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MDM2 inhibits TP53. 1000 / 5320
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"Normally, the p53 gene is inactivated by mouse double minute 2 proteins (mdm2),so the activated form of this antigen is low; however, when there are activators like cell-cycle abnormality, hypoxia, and DNA damage, this leads to the dissociation of mdm2 and then the p53 gene will be activated causing DNA repair and induction of apoptosis [ xref ]."
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"Because inhibition of p53 by MDM2 stems from their direct physical interaction, small-molecule inhibitors designed to bind to MDM2 and block the MDM2-p53 protein-protein interaction (hereafter called MDM2 inhibitors), can lead to accumulation and activation of wild-type p53, thus releasing the tumor suppressor function of p53 [ xref – xref ]."
sparser
"Upon induction by p53, Mdm2 inactivates p53 through at least two main mechanisms: (a) binding to p53 at its transactivation domain and blocking its transactivation activity, and (b) serving as an E3 ubiquitin ligase to promote a rapid degradation of p53 ( xref ; xref ; xref ; xref ; xref )."
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"Artificial inhibition of p53 using p53 siRNA, p53 dominant negative forms and p53 antagonist MDM2 can recover cell viability and HDR frequency ; however, it remains uncertain whether such forced suppression of physiological p53 activation is free from long-term genome instability and unexpected side effects."
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"This is supported by findings showing that telethonin promotes Mdm2 mediated degradation of the pro apoptotic transcription factor p53 in the nuclear compartment upon biomechanical stress.8 The ubiquitin-proteasome system (UPS), together with autophagy, controls skeletal muscle proteolysis and protein mass."
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"Proposed Model of the Mechanism whereby Hdm2 Recruits CtBP Proteins to Negatively Regulate p53 Dependent Transcription (A) Recombinant human p53, Hdm2, and GST-hCtBP2 (1-110) were mixed as indicated and subjected to either GST pull-down analysis or immunoprecipitation with mAb 2A9 to Hdm2."
eidos
"The signaling pathways described to play a role in neuroblastoma cells are ( 1 ) PI3K / AKT / mTOR pathway - - promotes NB cell survival and chemoresistance ; ( 2 ) Wnt signaling , which is involved in drug resistance , stemness , and increases MYCN levels ; ( 3 ) p53-MDM2 pathway , where MDM2 inhibits p53 activity , promotes angiogenesis , increases MYCN translation , and promotes drug resistance ."
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"Taken together, these studies present a strong case that in the embryo and in adult mice, MDM2 acts in a TP53-dependent manner to limit excessive TP53 overactivation and apoptosis in tissues, including in the endothelium.While the primary function of MDM2 might be to restrain TP53, additional evidence supports the idea that MDM2 is important for vascular homeostasis due to TP53-independent functions."
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MDM2 overexpression can downregulate P53 activity and promote P53 degradation through the proteasome pathway, which in turn leads to tumor suppressor P53 pathway inactivation, allowing cells to pass through the cell cycle in the presence of DNA damage, which in turn initiates tumorigenesis."
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"We have recently demonstrated that inhibitors of the MDM2 dependent degradation of p53 exert anti-cancer effects also in the cells carrying these mutations [XREF_BIBR], suggesting that in the absence of the transcriptional activity, the mitochondrial apoptotic pathway induced by p53 is still active [XREF_BIBR]."
sparser
"Comparedto normal splenic B cells, it has previously been shown that mdm-2 mRNA is increased in 30% of CLL patients, and overexpression at the RNA appears to correlate
with protein expression as assessed by immunohistochemistry of the CLL cells.[331As mdm-2 inactivates p53, it would be expected that those patients overexpressing mdm-2 mRNA might be drug resistant.[129131 However, althoughwe found a twenty-fold variation in mdm-2 mRNA levels in our patients, we found no correlation between expression and resistance to any of the drugs."
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"An earlier study on WI-38 fibroblasts reported that Nutlin3a, a small molecule that stabilizes p53 by interfering with MDM2-mediated degradation of p53, stimulates p53 transcriptional activity when cells are in a senescent state, but not to the same extent as when they are cycling ."
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"4 These small molecules have received much attention from academia and industry in the past decade, since the function of wild-type (WT) p53 is inactivated by overexpression 5 or amplification 6 of MDM2, even though the p53 gene is either deleted or mutated in approximately 50% of all human cancers."
sparser
"The most extensively studied p53 activators are targeted against MDM2 – an E3 ubiquitin ligase that negatively regulates the activity and stability of p53. xref ; xref ; xref ; xref MDM2 inactivates p53 primarily by two different mechanisms: (1) physically sequestering the N-terminal trans-activation domain of p53 to suppress the expression of p53-regulated responsive genes; (2) channeling the tumor suppressor protein into the ubiquitin-proteasome pathway for degradation."
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"26
Single nucleotide polymorphisms in the promoter region of MDM2, as well as amplified MDM2 gene, have been observed in various malignant tumors, including breast cancer, lung cancer, esophageal cancer, colon cancer, and various sarcomas,
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and antagonists of MDM2/MDMX can reactivate the p53 pathway and enhance the apoptosis of RB cells,
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while the high expression of MDMX and MDM2 subsequently inhibits the p53 pathway during tumor development."
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"* Ongoing clinical trials are examining treatment strategies using FAK inhibitors in combination with chemotherapy, targeted therapy, or checkpoint inhibitors to increase efficacy.This box summarizes key points contained in the article.of FAK acts as a scaffold for MDM2 and p53 and promotes MDM2 mediated p53 degradation by ubiquitination, thus inhibiting apoptosis and promoting cancer cell survival [19]."
sparser
"In neurodegeneration, p53 is hyperactivated in response to oxidative DNA lesions, promoting apoptosis and cellular senescence. xref Tau protein, commonly aggregated in tauopathies such as Alzheimer’s disease (AD), directly interacts with p53 and stabilizes its conformation during the DNA damage response. xref , xref Mechanistic studies have shown that Tau loss leads to decreased p53 stability through the direct disruption of this interaction, thereby favoring a shift from apoptosis to senescence in damaged neurons, which may sustain chronic neuroinflammation. xref , xref Conversely, in cancer, p53 is frequently inactivated through mutation or degradation by MDM2, enabling genomic instability and tumor proliferation. xref This context-dependent modulation of p53, pro-apoptotic in neurons and anti-apoptotic in cancer, illustrates a fundamental divergence rooted in shared regulatory nodes."
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"Subsequently, it was found to interact with p53 and to inhibit its function through two main mechanisms : first, the direct binding of Mdm2 to the N-terminal domain of p53 inhibits the transcriptional activation function of p53; second, Mdm2 possesses E3 ubiquitin activity that targets p53 for degradation through the 26S proteasome."
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"For examples, the E3-E4 pair of parkin-CHIP ubiquitinates Pael-R (Pael receptor) and signals its degradation to relieve endoplasmic reticulum (ER) stress in neuronal cells, and the E3-E4 pair of mouse double minute 2 (Mdm2)-E4B induces p53 degradation and promotes the survival of cancer cells."
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"Our results are in consistence with recent reports that MDM2 may negatively regulate genomic stability independent of p53 by directly binding to Nbs1 of the MRN complex to impair MRN complex mediated ATM activation and subsequent DNA damage response in other model systems XREF_BIBR - XREF_BIBR, XREF_BIBR."
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"A number of previous observations confirm that wild-type p53 alleles are present in the vast majority of cases of newly diagnosed neuroblastoma, but that p53/MDM2/ARF responses to chemotherapy are repressed, in part due to unscheduled inhibition of p53 by MDM2 XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"Under normal conditions, MDM2 promotes the degradation of p53 via protein-protein interactions while following genotoxic stress, the stress sensor ATM kinase is activated by double-stranded DNA breaks and phosphorylates MDM2(S395) inducing a conformational change which dramatically increases the affinity of MDM2 for the p53 mRNA [6–14]."
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"Although stress signals have been shown to compromise MDM2 induced ubiquitination and proteolysis of p53 and thus activate p53 in normal cells, cancer cells employ oncogenic molecules, such as MDMX, which strengthen MDM2 mediated inhibition of p53 and thus induce cell resistance to p53 activation."
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"Recently discovered is that MDM2 has been found to disrupt the function of p53 via blocking p53 transcriptional activity and p53 protein degradation; such inconsistent activity of MDM2 for suppression of p53 expression is related to the higher progression of various types of malignancies, especially brain cancer [20,21,22]."
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"The present results revealed that tanshinone IIA combined with imatinib not only synergistically inhibited MDM2 protein expression but also inhibited the phosphorylation of MDM2 (ser166) by synergistically inhibiting the phosphorylation of AKT (Ser473), thereby more effectively inhibiting MDM2-induced degradation of P53 and thus activating the P53 signaling pathway more effectively."
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"Thus, HDM-2 limits the ability of p53 to stimulate the apoptosis of transformed cells.PNC-27 was originally designed by our research group to block the binding of p53 to HDM-2 in the nuclei of cancer cells as a “decoy” peptide, i.e., the peptide would cross the cancer cell and nuclear membranes using its penetratin sequence and bind to HDM-2 in place of the full p53 protein, hopefully enhancing p53-induced apoptosis of the cancer cells [13]."