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phosphosite cbn pc11 biopax bel_lc signor biogrid tas lincs_drug hprd trrust | geneways tees isi trips rlimsp medscan sparser reach
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MDM2 inhibits TP53. 5 / 2777
| 17 197 2209
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"Recruitment of HDAC1 by MDM2 promotes p53 degradation by deacetylation."
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"Inhibition of MDM2 by Nutlins or other inhibitors has been explored as an approach to activate p53 in AML with varying efficacy underscoring the need to further dissect the heterogeneity and oncogene specific mechanisms."
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"Since MDM2 is negatively regulated by CDKN2A, MDM2 amplification and aberrations in the cyclin pathway will likely lead to suppression of TP53 (TP53 is negatively regulated by MDM2) [XREF_BIBR]."
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"The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53 mediated transregulation of gene expression."
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"Inhibition of MDM2 can restore p53 activity in cancers leading to anti-tumor effects with apoptosis and growth inhibition."
MDM2 bound to TP53 inhibits TP53. 10 / 41
| 41
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"Both DNA-PKcs and ATM can phosphorylate p53 at serine 15, which inhibits the MDM2 binding to p53 and promotes both nuclear accumulation and activation of p53 in response to DNA damage."
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"In the basal setting, Mdm2 binds p53 and promotes p53 degradation."
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"Small molecule inhibitors of the MDM2 and p53 interaction have been identified, such as the Nutlins XREF_BIBR, which were the first generation of agents directly targeting this pathway, and bind in MDM2 's p53 binding pocket in the N-terminal region to induce p53 accumulation."
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"XREF_BIBR, XREF_BIBR As proteasomal degradation is not compromised in E/R positive leukemic cell lines (data not shown), we tested whether Nutlin-3, a small molecule that disrupts the MDM2 and p53 interaction, can reactivate p53 signaling."
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"Ribavirin stimulated the expression of the p53 dependent gene Mdm2, which can bind to p53 and inhibit the activation of p53 by targeting p53 protein for degradation through the ubiquitin dependent proteolytic pathway XREF_BIBR."
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"Phosphorylation of p53 at serine 15 attenuates MDM2 binding to p53 and thus promotes p53 stability 55."
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"Experimental inhibition of HDM2 and p53 interactions restored p53 activity, and decreased survival of infected cells."
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"Mdm2, an important negative regulator of the p53 tumor suppressor, binds to p53 and inhibits p53 mediated transactivation."
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"For this reason, inhibition of the interaction between MDM2 and p53 to reactivate endogenous p53 activity offers the opportunity for therapeutic intervention, particularly in GBMs."
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"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."
MDM2 inhibits mutated TP53. 10 / 19
| 19
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"Therefore, MDM2 isoforms inhibit MDM2 mediated mutant p53 protein degradation, which in turn promotes mutant p53 accumulation and GOF in tumorigenesis [XREF_BIBR]."
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"Recent evidence demonstrate that two Bcl2 family proteins, BAG2 and BAG5, interact with mutant p53 preventing Mdm2 and CHIP dependent proteasome degradation of mutant p53, this promotes mutant p53 protein accumulation and GOF determining tumor growth, cell migration, and chemoresistance [XREF_BIBR, XREF_BIBR]."
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"MDM2 efficiently degrades wild type p53, but fails to degrade mutant p53 in tumor cells."
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"Mutant p53 can be inhibited by mdm2 E3 ligase, although this ligase can not be induced in tumors harboring the mutant p53 that is incompetent as a transcription factor."
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"Similarly, Ingallina et al. [XREF_BIBR] report that cerivastatin induces MDM2 mediated degradation of several TP53 mutants by inhibiting interaction between mutp53 and HSP90, leading to reduce colony formation of MDA-MB-231 cells [XREF_BIBR]."
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"Further, although MDM2 and MDMX antagonists may be beneficial in cancers with WT p53 and high MDM2 and MDMX expression, they are unlikely to be effective in tumors with a high prevalence of p53 mutations, where Hsp90 inhibits MDM2 mediated mutant p53 degradation."
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"Mdm-2 was able to inhibit all three functions of the wild-type and mutant p53 activities; transcriptional activation by the wild-type protein, transcriptional activation by the mutant p53 protein, and repression by the wild-type protein."
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"We found that although Mdm2 triggered the degradation of all these three p53 mutant proteins, Def was unable to promote the degradation of zebrafish zf-p53-R143H and -R250W but promoted zf-p53-R313C degradation at 6 hpi (XREF_FIG)."
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"Over-expression of Mdm2 in either tumor (which do express endogenous functional Mdm2) or in p53 null cells decreased the stability of mutant p53 suggesting that, despite its expression, Mdm2 and JNK are insufficient (amount and affinity) for targeting mutant p53 degradation."
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"In tumor with homozygous mutant p53, loss of MDM2, which mimics the inhibition of the MDM2-p53 interaction, can cause stabilization of mutant p53 and increased incidence of metastasis [XREF_BIBR]."
MDM2-C305F inhibits TP53. 9 / 9
| 9
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"Remarkably, a homozygous Mdm2 C305F background reversed the accumulation of p53."
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"The Mdm2 C305F mutation, which disrupts the binding of ribosomal proteins L11 and L5 to Mdm2 XREF_BIBR, causes an attenuation of p53 signaling, suggesting that the Mdm2 C305F mutation may alter the progression, rather than initiation, of prostate tumorigenesis in a similar way as p53 heterozygosity."
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"Furthermore, the MDM2 C305F, which is defective in RPL11- and RPL5- binding in vitro and in vivo, has been shown to impair the p53 response to ribosomal stress in animals, strongly demonstrating the essential role of RP-MDM2 interactions in activation of p53 upon ribosomal stress."
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"Upon induction of the Rps19 deficiency, Mdm2 C305F reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo."
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"MDM2 C305F mutation attenuates p53 activation in colon tumors."
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"Further evidence supporting the adverse effect of high p53 activity in promoting obesity was demonstrated in mutant MDM2 C305F mice that have impaired p53 regulation of lipid metabolism."
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"23 As a working model, we hypothesized that if the p53 response in Rps19 deficient mice is mediated through the 5S RNP-Mdm2 interaction, the Mdm2 C305F background should reverse the p53 activity and subsequently improve the erythroid phenotype of these mice."
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"Reduction of the p53 activity in Rps19 deficient hematopoietic stem and progenitor cells by Mdm2 C305F normalized their viability and improved their proliferative capacity, resulting in significantly increased expansion of these cells in vitro."
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"Mdm2 C305F mutation attenuates p53 response to ribosome biogenesis stress."
MDM2 bound to CDKN2A inhibits TP53. 8 / 8
| 8
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"As mentioned above, ARF interaction with MDM2 causes MDM2 to target MDMX for degradation, and in the event of mitogenic stimulation MDMX is often downregulated to allow p53 activation."
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"In vitro, nuclear p14 ARF binds Hdm2 to block Hdm2 dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53."
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"ARF bound Hdm2 blocks Hdm2 dependent nucleocytoplasmic shuttling of p53, to produce nuclear retention and activation of p53 [XREF_BIBR, XREF_BIBR]."
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"In the case of MDM2-p53, it is apparent that both mechanisms are observed under different experimental conditions : induced phosphorylation of p53 can attenuate the p53-MDM2 interaction, and alternatively the human protein p14 ARF can bind to MDM2 and prevent its destruction of p53."
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"Indeed, it has been shown that ARF interacts with MDM2 and prevents MDM2 mediated degradation of p53 [XREF_BIBR]."
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"When released from nucleoli, Arf binds the central acidic region of MDM2 to inhibit its ubiquitinylation of p53."
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"The tumour suppressor P19 ARF associates with MDM2 to inhibit the ubiquitination, export and subsequent degradation of p53 [XREF_BIBR, XREF_BIBR]."
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"ARF does this by binding to MDM2, a ubiquitin ligase that catalyses p53 degradation; this interaction sequesters MDM2 and also blocks its ligase activity, thereby stabilizing p53."
MDM2 inhibits TP53. 6 / 6
3 3 |
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"Furthermore, by coimmunoprecipitaton and cotransfection assays, we found that PTEN physically binds p53 in vitro as well as in vivo. Binding of PTEN to p53 attenuated MDM2-mediated p53 inhibition."
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"Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT1 receptor. Similarly, the amount of Bax, Aogen, and AT1 receptor proteins in these cells decreased"
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" mdm2 inhibits p53-mediated transactivation; it inhibits the expression of p53 dependent genes"
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"Furthermore, by coimmunoprecipitaton and cotransfection assays, we found that PTEN physically binds p53 in vitro as well as in vivo. Binding of PTEN to p53 attenuated MDM2-mediated p53 inhibition."
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"Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT1 receptor. Similarly, the amount of Bax, Aogen, and AT1 receptor proteins in these cells decreased"
bel
" mdm2 inhibits p53-mediated transactivation; it inhibits the expression of p53 dependent genes"
MDM2 bound to MDM4 inhibits TP53. 5 / 5
| 5
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"It has been indicated that MDM2 forms a heterodimer or heterooligomer with MDMX through their C-terminal domains to inhibit p53 during early embryogenesis."
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"This interaction between MDM2 and MDM4 activates the E3 ligase activity of MDM2 and induces proteosomal degradation of p53 to suppress its endogenous cellular levels below the threshold required for transactivation of target genes, such as the cyclin dependent kinase (CDK) inhibitor p21."
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"Although MDM4 alone is unable to target p53 for ubiquitin-proteasome-dependent degradation 6, the MDM2 and MDM4 heterodimer has been shown more potent degrading the p53 protein as compared to the MDM2 homodimer 7, 8."
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"Additionally, mutation or deletion of the Mdmx RING also prevents Mdm2 and Mdmx interaction and triggers p53 dependent lethality in vivo."
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"In addition, the interaction between p53 and Mdm2 or MdmX suppresses the transcriptional activities of p53."
Catalytically active MDM2 inhibits TP53. 4 / 4
4 |
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"the central module is the interplay between p53 and the Mdm2 protein, which inactivates p53 and targets it for rapid proteolysis."
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"The interaction of MDM2 with p53 inhibits p53 transcriptional activity and targets p53 for ubiquitin-dependent degradation. The ability of MDM2 to inhibit p53 functions is antagonized by the ARF oncosuppressor protein."
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"It has been proposed that ARF is expressed only when an E2F signaling threshold is exceeded following oncogenic activation. The main activity of ARF is its ability to bind to p53 inhibitors and to control ribosome biogenesis. Human double minute (HDM2) [mouse double minute 2 (Mdm2) in mouse] and ARF protein binding 1 (BP1)/Mule are two specific E3 ubiquitin ligases that mediate p53 degradation through ubiquitination."
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"Akt (PKB) directly phosphorylates multiple protein targets of relevance to apoptosis (Figure 2B), suppressing cell death clearly within the intrinsic pathway (e.g., BAD inactivation, human caspase-9 suppression) and possibly also the extrinsic pathway (e.g., FasL expression) in some types of cells."
MDM2 inhibits TP53-R175H. 4 / 4
| 4
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"These results indicate that CTM restores mutant p53 R175H function to wt like p53, thus activating the induction of MDM2, which then binds to and negatively regulates p53 R175H."
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"This experiment demonstrated that the absence of CHIP does not impair HSP70 moderated, MDM2 dependent degradation of p53 R175H (XREF_SUPPLEMENTARY)."
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"Ectopic expression of MDM2 clearly down-regulated mutp53 R175H in H1299 cells co-transfected with vectors expressing mutp53 R175H and MDM2 (XREF_FIG), which is consistent with previous reports."
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"Contrary to CHIP mediated degradation, MDM2 dependent degradation of p53 R175H is partially inhibited by HSP70 overexpression (XREF_FIG), while overexpression of dominant negative HSP70 K71S mutant protein stimulates p53 R175H degradation (XREF_FIG)."
MDM2-Y489A inhibits TP53. 3 / 4
| 3
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"In agreement with previous in vitro studies showing that Mdm2 Y489A does not degrade p53, this data demonstrates that endogenous Mdm2 Y487A has similarly lost this function."
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"Both Mdm2 Y489A and Mdmx F488A suppresses p53 transactivation function."
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"By normalizing the amount of p21 mRNA to p53 protein, we found that both Mdm2 Y489A and Mdmx F488A reduce p53 specific activity (XREF_SUPPLEMENTARY)."
Mutated MDM2 inhibits TP53. 3 / 3
| 3
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"Importantly, the Deltap1-23A Mdm2 mutant interacts with p53 similarly to wild-type Mdm2 (XREF_SUPPLEMENTARY) and degrades p53 as efficiently as wild-type Mdm2 (XREF_SUPPLEMENTARY)."
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"In the absence of antagonist, p53 function was reduced ~ 90% by wild-type and mutant HDM2."
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"The mutant MDM2 proteins were unable to inhibit p53 dependent transcription in vivo, which is consistent with prior indications that a physical interaction between the two proteins is required for MDM2 's inhibition of p53."
Modified MDM2 inhibits TP53. 3 / 3
| 3
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"On the other hand, Mdm2 over-expression in cancer cells negatively regulates p53 levels and increased Mdm2 levels would probably abrogate any inhibitory effect of p53 on the CMV promoter activity."
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"We found that the ectopic expression of MDM2 downregulated the cellular levels of Vif as well as p53 in transfected cells in a dose dependent manner, whereas Parkin and Cul5 did not affect their cellular levels (lanes 2-4 and 5-7, respectively), even though the latter proteins were expressed more than MDM2."
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"Mdm2 is an E3 ubiquitin ligase that targets p53 for mono- and poly-ubiquitination Monoubiquitination mediated by low levels of Mdm2 promotes mitochondrial localization of p53, and elevates nuclear export of p53 to block its transactivational activity; high Mdm2 levels promote polyubiquitination and subsequent proteasome dependent degradation of p53 [XREF_BIBR]."
MDM2 bound to proteins inhibits TP53. 2 / 2
| 2
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"On one hand, these ribosomal proteins bind MDM2 and inhibit the E3 ubiquitin ligase activity resulting in stabilization of p53."
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"The released ribosomal proteins bind to MDM2 to block its ubiquitinylation of p53, leading to p53 stabilization and subsequent induction of p53 mediated G 1 cell cycle arrest or apoptosis."
MDM2 bound to RPL11 inhibits TP53. 2 / 2
| 2
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"XREF_BIBR Nucleolar stress triggers the nucleoplasmic export of the ribosomal proteins RPL5 and RPL11, which bind MDM2 and block MDM2 mediated p53 degradation, resulting in p53 activation, cell cycle arrest and apoptosis."
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"RPL11, in turn, binds to MDM2, preventing the inactivation of p53."
MDM2 bound to it inhibits TP53. 2 / 2
| 2
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"p19 Arf accumulates in the nucleolus, where it binds NPM1 and Mdm2 to suppress tumor development by inhibiting ribosome biogenesis and initiating p53 dependent senescence and apoptosis, respectively."
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"While exogenous Arf can sequester MDM2 to nucleoli (XREF_FIG), subsequent studies indicate that nucleolar stress releases Arf to the nucleoplasm where it binds and blocks MDM2, XREF_BIBR, XREF_BIBR thus allowing p53 to accumulate and block cell cycle progression (XREF_FIG)."
MDM2 bound to LATS2 inhibits TP53. 2 / 2
| 2
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"Active LATS2 binds and inhibits the E3 ubiquitin ligase MDM2, which targets p53 for destruction, thereby indirectly leading to the stabilization of p53."
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"Active LATS2 also binds to and inhibits the E3 ubiquitin ligase MDM2, which normally targets p53 for destruction."
MDM2-R249S inhibits TP53. 1 / 1
| 1
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"Thus, inhibition of RhoA activity through inhibition of the mevalonate-RhoA axis by an HMG-CoA-R inhibitor (cerivastatin) or an inhibitor of geranylgeranyltransferase type I (GGTI-298) reduces HDAC6 activity and hence induces hyperacetylation of HSP90, leading to dissociation of mutp53 from HSP90 and degradation of mutp53 by MDM2 (R175H, L194F, M237I, R249S, R273H)."
MDM2-Y487A inhibits TP53. 1 / 1
| 1
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"Endogenous Mdm2 Y487A Does Not Degrade p53 but Maintains Normal Binding Dynamics."
MDM2-L194F inhibits TP53. 1 / 1
| 1
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"Thus, inhibition of RhoA activity through inhibition of the mevalonate-RhoA axis by an HMG-CoA-R inhibitor (cerivastatin) or an inhibitor of geranylgeranyltransferase type I (GGTI-298) reduces HDAC6 activity and hence induces hyperacetylation of HSP90, leading to dissociation of mutp53 from HSP90 and degradation of mutp53 by MDM2 (R175H, L194F, M237I, R249S, R273H)."
MDM2-R273H inhibits TP53. 1 / 1
| 1
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"Thus, inhibition of RhoA activity through inhibition of the mevalonate-RhoA axis by an HMG-CoA-R inhibitor (cerivastatin) or an inhibitor of geranylgeranyltransferase type I (GGTI-298) reduces HDAC6 activity and hence induces hyperacetylation of HSP90, leading to dissociation of mutp53 from HSP90 and degradation of mutp53 by MDM2 (R175H, L194F, M237I, R249S, R273H)."
MDM2-C464A inhibits TP53. 1 / 1
| 1
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"Consistently, when Axin was immunoprecipitated, both HIPK2 and p53 in the precipitates were simultaneously reduced by co-expression of MDM2 or its mutant MDM2 (C464A) (XREF_FIG)."
MDM2 bound to RPL5 inhibits TP53. 1 / 1
| 1
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"XREF_BIBR Nucleolar stress triggers the nucleoplasmic export of the ribosomal proteins RPL5 and RPL11, which bind MDM2 and block MDM2 mediated p53 degradation, resulting in p53 activation, cell cycle arrest and apoptosis."
Phosphorylated MDM2 inhibits TP53. 1 / 1
| 1
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"The phosphorylated MDM2 enhances p53 degradation 15; in addition, blocking MDM2 binding to p53 with a small molecule nutlin-3 protects rabbits from retinal detachment in a PVR rabbit model."
MDM2 bound to S100A9 inhibits TP53. 1 / 1
| 1
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"13 p14 arf lies upstream of p53 and binds the p53 inhibitor HDM2 in order to activate p53."
MDM2 bound to MDM4 and TP53 inhibits TP53. 1 / 1
| 1
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"In the present study, however, we have uncovered a novel mechanism of p53 inactivation for inducing cisplatin resistance whereby the heterozygous V172F missense mutation in p53 enhances MDM4 recruitment into the p53, MDM2, and MDM4 complex that prevents p53 dependent transcriptional activity and apoptosis."
MDM2 bound to TRIM28 inhibits TP53. 1 / 1
| 1
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"TRIM28 through its coiled-coil domain binds to MDM2 and promotes p53 degradation."
MDM2 inhibits phosphorylated TP53. 1 / 1
| 1
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"The dephosphorylated p53 can then be degraded by MDM2 induced mechanisms, resulting in nicotine induced cell survival and tumorigenesis."
MDM2 bound to PSMD10 inhibits TP53. 1 / 1
| 1
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"The studies of gankyrin dependent promotion of liver cancer have indicated that gankyrin could not only bind to mdm2 and enhance degradation of p53 but also interact with Rb to reduce its stability."
MDM2 bound to EBNA-LP inhibits TP53. 1 / 1
| 1
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"The binding of EBNA-5 to MDM2 also could impair the functional activity of p53."
MDM2 bound to MYL6B inhibits TP53. 1 / 1
| 1
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"But, in this study we found that MYL6B could bind both MDM2 and p53 protein, accelerate the p53 degradation and promote HCC development."
MDM2-M237I inhibits TP53. 1 / 1
| 1
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"Thus, inhibition of RhoA activity through inhibition of the mevalonate-RhoA axis by an HMG-CoA-R inhibitor (cerivastatin) or an inhibitor of geranylgeranyltransferase type I (GGTI-298) reduces HDAC6 activity and hence induces hyperacetylation of HSP90, leading to dissociation of mutp53 from HSP90 and degradation of mutp53 by MDM2 (R175H, L194F, M237I, R249S, R273H)."
MDM2 inhibits TP53-Y107G. 1 / 1
| 1
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"Interestingly, the three unfolded mutants p53 Y107G, p53-T155D, and p53-L265A were still degraded by MDM2."
MDM2 bound to NUMB inhibits TP53. 1 / 1
| 1
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"Interestingly, NUMB, a suppressor of NOTCH, forms a tri-complex with TP53 and its ubiquitin ligase HDM2 to prevent ubiquitination and consequent TP53 degradation."
MDM2 bound to RB1 inhibits TP53. 1 / 1
| 1
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"Rb directly binds to MDM2 to antagonize these functions and then inhibits p53 activity."
MDM2 bound to POL2A inhibits TP53. 1 / 1
| 1
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"Interestingly, in mammals, a link exists between the regulation of Pol epsilon activity and p53, the functional homologue of SOG1 : MDM2 (Mouse Double Minute 2) can bind the C-terminus of Pol2A and is thought to simultaneously modulate Pol epsilon functions in response to stress and control cell cycle progression by regulating p53 degradation, similar mechanisms might be conserved in plants to maintain genome integrity."
MDM2-R175H inhibits TP53. 1 / 1
| 1
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"Thus, inhibition of RhoA activity through inhibition of the mevalonate-RhoA axis by an HMG-CoA-R inhibitor (cerivastatin) or an inhibitor of geranylgeranyltransferase type I (GGTI-298) reduces HDAC6 activity and hence induces hyperacetylation of HSP90, leading to dissociation of mutp53 from HSP90 and degradation of mutp53 by MDM2 (R175H, L194F, M237I, R249S, R273H)."
MDM2 bound to PTK2 inhibits TP53. 1 / 1
| 1
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"Recently, the direct interaction of the N-terminal FERM domain of FAK and p53 proteins has been shown and also FAK interaction with Mdm-2 protein has been demonstrated to down-regulate p53 [XREF_BIBR]."
MDM2 bound to NOP16 inhibits TP53. 1 / 1
| 1
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"In the cytoplasm, HSPC111 might directly interact with and stabilize MDM2, which could promote P53 degradation via ubiquitination and subsequently accelerate tumor progression [XREF_BIBR]."
MDM2-C462A inhibits TP53. 1 / 1
| 1
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"Here, we show in vivo that the Mdm2 (C462A) protein not only fails to suppress p53, but compared to the complete absence of Mdm2, Mdm2 (C462A) actually enhances p53 transcriptional activity toward p53 target genes p21 and CDKN1A, MDM2, BAX, NOXA, and 14-3-3sigma."