IndraLab

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TP53 bound to MDM2 activates TP53. 30 / 30
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"It also results to the translocation of ATM to the nascent p53 promoting its phosphorylation at p53(S15) that prevents the binding of p53 to MDM2 and its degradation via the E3 ligase activity, thus activating p53 towards the DDR [6]."
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"Particularly, it was shown that CDR1as inhibited carcinogenesis by disrupting the p53/MDM2 complex, which in turn reduced MDM2-mediated ubiquitination and allowed CDR1as to maintain p53 [70,71]."
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"Separation of the p53-MDM2 complex can lead to ROS accumulation, while JNK can activate the downstream gene p53 [95]."
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"MDM2 binds p53 at its transactivation domain to block its ability to activate transcription, promotes the nuclear export of p53, and may enhance p53 degradation by serving as a ubiquitin ligase."
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"One of the major endogenous negative regulators of p53 in humans is hDM2, a ubiquitin E3 ligase that binds to p53 causing proteasomal p53 degradation."
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"P53 alpha-Helix mimetics antagonize p53 and MDM2 interaction and activate p53."
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"Upon induction of DNA damage, the inhibitory interaction between p53 and Mdm2 is disrupted by phosphorylation of both proteins, resulting in p53 accumulation [XREF_BIBR]."
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"Furthermore, high levels of phosphorylation of p53 at Serine 15 (Ser15), modulate cell cycle checkpoint kinase Ataxia-Telangiectasia Mutated (ATM) and Ataxia-Telangiectasia and Rad3 related (ATR) that impede MDM2 binding to p53 and subsequently promote p53 accumulation and activation in response to DNA damage [XREF_BIBR, XREF_BIBR]."
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"Such phosphorylation might, for instance, weaken the interaction between p53 and Mdm2 (S. Shieh, C. Prives), thereby rescuing p53 from the inhibitory effects of Mdm2."
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"Mdm2 binds to P53 and leads to complete elimination of P53 through proteolytic degradation."
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"Nutlins are cis-imidazoline analogs that target the interaction between MDM2 and p53 preventing the degradation of p53 and allowing the p53 to accumulate."
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"Next we used a dual luciferase reporter assay to measure theactivation of the TP53 pathway in response to treatment with three DNA damage inducing agents (mitomycin C, doxorubicin, or UV-C) or nutlin-3a, which inhibits the interaction between MDM2 and TP53 and thus promotes TP53 signaling."
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"22 Furthermore, the mechanism by which E2F1 induces apoptosis has not been fully elucidated, but at least 2 distinct pathways seem to play a role in cancer cells: first, a p53-dependent pathway by act[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"MDM2 binds to a tumour suppressor protein p53 and induces ubiquitin dependent degradation of p53, which inhibits p53 functions XREF_BIBR."
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"E3 ligases PHF1 and RFWD3 prevent complex formation between MDM2 and p53 thus promoting the stability of p53."
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"In an inactive state, p53 is bound to Mdm2, which antagonizes the transcriptional activity of p53, induces its ubiquitylation, and promotes nuclear export of p53 [43,44]."
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"This interaction between MDM2 and p53 also allows MDM2 to shuttle p53 out of the nucleus in a RING-domain dependent manner."
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"To investigate the efficacy of PFT-α inhibition of p53 in cancer cells, we reactivated p53 by Nutlin-3, which inhibits the E3-ubiquitin ligase MDM2 by direct binding, disrupts the p53-MDM2 complex and prevents subsequent p53 degradation by the proteasome ."
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"It has been described that DNA damage-mediated NH 2 -terminal phosphorylation of p53 such as Ser-15 prevents the interaction between p53 and MDM2, and thereby increasing the stability of p53 [18] ."
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"Nutlin-3 activates p53 by inhibiting the interaction between p53 and MDM2 (inducer of p53 proteasomal degradation) (Vassilev et al., 2004)."
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"However, in stressed cells, such as those experiencing DNA damage or oncogenic stress responses, the interaction between p53 and MDM2 is interrupted, leading to the stabilization and activation of p53 to carry out its functions.17 Mutations in the p53 gene, often missense mutations, result in the loss of its tumor-suppressing function and promote the development and progression of various tumors, including those in the digestive system."
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"This inspires the idea of developing small molecules reactivating p53 to fight cancer.We have identified a small-molecule RITA (reactivation of p53 and induction of tumor cell apoptosis), which prevents p53/MDM2 interaction, induces p53 accumulation and transcriptional activity, and triggers p53-dependent apoptosis in tumor cells of a different origin in vitro and in mice (11–13)."
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"MDM4 negatively regulates p53 in both MDM2 dependent and -independent manners; MDM4 interacts with MDM2 and promotes MDM2 mediated ubiquitination and degradation of p53, and also interacts with p53 to suppress the transcriptional activities of p53."
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"Thus, CDR1as binding disrupts the P53/MDM2 complex to prevent P53 from ubiquitination and degradation, leading to tumor growth inhibition."
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"Nutlins were originally identified as potent small molecules that inhibit the interaction between p53 and MDM2, which promote p53 degradation XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"For instance, SAR405838 is an oral spirooxindole-derivative inhibitor of the MDM2–p53 interaction, which binds the pocket of MDM2 and activates the p53 pathways."
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"Later, Zawacka-Pankau et al. showed that in cultured cells, PpIX binds to p53 at its N-terminus and disrupts the interaction between p53 and HDM2 (the human homologue of MDM2), thereby disrupting HDM2 's negative regulation of p53."
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"Under cellular stress, post-translational modification of p53, such as Ser15 phosphorylation, disrupts p53/MDM2 interaction, reducing thereby p53 ubiquitinization and degradation, which induces an inc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"N3 increases p53 levels by inhibiting the interaction between p53 and Mdm2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation (Vassilev et al., 2004)."
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"Thus, CDR1as binding disrupts the p53 and MDM2 complex to prevent p53 from ubiquitination and degradation."
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