IndraLab

Statements

MDM2 activates mutated TP53. 24 / 24
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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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"Inactivation of Mdm2 restores apoptosis proficiency of cooperativity mutant p53 in vivo."
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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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"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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"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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"XREF_FIG, ectopic expressed Mdm2 could enhance mutant p53 ubiquitination, indicating that Mdm2 could still target mutant p53 to decompose."
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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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"MDM2 and MDMX can target WT and mutant p53."
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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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"Inhibition of MDM2 mediated mutant p53 degradation by MDM2 short isoforms."
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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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"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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