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MDM2 activates mutated TP53. 36 / 36
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"These results suggested that pH-responsive PMPC- b -PDPA/siRNA complex nanoparticles could induce apoptosis in p53 mutant NSCLC by downregulation of MDM2."
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"Although mutant p53 can be targeted by MDM2 in normal cells, MDM2 can not polyubiquitinate mutant p53 in cancer cells XREF_BIBR."
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"Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells."
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"In addition, another MDM2-targeting small-molecule compound, CP-31398, a synthetic styrene quinazoline, was able to down-regulate MDM2 expression and restore p53 mutant function in EC [205]."
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"The major mechanisms causing p53 dysfunction include the MDM2/MDMX-mediated destabilization and inactivation of wtp53 and somatic p53 mutations."
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"Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells."
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"We show for the first time that in the presence of activated DNA damage checkpoint signaling, MDM2 acts to increase mutant p53 abundance, by facilitating monoubiquitination of mutant p53, and inactivation of checkpoint signaling serves as a switch that turns MDM2 from an activator of mutant p53 abundance to facilitating its degradation."
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"Interestingly, PLK3 and MDM2, both involved in p53 activation, were upregulated in WM793B and WM1382 but not in 451Lu cell line harboring p53 mutation in both alleles."
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"In order to maintain the long-term survival of hepatocytes, hepatitis virus induces TP53 mutation and silencing, promotes MDM2 overexpression, which ultimatedly accelerates p53 degradation and stabilizes MDM2 [27]."
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"Meanwhile, other biomolecules such as a member of the anti-apoptotic factor Bcl-2 family (BGA2/BAG5), or the heat shock protein family (Hsp40, Hsp70 and Hsp90), are involved to regulate mutant p53 stability, for example, E3 ubiquitin ligase MDM2 and Hsp70 induce conformational changes in mutant p53 cells, and Hsp90 is recruited by BGA2 to assemble in the mutant p53 status (Wiech et al., 2012; Yue et al., 2016)."
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"Hsp90 and Hsp70 are two molecular chaperones that stabilize mutant p53 protein by affecting the MDM2 mediated turnover of mutant p53."
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"Mutant p53 proteins and YAP/TAZ promote tumorigenesis via direct interaction or mediated by LATS2/MDM2 ."
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"Our results suggest that reduced RSL1D1 function and HDM2 induction by p53 mutation promote accumulation of p53 mutants in response to DNA damage stress, thereby causing drug resistance in CRC cells ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Inhibition of MDM2 mediated mutant p53 degradation by MDM2 short isoforms."
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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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"Both wild-type and mutant p53 can be targeted for proteasomal degradation in otherwise normal cells by the ubiquitin ligase MDM2."
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"A recent study from our group revealed that MDM2 isoform B (MDM2-B), the most frequently overexpressed MDM2 isoform in human tumors, can promote mutant p53 protein accumulation in cancer [XREF_BIBR]."
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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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"This mouse MDM2 short isoform also promotes mutant p53 accumulation and the growth of xenograft tumors in a largely mutant p53 dependent manner [XREF_BIBR]."
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"A CANCER PERSISTENT DNA REPAIR CIRCUIT DRIVEN BY MDM2, MDM4 (MDMX), AND MUTANT P53 FOR RECRUITMENT OF MDC1 AND 53BP1 TO CHROMATIN."
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"The knockdown of MDM2 blocked NSC59984-mediated downregulation of mutant p53 in the cancer cells (Figure 3C)."
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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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"XREF_BIBR Moreover, because in the absence of this Hsp90 activity MDM2 is able to inactivate p53, XREF_BIBR, XREF_BIBR, XREF_BIBR the use of MDM2 and MDMX antagonists in premalignant lesions may increase the number of p53 mutant forms and the risk of tumor progression."
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"On the contrary, MDM2 overexpression induced migration in DU-145 cells bearing a p53 mutation; this effect was partially dependent on MDM2 E3 ligase activity (XREF_SUPPLEMENTARY) and suggests that effects of MDM2 modulation on cellular motility are cell type and context specific."
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"Moreover, since MDM2-FL and other isoforms can modulate mutant p53 stability, it is possible that MDM2 antagonists could promote stabilization of mutant p53."
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"In mutant p53 triple negative breast cancer cells, however, we did not see increased stability of mutant p53 in cells treated with the MDM2 antagonist, Nutlin3a [XREF_BIBR]."
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"Mechanistically, this is supported by a study showing that Mdm2 could drive metastasis in cancer cells with mutant p53 (4)."
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"As such, overexpression of MDM2 or CDK2NA homozygous deletions can cause degradation of mutant p53 with either mechanism potentially resulting in a false-negative p53 IHC result."
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"These results demonstrated that inhibition of HDM2 efficiently leads to decrease of RRM1 and RRM2 via p53-mTORC1 signaling in TP53 wild type Rh18 but not TP53 mutant Rh30 cells."
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"MDM2 and MDMX can target WT and mutant p53."
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"Inactivation of Mdm2 restores apoptosis proficiency of cooperativity mutant p53 in vivo."
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"XREF_FIG, ectopic expressed Mdm2 could enhance mutant p53 ubiquitination, indicating that Mdm2 could still target mutant p53 to decompose."
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"A number of natural products have been developed to target the p53-MDM2 pathway by 1) inhibiting MDM2 expression or protein stability, 2) inhibiting the p53-MDM2 interaction, 3) inhibiting the E3 ligase activity of MDM2, 4) reactivating or reinstating the wild-type functions of mutant p53, and/or 5) inhibiting the expression or protein stability of mutant p53."
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"Hsp90 can promote the stabilization and accumulation of mutant p53 by inhibiting the degradation of mutant p53 mediated by MDM2 and CHIP [XREF_BIBR - XREF_BIBR, XREF_BIBR]."
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"Such a mutant p53 would be able to transactivate mdm2, and the resultant Mdm2 protein would target the endogenous, inactive mutant p53 for degradation, without affecting the stability of the exogenous[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Furthermore, the mutant p53 protein half-life can be increased by HSP70- and MDM2-dependent protein co-aggregates [70]."
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