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MDM2 inhibits mutated TP53. 32 / 32
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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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"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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"In addition to p53 mutations, some tumors inactivate p53 by the amplification of the MDM2 gene (about one third of all sarcomas) (Oliner et al. 1992) or by the localization of p53 in the cell cytoplas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Interestingly, Hsp70 is found to partially inhibit Mdm2 mediated degradation of mutant p53."

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"These results suggest that MDM2 maintains mutant p53 protein levels low in normal tissues, whereas some changes in tumors disrupt MDM2 mediated mutant p53 degradation, thereby leading to mutant p53 protein accumulation in tumors."

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"MDM2 can promote the degradation of mutant p53, XREF_BIBR, XREF_BIBR although in tumor cells this regulation is disrupted, for example, through the expression of MDM2 isoforms that inhibit full-length MDM2 E3 ligase activity, 51 and mutant p53 protein accumulates."

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"While L11 could inhibit p53 degradation targeted by cotransfected HDM2, L11 expression had no effect on the stability of a p53 mutant that lacks the HDM2 binding site and is not degraded by HDM2 (data[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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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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"This result is consistent with our previous report that Nutiln, an inhibitor of MDM2 abrogated NSC59984-mediated mutant p53 protein degradation (34)."

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"In most cases, reactivated mutant p53 is inhibited and degraded by MDM2."

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"Inhibition of HDAC6 leads to inactivation of HSP90 and allows for reactivation of ubiquitin ligases MDM2 and CHIP E3 to mediate mutant TP53 degradation, but not degradation of WT TP53 [33]."

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"Unlike Hsp90, Hsp70 partially inhibits MDM2 mediated mutant p53 degradation and promotes CHIP mediated mutant p53 degradation [XREF_BIBR, XREF_BIBR]."

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"Mdm2 can also drive the degradation of mutant p53, which indicates that the mutant p53 proteins are not intrinsically resistant to Mdm2 associated degradation, although in tumor cells this regulation is disrupted because p53 dependent transcription of Mdm2 is inhibited by the loss-of-function of mutant p53 or by the dominant negative effect of mutant p53 over WT p53 [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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"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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"These results suggest that MDM2 is required for NSC59984 to decrease mutant p53 protein in cancer cells."

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"Interestingly, mdm-2 was also shown to induce degradation of certain p53 mutants."

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"However, the notion that mutant p53 can be degraded by MDM2 is not without precedent."

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"Abrogation of HDAC6 binding results in the dissociation of the heat shock proteins from mutant p53 and allows for mutant p53 degradation by MDM2 and CHIP."

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"Additionally, increased expression of MDM2, has been shown to strongly repress mutant p53 accumulation in tumors cells [26–30]."

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"XREF_BIBR MDM2 can also target degradation of mutant p53."

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"Furthermore, it may be advantageous to treat cSCCs where p53 is mutated with an SF3B1 independent inhibitor because a reduction in MDMX and MDM2 levels could enhance the gain of function activity of mutant p53."

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"MDM2 efficiently degrades wild type p53, but fails to degrade mutant p53 in tumor cells."

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"Consistent with its known role in regulating wild type p53, MDM2 promotes degradation of mutant p53 in normal and premalignant tissues [30]."

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"These results taken together suggest that NSC59984 induces mutant p53 degradation via activation of MDM2 through a ROS-ERK2-MDM2 axis, and high levels of ROS enhance the efficacy of NSC59984-induced MDM2 binding to mutant p53 (Figure 3F)."

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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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"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]."

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"P53 mutants at the DBD that have partial transactivation function were also inhibited by MDM2, whereas mutations introduced into the p53 N-ter domain that mimic phosphorylation events could relieve p53 from the MDM2 dependent inhibition."

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"Studies have shown that the degradation of mutant p53 mediated by murine double minute 2 (MDM2) can be induced by As2O3, which probably contributes to the inhibition of SCLC, but the detailed mechanism is still unclear."

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"Morpholino knockdown of the zebrafish homologs of Mdm2 and Mdm4 caused dramatic accumulation of mutant p53 protein."