsequent to p53 activation induced by the small molecules."
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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."
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"Transcriptionally activated by p53, MDM2 acts as an E3 ligase targeting p53 for proteasomal degradation [XREF_BIBR, XREF_BIBR]; of note, the formation of MDM2 and MDM4 heterodimer complexes is essential for p53 polyubiquitination, while MDM2 alone marks p53 for monoubiquitination and thus does not promote complete p53 degradation [XREF_BIBR]."
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"We have shown how the orientation of Y100 modulates the thermodynamics of the peptidic inhibitors [XREF_BIBR], a feature also demonstrated in other computational studies [XREF_BIBR, XREF_BIBR]; (b) the increasing importance of the MDM2 lid region, which is strictly conserved in mammals, in modulating the binding of p53 [XREF_BIBR, XREF_BIBR]; it is possible that by gating the dynamics of Y100, the lid region may influence the kinetics of binding of p53."
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"It is well known the autoregulation mediated by Hdm2 targeting p53 for degradation in the proteasome XREF_BIBR, and it has been detected in the case of other activating kinases such as ATM XREF_BIBR and CHK2 XREF_BIBR, but this action requires a p53 induction of phosphatases, such as PPM1D XREF_BIBR and Wip1 XREF_BIBR."
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"To further investigate downstream p53-effector genes contributing to this cancer phenotype, we used Nutlin-3a, an MDM2 antagonist, which specifically activates p53 leading to apoptosis and tumor regression of both chemosensitive and chemoresistant neuroblastoma cell lines XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"These and several recent studies suggest the contribution of several known tumor suppressor genes in HNSCC, such as p16 and p14 ARF (9p21), which are responsible for G1 cell cycle regulation and MDM2 mediated degradation of p53, respectively, APC (5q21-22) and P53 (17p13), as well as the existence of many putative tumor suppressor genes affected in HNSCC, including FHIT (3p14), and RASSF1 (3p21)."
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"The importance of MDM2 mediated p53 inactivation has been verified by elegant studies showing that genetic disruption of the p53 gene rescues the lethal phenotype of Mdm2 knock-out mice [XREF_BIBR, XREF_BIBR] and that inhibition of MDM2 results in robust p53 activation in tumor cells [XREF_BIBR, XREF_BIBR]."
eidos
"Furthermore , we have demonstrated that BCL-2 is a key survival factor of CML stem cells , and targeting BCL-2 , combined with a TKI , had the potential to eradicate CML stem cells.20Adding a MDM2 inhibitor , which activates p53 and induces pro-apoptotic BCL-2 proteins to the combination , will likely further improve the therapeutic potential for patients with CML , which certainly warrants future clinical investigations ."
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"While mutations of p53 are observed in more than half of human tumors [ xref ], dysregulation of the ARF tumor-suppressor protein (p14 ARF in humans and p19 ARF in mouse), which increases and activates wild-type p53 by sequestering Mdm2 in the nucleolus [ xref ] or by directly inhibiting the enzymatic activity of Mdm2 [ xref , xref ], is a common characteristic in cancer as well."
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"As mdm2 is a transcriptional target of p53, the introduction of Hsp53 into the p53 -/- H1299 cells resulted in an expected up-regulation of MDM2 (HDM2, the human homologue of mouse MDM2) expression : approximately 3-fold increase in mRNA and a 2-fold increase in MDM2 protein (data not shown)."
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"We found that the peptide d PMI-delta (2-6), a non binder of Mdm2, and d PMI-delta (6-10), a binder of Mdm2, both disrupt the membrane, and are found to activate p53 even at 16 hours, showing counter screen activity; this could result from membrane disruption or off-target activity, or both."
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"Although the majority of lymphoma tumors retain wt-p53 status, mechanisms to compromise p53 signaling, such as HDM2 overexpression, deletions in p14ARF, and viral oncogenes exist to prevent p53 activation in response to stress or initiate programmed cell death [XREF_BIBR - XREF_BIBR]."
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"Although the increase in p53 stability can be attributed to USP7 degradation by ICP0, an event which will result in decreased stability of MDM2, an E3 Ub ligase that directs p53 for degradation [XREF_BIBR], p53 stabilization in response to HSV-1 infection has been shown to be independent of ICP0 or USP7 [XREF_BIBR]."
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"Considering its role of " guardian of the genome ", acting as a key checkpoint of cellular behaviour in response to DNA damage XREF_BIBR, one could expect p53 to be activated by cadmium induced genotoxic stress, through ATM and ATR protein kinases mediated uncoupling of p53 from its main negative regulators MDM2 and MDM4, leading to accumulation of stable active p53 protein XREF_BIBR."
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"Introduction of a minimal cationic motif within the folded structure of a high-affinity beta (3)-peptide ligand for hDM2 led to molecules with high 3 (14)-helical structure, high hDM2 affinity and sufficient cell permeability to upregulate p53 dependent genes in live mammalian cells."
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"The aim of our study was to detect changes in expression of the following proteins : the tumor suppressors PTEN, p53, and p21Waf1 and Cip1, glial fibrillary acidic protein (GFAP, as a marker of astroglial differentiation), the phosphorylated form of protein kinase B/Akt (PKB and Akt), which is downstream to the epidermal growth factor receptor (EGFR), and MDM2, which degrades p53."
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"Extensive studies have been conducted to identify small molecules that manipulate p53, including restoration of mutant p53 conformation to wild-type, disruption of murine double minute-2 (Mdm2)-p53 binding to increase p53 level and inhibition of Mdm2 E3 ubiquitin ligase activity to prevent p53 degradation."
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"3 Although mutations in the tumor suppressor p53 gene (TP53) are found in only about 5-10% of AML patients, inactivation of wild-type p53 protein frequently occurs through overexpression of its negative regulatory molecule, murine double minute 2 (MDM2), which targets p53 for ubiquitin mediated degradation."
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"Our results demonstrate that early NMDA-PC confers neuroprotection against ischemia by increasing MDM2 protein level, which promotes its interaction with p53 and triggers p53 nuclear and cytosolic destabilization and prevents ischemia induced p53 mediated neruronal apoptotic death."
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"However, since many sarcomas overexpress Mdm2, and high levels of Mdm2 inactivate and cause degradation of p53 (Haupt et al, 1997a; Momand et al, 1992; Oliner et al, 1992, 1993; Nakayama et al, 1995; Momand et al, 1998; Vogelstein et al, 2000), wt p53 transfer into sarcoma cells that overexpress Mdm2 is unlikely to be efficacious (Chen et al, 1996; Meng et al, 1998)."
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"Initial work suggested the involvement of MdmX as part of a neddylating complex and reported that while co-expression of MdmX did not significantly affect Mdm2 mediated neddylation of p53, it was sufficient to rescue Mdm2 mutants that had impaired neddylation activity in transient transfections [XREF_BIBR]."
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"For example, impaired ribosome production causes ribosomal proteins such as rpL5, rpL11, and rpL23 to exit the nucleolus, and bind to and inhibit the E3-ligase activity of Mdm2, which in turn activates the tumor suppressor p53 and its downstream effectors, thereby inducing cell cycle arrest or apoptosis xref ."
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"David Lane (Cyclacel and University of Dundee, UK) followed a similar theme, starting from a molecular understanding of p53 and proceeding via structural biology to the in silico identification and engineering of small-molecule inhibitors of Mdm2, a ubiquitin ligase that targets p53 for degradation."
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"The BL-0293 bladder PDX model was previously shown to have very low levels of MDM2, which is known to reactivate TP53, and of RB1, a tumor suppressor gene involved in regulating the cell cycle and the tumor 's response to DNA damage caused by cytotoxics like gemcitabine [XREF_BIBR]."
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"The main features of this network, relevant for our analysis, are : 1) MDM2 is an ubiquitin E3 ligase that promotes p53 degradation but it is also a transcriptional target of p53, resulting in a feedback loop; 2) activated AKT can phosphorylate MDM2 on Ser166 and Ser186, stimulating nuclear localization and ubiquitylating activity; 3) MDM4 forms hetero-oligomers with MDM2 that enhance ubiquitylation and degradation of p53; 4) MDM4 is a direct substrate of MDM2 for targeted ubiquitylation and degradation."
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"Interestingly, while MDH1 does not interfere with the p53 and MDM2 interaction, overexpression and depletion experiments show that MDH1 inhibits p53 ubiquitylation and prevents MDM2 dependent cytoplasmic retention of p53, thereby promoting apoptosis in response to glucose starvation 61."
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"For instance, TRIM59 promotes gastric carcinogenesis via interacting with p53 and promoting its ubiquitination and degradation (26); TRIM67 interacts with p53, resulting in inhibition of MDM2-mediated p53 degradation, finally activates p53 to suppress the initiation and progression in colorectal cancer (24)."
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"Mdm2 overexpression in MCF-7 human breast cancer cells enhances their estrogen dependent growth and, in p53 deficient Saos-2 osteosarcoma cells and MCF-7 cells, Mdm2 enhances 17beta-estradiol (E2)-dependent activation of a construct containing an estrogen response element (ERE) insert."
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"Furthermore, metastasis were also promoted by ROS activation due to a MCU-dependent mitochondrial Ca inhibition of the NAD(+)/SIRT3/SOD2 pathway or AKT/MDM2-mediated p53 degradation, and subsequent changes in hepatocellular carcinoma cells in the expression of pro-apoptotic or cell-cycle related proteins, respectively [185,186]."
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"Removing MDM2 caused a transient upregulation of p53 during early lung development in part of the epithelium and modestly increased apoptosis, disrupted separation of the esophagus and trachea, and delayed but did not block branching and differentiation of the airway epithelium (Bowen et al., 2019; Sui et al., 2019)."
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"UBE2B and the E3 ligase UBR2 are known to mediate transcriptional silencing via histone H2A ubiquitination in testis,43 and when combined with the UBR1 E3 ligase, UBE2B is implicated in the ubiquitination of myc proteins.44 In Hela cells, UBE2B and Mdm2 target p53 for degradation by the proteasome,45 while UBE2B interacts with the E3 ligase Rad18 and is implicated in meiotic functions in testis46 and DNA repair through PCNA ubiquitylation.36 Last, but not least, UBE2B mediated histone (H2B) ubiquitylation in conjunction with hBRE1 E3 ligase is responsible for Histone H3 methylation and subsequent increased transcriptional activity in Hela cells.47 Thus, UBE2B is a good example of the multiplicity of action of a single E2 depending on the cellular context."
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"In summary, this study demonstrated that the scutellarein on AGS and SNU-484 cells significantly inhibits cell proliferation and induces apoptotic cell death via down regulated MDM2 which activated the tumor suppressor protein p53 and downregulate the IAP family proteins (cIAP1, cIAP2, and XIAP), leads to caspase dependent apoptosis in AGS and SNU-484 cells."
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"Our recent in vivo study showed that Rps27l disruption triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase activity towards p53, leading to p53 dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which can be rescued by heterozygous deletion of Trp53 19."
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"Therefore, down-regulation of MDM2 or MDMX protein in cancer cells is a straightforward approach and has been proved to activate the p53 pathway and inhibit tumor growth using small interfering RNA (siRNA), short hairpin RNA (shRNA) or miRNA in tumor xenografts in nude mice [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"P53 pathway activation is mediated by the protein stabilization, via the disruption of a p53 and murine double minute 2 (MDM2) negative feedback loop, and is further enhanced by many types of post-translational modifications, such as phosphorylation, acetylation, sumoylation, ubiquitination, and methylation [XREF_BIBR]."
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"Persistence of chemotherapy induced DNA damage has been observed in wild-type p53 glioblastoma cells [XREF_BIBR] as well as p53 deleted or mutant p53 ovarian cells [XREF_BIBR] treated with the first generation MDM2 antagonist Nutlin3a and this correlated with increases in MDM2 expression and cell death."
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"A previous modeling study has proposed the role of a different positive feedback loop in enhancing the robust stability of p53 oscillation [XREF_BIBR], whereby the cytosolic MDM2 protein translocates into nucleus to interact with the mRNA of p53 through direct binding and promote the translation of p53 mRNA to close the loop [XREF_BIBR, XREF_BIBR]."
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"Phosphorylation at serine MDM2(S395) and MDMX(S403) by the ATM kinase induces conformational changes both on MDM2 and MDMX [94, 95], allowing their RING domains to bind the p53 mRNA sequence that encodes the BOX-I motif [93], resulting to an increase in p53’s rate of synthesis and to the suppression of the MDM2’s E3 ubiquitin ligase activity [10, 89, 93, 96]."
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"As for p16 CDKN2A, the p14 CDKN2A protein exerts a tumour suppressor effect by inhibiting the oncogenic actions of the downstream MDM2 protein, whose direct interaction with p53 blocks any p53 mediated activity and targets the p53 protein for rapid degradation [XREF_BIBR] (XREF_FIG)."
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"The protein p53 can be regulated at different levels : by posttranslational modifications, such as phosphorylation, sumoylation, or acetylation of the protein [XREF_BIBR, XREF_BIBR], (ii) by increasing the protein concentration : one of the key regulators of p53 is Mdm2 which targets p53 for breakdown by the proteasome [XREF_BIBR], (iii) by cellular localization : import and nuclear export is closely regulated because the functions of p53 depend on its nuclear localization."
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"Expression of the apoptosis regulator p53 is governed by minute double minute 2 (MDM2), an E3 enzyme that targets p53 for ubiquitination and proteasomal processing, and by the deubiquitinating enzyme, herpesvirus associated ubiquitin specific protease (HAUSP), which rescues p53 by removing ubiquitin chains from it."
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"Unlike p53 +/- tumors which lose their wild-type allele, the tumors which retain an intact p53 allele express p53 protein that induces apoptosis following gamma irradiation, activates p21 (WAF1 and CIP1) and Mdm2 expression, represses PCNA expression (a negatively regulated target of wild-type p53), shows high levels of binding to oligonucleotides containing a wild-type p53 response element and prevents chromosomal instability as measured by comparative genomic hybridization."
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"RNA interference showed that p53 knockdown increased the protein level of Gli1 but decreased the level of MDM2, and enhanced cell invasion and migration in wild-type p53 Capan-2 cells; whereas Gli1 or MDM2 knockdown did not change p53 expression, but decreased the protein level of MDM2 or Gli1, respectively, and inhibited cell invasion and migration in mutant p53 PANC-1 cells."
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"The activity of p53 protein is regulated by MDM2 protein (the human protein is often termed HDM2), which inhibits the transcriptional activity of p53 through binding with N-terminal domain, or induces p53 export from nucleus, or due to E3 ubiquitin ligase activity, HDM2 directs p53 to proteasomal degradation."
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"Interestingly, cells treated with nutlin, a small-molecule inhibitor of MDM2 that activates p53 and some senescent phenotypes in the absence of DNA damage or other stress ( xref ; Fig. S2, E–H) also induced robust engulfment ( xref ), indistinguishable from that observed after chemotherapy-induced senescence (Fig. S2 I and Video 8)."
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"Therefore, in contrast to findings by others, their results suggest that the disrupted nucleoli may provide a platform for L5- and L11-dependent p53 activation.Watkins and Thomas labs both pointed out that 5S RNA complexes with L5 and L11, and functions either in pre-60S assembly, or inhibiting MDM2 induced p53 degradation 118119.Recently, using immunostaining, Kayama et al. demonstrated a nucleoplasmic translocation of FLAG-tagged RPL11 in HCT 116 cells upon low dosed Act.D treatment 120.In our experiments, immunostaining of RPL11 in U2OS cells showed a predominant location in the cytoplasm and no redistribution to the nucleoli or nucleoplasm was detectable upon Act.D-induced nucleolar stress (unpublished data)."
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"While some data sets indicate that the regulation of ongoing replication forks by p53 may be mediated by p53 targets such as MDM2 (murine double minute 2) and polymerase (POL) eta other evidences demonstrate that p53 is capable of controlling DNA replication by directly interacting with the replisome and altering its composition."
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"These observations are of clinical significance, as they suggest that the temporal inhibition of Mdm2 phosphorylation by short acting kinase inhibitors or by use of excess decoy ATM target-sites (a molecular sponge of sorts) would reduce p53 activation and alleviate the toxicity associated with radiotherapies."
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"However, as chronic adipose tissue p53 elevation is a phenomenon that seems impossible to measure, this will likely remain a plausible, but hard-to-prove, hypothesis.Parallel to p53 induction, reduced expression of MDM2 was observed in human omental WAT [72], implying a disturbed MDM2-mediated p53 regulation in obesity."
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"P53 plays a pivotal role for senescence induction; the DNA damage response activates ataxia telangiectasia (ATM) and Rad3-related (ATR) kinases, which in turn activate the p53/p21 axis by phosphorylation of both p53 and its ubiquitin ligase Mdm2, leading to the stabilization of p53 levels [51]."
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"EBNA-3C associates with SUMO-1, P300, prothymolysin (ProTalpha), histone deacetylase 1/2, metastatic suppressor NM23-H1 through EBNA-3C glutamine- and proline rich domain, corepressor mSinA and NCoR, SCF-Skp2, cyclin A/D1 277 and cMyc, Gemin3 (also called DDX20 or DP103), p53, p53 regulatory proteins, the inhibitor of growth family proteins ING4/5, IRF4/8, aurora kinase B, H2AX and Pim-1; XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR it regulates chromatin remodeling via recruitment of histone (de) acetyltransferases, facilitates cell cycle entry, stabilizes Geminin3 and cMyc, induces the Mdm2 mediated p53 degradation and represses p53 dependent transactivation on its downstream genes p21 and Bax, as well as p53- and E2F mediated apoptosis in part through targeted regulation of interferon regulatory factors 4 and 8."
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"It has long been accepted that Mdm2 E3 ligase activity is an essential mechanism for Mdm2 mediated p53 regulation; with this in mind, the most unanticipated finding of the current study is that fully intact Mdm2 E3 ligase activity towards p53 is dispensable in vivo, as demonstrated by the viability, normal development, and lifespan of Mdm2 Y487A and Y487A mice."
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"Nevertheless, this correlates with recent work demonstrating that ceramide, the cellular target for degradation by AC, binds to p53 leading to its cellular accumulation and stress response activation through disruption of interaction with the E3 ubiquitin ligase MDM2 that targets p53 for degradation [XREF_BIBR]."
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"Apart from a direct dephosphorylation of pSer15 on p53, Wip1 has been shown to decrease p53 levels by activating the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation, and also through activation of MdmX, which directly inhibits transcriptional activity of p53 at promoters [XREF_BIBR, XREF_BIBR]."
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"XREF_BIBR, XREF_BIBR Moreover, the qualitative nature of negative regulation of p53 is dependent on MDM2 and MDM4 levels, with relatively greater levels of MDM4 inhibiting MDM2 mediated p53 degradation and/or competing with MDM2 for the p53 binding site to inhibit its transcription activity."
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"Importantly, monitoring cellular levels of p53 and HDMX complex can both predict cancer cell susceptibility to single agent HDMX inhibition and determine the efficacy of HDM2 mediated p53 upregulation, which forms the basis for enhancing the therapeutic impact of dual HDM2 and HDMX targeting."
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"In the present study, MDM4 and MDM2 double knockdown with the siRNAs enhanced 5-FU-induced p53 activation, arrested cell cycle at the Gap (G) 1 phase, and potentiated the antitumor effect of 5-FU in wtTP53 and highMDM4 human colon (HCT116 and LoVo) and gastric (SNU-1 and NUGC-4) cancer cells."
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"More than 150 clinical studies are listed in the clinical trial database of the National Cancer Institute (http://www.cancer.gov/clinicaltrials/), which aim to assess the p53 status of patients to optimize drug and radiation regimens, and to evaluate p53 gene transfer and Mdm2 blockage to restore the tumor suppressive activity of p53."