"Recruitment of HDAC1 by MDM2 promotes p53 degradation by deacetylation."
"Inhibition of MDM2 by Nutlins or other inhibitors has been explored as an approach to activate p53 in AML with varying efficacy underscoring the need to further dissect the heterogeneity and oncogene specific mechanisms."
"Since MDM2 is negatively regulated by CDKN2A, MDM2 amplification and aberrations in the cyclin pathway will likely lead to suppression of TP53 (TP53 is negatively regulated by MDM2) [XREF_BIBR]."
"The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53 mediated transregulation of gene expression."
"Inhibition of MDM2 can restore p53 activity in cancers leading to anti-tumor effects with apoptosis and growth inhibition."
"On the other hand, the intensity of Mdm2 staining was not significantly increased in leukemic cells, questioning Mdm2-dependent p53 inhibition at the level of single CN-AML and APL cells."
"However, overexpression of MDM2 can downregulate p53 in cells that should undergo apoptosis, causing aberrant cell cycle progression."
"Mdm2 represses p53 activity by binding and sequestering p53 away from p53 target gene promoters."
"However, upon cellular stress, p53 is phosphorylated resulting in the shutdown of Mdm2 mediated degradation and accumulation of transcriptionally active p53 which activates several targets including cell cycle inhibitors and pro apoptotic proteins resulting in apoptosis or proliferation arrest."
"MDM2 also enhances the degradation of p53 XREF_BIBR, XREF_BIBR suggesting that it can regulate p53 functions through multiple mechanisms."
"MDM2 promotes p53 degradation by forming a stable complex through N terminal domains."
"In the setting of radiation induced damage, AKT regulates cell cycle progression, in part, by direct phosphorylation of the Chk1 protein kinase, a key component of the DNA damage sensing and repair mechanism, or through phosphorylation of MDM2 modulating p53 degradation [XREF_BIBR, XREF_BIBR]."
"Blocking ETV6 and RUNX1 induced MDM2 overexpression by Nutlin-3 reactivates p53 signaling in childhood leukemia."
"Mechanistically, RASSF6 blocks MDM2 mediated p53 degradation and enhances p53 expression."
"MDM2 (also named Mdm2 p53 binding protein homolog) can inactivate the p53 via binding to the transactivation domain of p53."
"The N-terminus of MDM2 proto-oncoprotein interacts with p53 and down modulates p53 activity by inhibiting transcriptional activity and promoting p53 degradation."
"Taken together, our data suggest that inhibition of SIRT1 by MHY2256 causes increased activation of p53 by decreasing MDM2 expression."
"Phosphorylation of S315 and S376 may induce p53 degradation in endoplasmic reticulum (ER) stressed cells [XREF_BIBR] or MDM2 mediated inhibition of p53 [XREF_BIBR]."
"In cellular stress conditions, such as radiation induced DNA damage, the p53 levels are reported to oscillate in a sustained (undamped) way as the p53 suppression by MDM2 is decreased (XREF_FIG) XREF_BIBR."
"Mdm2 inhibits p53 function by acting as an ubiquitin ligase to target p53 for proteasomal degradation as well as by binding and blocking the DNA binding domain of p53, inhibiting its activity as a TF."
"Siva1 binds to Hdm2 and enhances Hdm2 mediated p53 degradation."
"If the HDM2 feedback inhibition of p53 is interrupted, an increase in functional p53 levels should augment the therapeutic effectiveness of such agents by restoring p53 functions that lead to apoptosis, or by reversing p53 associated drug resistance."
"One of the key regulators of p53 is MDM2 84, which inhibits p53, and targets it to proteasome degradation 85."
"The inhibition of Mdm2 under stress conditions enables p53 to stabilize."
"The data imply that the amino terminal half of p14ARF, encoded by the alternative first exon (exon 1beta) contacts MDM2 through multiple domains that can independently impede MDM2 mediated degradation of p53, provided that they are localized in the cell nucleus."
"Indeed Nutlin-3, a small molecule inhibitor of Mdm2, is able to activate p53, and exhibits antitumor efficacy in cancer cells that express high levels of Mdm2."
"As described above, MDM2 and MDMX are two physiological inhibitors of p53 and work together as a complex to independently or together control p53 level and activity in a spatial-temporally specific manner."
"XREF_BIBR It has been reported that inhibition of MDM2 expression in cancer cells can reactivate p53, leading to apoptosis."
"It is connected to three genes : TP53 in its active state in the nucleus (through state_transition), TPPP (TPPP can phosphorylate TP53) and MDM2 (MDM2 can inhibit the activation of TP53)."
"Consequently, another oncosuppression route derives by the ability of p19 and ARF to bind MDM2, which remains locked inside the nucleolus instead of moving to the cytoplasm; thus, MDM2 can not induce p53 degradation, and this enhances p53 function as a pro apoptotic protein [XREF_BIBR]."
"MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity."
"P14ARF blocks HDM2 inhibition of p53 activity, so that this locus impacts on two key pathways in cancer, the retinoblastoma pathway and the p53 pathway [XREF_BIBR]."
"Nutlin-3a inhibits the binding site of MDM2-p53, promotes p53 function, and increases chemotherapy induced apoptosis in cancer cells lacking functional p53 by activating E2F2, while RITA avoids MDM2 induced p53 repression by binding to p53 [XREF_BIBR]."
"In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways."
"The MDM2 gene which inactivates p53 by binding to it was neither amplified nor rearranged in 28 leukemias studied."
"The ability of Mdm2 to inhibit the apoptotic function of p53 was linked to its ability to inhibit the transrepression but not the transactivation function of p53."
"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."
"Upon induction of cell stress by DNA damaging agents such as ionising radiation, phosphorylation processes lead to stabilisation of p53 by dissociation from the E3 ubiquitin-protein ligase MDM2 which [MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"In normal unstressed cells TP53 is kept at a low level through ubiquitylation by its major negative regulators MDM2 and MDM4 (MDMX) which target TP53 for proteasomal degradation."
"This suggests that MDM2 mediated p53 degradation may be altered in our leukemic cell lines."
"AURKA also directly phosphorylates TP53, resulting in the inactivation of TP53 function and the MDM2 mediated proteolytic degradation of TP53, respectively."
"It is now widely recognized that RPL5 and RPL11 not incorporated into the 60S ribosome bind preferentially to MDM2, so inhibition of p53 by MDM2 is compromised, causing a stimulation of the p53 pathwa[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival."
"Our results support the hypothesis that p53 function is suppressed by aberrant HDM2 activity and suggest the possibility of targeting the p53-HDM2 regulatory axis as a therapeutic strategy in synovial sarcoma."
"To do so, T cells were treated with Nutlin-3 which has been shown to increase p53 protein levels by preventing Mdm2 mediated p53 degradation."
"For example, up-regulation of both AurkA and AurkB can contribute to cancerogenesis through the phosphorylation of p53, which accelerates MDM2 dependent degradation of the same p53 protein by the poly-ubiquitination-proteasome pathway."
"MDM2 isoform B (MDM2-B), the MDM2 isoform most frequently over-expressed in human tumours, interacts with full-length MDM2 to inhibit MDM2 mediated mutp53 degradation, promoting mutp53 accumulation and GOF in tumorigenesis."
"In contrast, in the p53 Delta31 mouse model, the deletion of the p53 C-terminus would attenuate the negative regulation by Mdm2 leading to an abnormal hyperactivation of p53 to cause defects in telomere maintenance and DNA repair."
"However, an arrestin-3 mutant that did not bind IP6 was found to lack tight association with another partner, ubiquitin ligase Mdm2, and in contrast to WT arrestin-3, these presumably monomeric mutants did not suppress Mdm2 dependent degradation of p53."
"MDM2 negatively regulates p53 via various mechanisms such as cell cycle control, genome stability, apoptosis, and tumor neoangiogenesis by ubiquitination, transcription factor activation, and regulation of mRNA stability [XREF_BIBR]."
"The N-terminus of MDM2 interacts with N-terminal transactivation domain of p53 and effectively blocks p53 mediated transactivation [XREF_BIBR, XREF_BIBR]."
"p53 can be activated by a wide variety of different signals such as DNA double strand breaks, inhibition of RNA production and pharmacological inhibition of MDM2."
"The protein responsible for p53 regulation by 280B is Mdm2, the E3 ubiquitin ligase that promotes p53 degradation by inducing its nuclear export."
"The ability of S7 to inhibit MDM2 induced p53 degradation is most likely related its ability to inhibit both MDM2 mediated p53 ubiquitination and MDM2 autoubiquitination in vivo (XREF_FIG)."
"Hence, mdm2 negatively regulates p53, and genotoxic stress alleviates this by suppressing interaction between the two proteins."
"In particular, Mdm2 can inhibit p53 through its p53-binding domain and its carboxyl terminal ring finger domain, which is an E3 ubiquitin ligase of p53."
"Trisomy 12 (possibly involving MDM2 an inhibitor of p53 gene) has an intermediate prognosis."
"The current model predicts that MDM2 is primarily overexpressed in cancers with wild-type (WT) p53 and contributes to oncogenesis by degrading p53."
"Apart from this critical function, MDM2 overexpression may inhibit DNA repair independent of p53."
"In addition, IRF-8, which is expressed in GC cells, induces expression of MDM2, which inhibits p53 (XREF_FIG)."
"Ubiquitination mediated repression of p53 by Mdm2 acts at least, in part, through inhibiting the sequence specific DNA binding activity."
"In contrast to Mdm2 deletion or reduction, transgenic Mdm2 overexpression in the mouse supports increased tumour development, presumably because of increased p53 inhibition."
"In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein -- protein interaction."
"The lack of mut p53 protein stabilization was already reported for other mut p53 reactivators, and has been attributed to a reestablishment of the MDM2 mediated p53 degradation [XREF_BIBR]."
"Our data demonstrated that AXL overexpression or activation through growth arrest specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity."
"As the acetylated p53 lysine residues overlap with those that are ubiquitylated, our results suggest that one major function of p53 acetylation is to promote p53 stability by preventing MDM2 dependent ubiquitylation, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups."
"Furthermore, it was demonstrated that MDM2 not only inhibits p53 transactivation of its target genes but also mediates degradation of p53 by serving as an E3 ubiquitin ligase."
"Phosphorylation of MDM2, as observed in the data as a result of 60-minute PMA exposure, facilitates MDM2 ubiquitination of p53 and prevents p53 arrest of cell division."
"The absence of LRF increases the expression of p19ARF, which in turn inhibits the expression of the ubiquitin ligase MDM2, causing up-regulation of p53 and induction of senescence [XREF_BIBR]."
"Several studies have confirmed that wild-type TP53 alleles exist in most cases of newly diagnosed neuroblastoma, but after chemotherapy, the P53/MDM2/P14 ARF pathway is repressed, in part because of the abnormal inhibition of P53 by MDM2 [XREF_BIBR - XREF_BIBR]."
"These results are consistent with the experimental observation that Mdm2 promotes HIF-1alpha degradation in a p53 dependent way XREF_BIBR."
"We further demonstrated that the survival promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2 mediated TP53 degradation, and NFKBIA- and IKK mediated transcriptional activity of NFKB in HCC cells."
"Mdm2, an oncoprotein, inhibits p53 and promotes p53 degradation."
"Alternatively, Hdm2 and p53 could be exported separately from the nucleus and then associate in the cytoplasm, where Hdm2 promotes the degradation of p53."
"MDM2 attenuates p53 functions in cell cycle arrest, apoptosis, and response to DNA damage [XREF_BIBR]."
"Human mouse double-minute 2 protein (Mdm2) (gene locus on chromosome 12q14.3-q15) is a cellular E3 ligase able to ubiquinate and degrade p53 (Haupt et al, 1997)."
"Lysates were analysed with specific antibodies for expression levels of p53 and the p53 antagonist MDM2."
"Recently, studies from this group reported that Notch-1 signaling sensitizes tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced apoptosis in HCC cells by inhibiting Akt and HDM2 mediated p53 degradation and by up-regulating p53 dependent DR5 expression [XREF_BIBR]."
"Because it is known that Mdm2 can degrade p53, it is possible that, in its trimeric form, p14 (ARF) is able to stabilize mutant p53 by inhibiting Mdm2."
"HDM2, whose protein product binds to and inactivates p53 protein, is amplified in some soft tissue sarcoma, including atypical lipomatous tumor and well differentiated liposarcoma and in some bone tumors such as low grade parosteal and intramedullary osteosarcoma."
"In case of low DNA damage, Mdm2 activity is not effectively suppressed by ATM resulting in sustained oscillations of both p53 and Mdm2."
"For example, EI24 degrades MDM2, which negatively regulates TP53, and it also degrades TRAF2, which positively regulates MTOR (XREF_FIG)."
"SMAR1 mediated stabilization of p53 is brought about by inhibiting Mdm2 mediated degradation of p53."
"Specifically, MDM2 has been proposed to repress p53 activity when co-occupied on these promoters, with p53 stress stimuli relieving such repression."
"These stress signals also result in the activation of mouse double minute 2 homolog (MDM2), a protein that degrades p53."
"hdm2 binds to the N-terminal transactivation domain of p53 to block the transcriptional activity of p53 directly."
"This inhibition of p53 by MDM2 has been gracefully verified by TP53 and mdm2 double knockout studies."
"HDM2 dependent suppression of p53 may be related with its E3 ligase activity on p53."
"The p53 protein stability is reduced by Mdm2 via proteasomal degradation XREF_BIBR."
"The conditional knockout of mdm2, a major inhibitor of p53, in the intestinal epithelium in mouse induces massive p53 dependent apoptosis."
"MDM2 promotes ubiquitinylation and proteasomal degradation of p53."
"Many cellular factors such as antagonism by TCTP [XREF_BIBR], MDM2, Sir2alpha [XREF_BIBR] or by factors derived from pathogens such as Tax from human T-cell leukemia virus type 1 [XREF_BIBR], SV40 T large antigen [XREF_BIBR], adenovirus E1B 55K protein [XREF_BIBR], and hepatitis B virus X protein [XREF_BIBR] are involved suppressing the p53 activities."
"Therefore, the GNL3L stabilized MDM2 may inhibit the transcriptional activation of p53 through a direct binding mechanism without affecting the p53 protein level."
"The isolated p53 activation domain fused to another DNA binding protein is also inactivated by MDM2, confirming that MDM2 can inhibit p53 function by concealing the activation domain of p53 from the cellular transcription machinery."
"SIRT3 inhibits hepatocellular carcinoma cell growth through reducing Mdm2 mediated p53 degradation [XREF_BIBR]."
"Overexpression of MDM2 also attenuates p53 function."
"JMJD2B activation might either affect the binding affinity of MDM2 to p53, or promote a sustained increase in MDM2 levels under stress conditions, followed by ubiquitylation and, ultimately, degradation of p53."
"Mdm2, in turn, negatively regulates p53 by both inhibiting its activity as a transcription factor and by enhancing its degradation rate."
"XREF_BIBR, XREF_BIBR The acidic domain is also critical for MDM2 mediated p53 degradation, 218 although how exactly the acidic domain of MDM2 contributes to the regulation of p53 stability is unclear."
"There is a negative feedback loop between P53 and MDM2, in which activating p53 protein increases MDM2 transcription, and the resulting MDM2 protein interacts with p53, thereby causing p53 degradation."
"The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters and enhancers of its target genes."
"MTF2 deficiency impaired expression of the PRC2 complex and deposition of H3K27me3 at many genes, including the key target gene MDM2, leading to increased MDM2 expression that in turn depleted p53 and thereby conferred chemoresistance."
"Although Chlamydia infection alone conferred significant resistance to TNF-alpha-induced apoptosis, inhibition of MDM2 mediated degradation of p53 with Nutlin3a was sufficient to partly reverse this phenotype (XREF_FIG)."
"MDM2 inhibits p53 functions via several different mechanisms: MDM2 interacts with and conceals the N-terminal transcriptional activation domain of p53."
"As previously mentioned, various studies have shown that MDM2 largely inhibits and degrades p53 by ubiquitinating it, causing its nuclear export and ultimate degradation."
"Mdm2 is known to promote ubiquitin dependent degradation of p53 [XREF_BIBR]."
"Under basal conditions, p53 is degraded by the E3 ubiquitin ligase MDM2 and transcriptionally inactivated at promoters by its enzymatically inactive homolog MDMX [XREF_BIBR - XREF_BIBR]."
"It had long been thought that the inability of MDM2 to degrade mutp53 was the main cause for mutp53 protein accumulation in tumors."
"Murine double minute 2 (MDM2) is a key negative regulator of p53 and its expression; inhibition of MDM2 is postulated to reactivate WT-p53 and its tumor suppressor functions."
"Optimal degradation of p53 by Mdm2 requires heterodimer formation via RING domain interaction with its paralog, Mdm4, in higher eukaryotes XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR."
"As it is known that NPM1 interacts with the E3 ligase HDM2 and reduces HDM2 mediated p53 degradation, we examined whether SAMD12-AS1 can affect p53 stability."
"As indicated above, Mdm2 inhibits p53, but in turn, overexpression of p53 can activate Mdm2 xref , resulting in a subsequent decrease in p53 levels."
"Under normal physiological conditions, MDM2 inhibits p53 by binding to its transcriptional activation domain xref and by promoting its degradation via an E3-ubiquitin ligase activity xref maintaining low steady-state levels of p53 expression."
"9 STAT1 can also block mdm2, a molecule that inhibits p53 transcriptional activity and stimulates its degradation."
"Mdm2 over-expression in tumours is reminiscent of p53 mutations with gain of function, in that Mdm2 both transforms cells and inhibits p53 activity."
"Roughly one third of all human cancers are attributable to the functional inhibition of the tumor suppressor protein p53 by its two negative regulators MDM2 and MDMX, making dual-specificity peptide antagonists of MDM2 and MDMX highly attractive drug candidates for anticancer therapy."
"We found that in addition to the well-known abilities of MDM2 and MDMX to inhibit the p53 function, MDM2 and MDMX co-expression stabilizes AR."
"Inhibition of p53 as well as other components of the DNA damage response by Mdm2 and Mdmx can result in delayed DNA repair and increased genome instability, making Mdm2 and Mdmx a danger to the genome when aberrantly expressed."
"For instance, HIPK2 was shown to be proapoptotic in response to UV light exposure through direct phosphorylation of p53 at Serine 46, preventing MDM2 mediated p53 degradation and ultimately leading to activation of p53 dependent apoptotic pathways."
"PP2A inactivates MDM2 by dephosphorylating it; in its inactive state, MDM2 cannot bind and inactivate p53 [ xref ]."
"In addition, more research is necessary to assess the spatial and temporal pattern of p53 inhibition by Mdm2 in the lens."
"XREF_BIBR - XREF_BIBR In the p14 ARF -MDM2-p53 pathway, MDM2 negatively regulates p53 via several different mechanisms, including inhibition of p53 mediated transcriptional activity through binding with the p53 trans-activation domain and degradation of p53 through directly functioning as an E3 ubiquitin ligase or shuttling p53 from nucleus to cytoplasm to expose it to proteasome."
"Therefore, MDM2 mediated degradation of p53 in Chlamydia infected cells contributes to the anti-apoptotic influence upon the host cell."
"Levels rise precipitously in response to DNA damage, and WT p53 is then downregulated by MDM2."
"35 The resulting MDM2 activation promotes degradation of p53 through ubiquitinization in an early stage of pancreatic carcinogenesis causing faster progression of Pan-IN lesions to an invasive tumor."
"Thus, SAHA ultimately inhibits HSP90 activity, releasing mutp53 from the HDAC6, HSP90, and mutp53 complex, enabling mutp53 degradation by MDM2 and CHIP [XREF_BIBR]."
"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 ]."
"Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo."
"It is plausible that tumour cells in which high levels of MDM2 suppress p53 may allow E1B deleted adenovirus replication."
"Genetic disruption of MDM2 in adipocytes triggers canonical p53 mediated apoptotic and senescent programs, leading to age dependent lipodystrophy and its associated metabolic disorders including type 2 diabetes, non alcoholic fatty liver disease, hyperlipidemia and energy imbalance."
"p53 is inhibited by Mdm2, a ubiquitin ligase that is often overexpressed in tumors [XREF_BIBR]."
"Thus, alerted levels of MDM2, MDM4, or WIP1, which are often mutually exclusive with p53 mutations, could attenuate p53 function in tumor suppression."
"In most cancers, the p53 pathway is inactivated by mutation of TP53 or CDKN2A ARF, or by amplification of MDM2."
"Through binding to p53 at its N-terminal transactivation domain, mdm2 directly blocks the transcriptional activation function of p53."
"MDM2 hyperactivity, due to amplification and overexpression or mutational inactivation of the ARF locus, inhibits the function of wild-type p53 and can lead to the development of a wide variety of cancers."
"Subsequently, this p53 mediated increase in MDM2 expression will begin to degrade p53 and repress its function, which is part of mechanism for the development of chemoresistance."
"This offers the possibility of distinct regulation of p53 and Mdmx inhibition by Mdm2."
"Mdm2, by acting as an E3 ubiquitin ligase, down-regulates p53 through proteasome mediated degradation."
"Phosphorylation of HDM2 on serine 166 by AKT has been shown to enhance HDM2 activity and promote the degradation of p53."
"It was recently shown that MYCN directed centrosome amplification, leading to increased tumorigenesis, requires MDM2 mediated suppression of p53 activity in Neuroblastoma cells."
"Not only does Mdm2 promote proteasomal degradation of p53, but it also inhibits the transactivation domain of the tumor suppressor protein 89."
"MYCN directed centrosome amplification requires MDM2 mediated suppression of p53 activity in neuroblastoma cells."
"Small-molecule inhibitors of the p53 suppressor HDM2 : have protein protein interactions come of age as drug targets?"
"These data suggest that nutlin-3A stabilized p53 by preventing MDM2 mediated p53 degradation in HRS cells."
"The reduction of MDM2 may be associated with the increase of p53, suggesting the suppression of p53 by MDM2 that may have been eliminated by exercise."
"However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53."
"Because nutlin-3a is known to induce p53 by blocking MDM2 mediated p53 degradation without inducing DNA damage, our data suggested that increased p53 expression without DNA damage does not efficiently induce apoptosis in ESCs (XREF_FIG A-7C); however, such an increase strongly inhibited differentiation (XREF_FIG J-4L)."
"MDM2 inhibits p53 mediated transcriptional activity by direct binding to the DNA binding motif of p53 and by ubiquitination of p53, which results in nuclear export to the cytoplasm."
"Negative regulation of HDM2 to attenuate p53 degradation by ribosomal protein L26."
"We discovered a novel mechanism in pterygium whereby MDM2 suppresses p53 transcriptional activity despite abundant p53 in pterygium."
"T --> G single-nucleotide polymorphism at position 309 (SNP309) of mdm2 induces overexpression of mdm2, but inhibits p53."
"If the MDM2 feed-back inhibition of p53 is interrupted, a significant increase in functional p53 levels will increase p53-mediated therapeutic effectiveness."
"MDM2 suppresses wild type TP53 leading to a more or less impaired but still specific transcriptional activity [XREF_BIBR]."
"Under unstressed conditions, p53 is negatively regulated by Mdm2 that binds to and inhibits p53 activity and leads to its degradation by the ubiquitination mediated proteasomal pathway."
"Indeed, a recent study identified a positive feedback loop between Roralpha and p53, in which after gamma irradiation, p53 active induces the expression of Roralpha and increased RORalpha protein inhibits the Mdm2 dependent degradation of p53 XREF_BIBR, XREF_BIBR."
"Mdm2 degrades p53 following upregulation of the MDM2 promoter by elevated p53 levels."
"Our real-time PCR finding is consistent with recent reports by Bond et al. and Hong et al [XREF_BIBR, XREF_BIBR] that the MDM2 309GG genotype carriers had significantly higher MDM2 expression in NPC tissues than the TT and TG genotype carriers, suggesting the variant MDM2 genotype may cause attenuated TP53 function."
"p53 in HepG2 cells was either downregulated by short hairpin (sh) RNA or activated by Nutlin-3a treatment, which inhibits p53 degradation mediated by MDM2."
"Indeed, growth-inhibitory forms of NIAM also bind to Mdm2, and increased NIAM expression levels disrupt p53-Mdm2 association, inhibit p53 polyubiquitylation, and prevent Mdm2 mediated inhibition of p53 transcriptional activity."
"MDM2 inhibits the P53 pathway by inducing P53 ubiquitination [XREF_BIBR]."
"The inhibition and degradation of p53 by MDM2 are subjected to negative regulation by ARF [19,20] , which sequesters MDM2 to the nucleolus [21,22] ."
"The repression of p53 by HDM2 and HDMX is non overlapping, because neither regulator can compensate for the embryonic lethality caused by the loss of the other [XREF_BIBR]."
"For instance, Mdm2 primarily degrades p53 in unstressed cells, but Pirh2 is able to degrade p53 upon DNA damage."
"Also, the expression of MDM2, an oncoprotein that degrades p53, is often amplified or overexpressed in human glioblastoma multiforme but is low in this mouse model of glioblastoma multiforme (XREF_SUPPLEMENTARY), probably because p53 expression is low in the tumor (XREF_SUPPLEMENTARY) and MDM2 is known to be transcriptionally activated by p53."
"Degradation of p53 by Mdm2 has been reported to be critical for CD4 + T cell proliferation on TCR stimulation XREF_BIBR."
"Levels of p53 are tightly regulated by MDM2, whereby elevated levels of p53 activate MDM2 expression, which in turn sequesters p53, ubiquinates it and marks it for proteasomal degradation."
"Particularly, MDM4-211 seems to function as an inhibitor of MDM2 degradative function causing stabilization of p53 in addition to MDM2."
"Furthermore, the MDM2 C-terminus acts as an E3 ubiquitin ligase, mediating the degradation of p53."
"In these series of elegant studies, investigators identified that low levels of MDM2 induced mono-ubiquitination and nuclear export of p53, whereas high levels of MDM2 promoted poly-ubiquitination and nuclear degradation of p53 [XREF_BIBR]."
"Intriguingly, it 's reported that both Mdm2 and Notch1 can antagonize p53 by promoting its degradation."
"This may indicate sufficient degradation of P53 by MDM2 alone."
"In cells treated only by PEPD siRNA, it seems likely that increase in MDM2 mediated degradation of nuclear and cytosolic p53 is offset by p53 translocation to mitochondria."
"It binds in the p53 binding pocket of HDM2 to block the HDM2 directed degradation of p53."
"MDM2 negatively regulates p53 activity through the induction of p53 protein degradation."
"We discuss two such loops, one involving the beta catenin protein and the other centering on the Akt/protein kinase B. In both cases, the central module is the interplay between p53 and the murine double minute 2 (Mdm2) protein, which inactivates p53 and targets it for rapid proteolysis."
"MDM2 and MDMX can also inhibit p53 independently of each other."
"Moreover, when transfected together, MYL6B and MDM2 synergistically down-regulated the level of p53 protein."
"Mdm2 is an E3 ubiquitin ligase for p53, and degrades p53 protein in a proteasome dependent manner [XREF_BIBR], suggesting that sentrin-1 is able to modulate the apoptotic pathway in RA synovial tissues."
"Akt also phosphorylates and activates the E3 ubiquitin ligase murine double minute 2 (MDM2), which triggers p53 degradation."
"Recently, the MDM2 homologue MDM4 has been shown to also inhibit p53 in cardiomyocytes."
"Src also reduces p53 levels in a different way; Src inactivates the phosphatase PP2A by phosphorylating Tyr307, leading to MDM2 mediated p53 degradation through an increase in MDM2 phosphorylation at Ser166, which enhances its interaction with p53 [XREF_BIBR]."
"XREF_BIBR In unstimulated cells, p53 is restrained by its target gene Mdm2 which promotes p53 degradation."
"In wild-type cells, p53 is often suppressed and destabilized by mdm2, mdm4, and mdmx which behave like E3 ligases, marking P53 by ubiquitination for degradation."
"Our work on the design of ultrahigh affinity D-peptide antagonists of MDM2 and MDMX to activate the p53 tumor suppressor may spearhead the development of new classes of anticancer therapeutics."
"Finally, p53 was also inactivated by the frequent deletion of CDNK2A and the overexpression of MDM2 in ALL patients."
"This study called into question two major dogmas about Mdm2 by suggesting that when endogenously expressed, (1) Mdm2 cannot inhibit p53 sufficiently by binding without ubiquitination, and (2) Mdm2 may not be regulated by autoubiquitination."
"Because MDM2 is an important inhibitor of the tumor suppressor p53, and because the overexpression of MDM2 occurs in a variety of cancers, many efforts have been made to target the MDM2-p53 interaction, in order to prevent its apparent promotion of cancer and improve the power of anticancer therapies."
"Moreover, E343K mutation in two hotspot R175H and R248W mutp53 results in enhanced degradation of mutp53 by MDM2."
"The oncoprotein MDM2 (murine double minute 2) is often overexpressed in human tumors and thereby attenuates the function of the tumor suppressor p53."
"A previous study showed that Mdm2 mediated p53 degradation could be inhibited by the ectopic expression of Abl or a kinase defective Abl."
"Adp53 gene therapy, as well as small molecules, such as PRIMA-1 and PRIMA-1 MET, which can restore the transcriptional function of mutant TP53, or RITA, which interferes with MDM2 directed TP53 degradation, has been tested in a preclinical setting, and some of these approaches are currently in clinical development."
"In cells with high MDM4 expression, knockdown of MDM4 or MDM2 reactivated TP53, and simultaneous knockdown of MDM2 and MDM4 synergistically reactivated TP53."
"For example, NOTCH1 signaling can inhibit Akt and Hdm2 mediated p53 degradation and sensitizes human hepatocellular carcinoma (HCC) cells to TRAIL induced apoptosis."
"By blocking the p53 binding cleft of MDM2, nutlins inhibit MDM2 mediated degradation of wild-type p53, increasing p53 transcriptional activity."
"MDM2, as p53 specific E3 ubiquitin ligase, can promote p53 protein degradation [XREF_BIBR]."
"Suppression of the p300 dependent mdm2 negative-feedback loop induces the p53 apoptotic function."
"The Mdm2 interacting protein Mdm4 (also known as MdmX) also negatively regulates the tumor suppressor function of p53 by binding and masking the amino terminal transcriptional activation domain of p53."
"We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis."
"This mechanism takes place through the protein MDM2 degrading the protein p53 by an E3 ubiquitin ligase activity."
"Thus far, these studies together suggest that Mdm2 inhibits p53 activity in both proliferative and fully differentiated cells in all tissues analyzed."
"TP53 inactivation via mutation is known to occur in less than 2% of primary neuroblastomas [XREF_BIBR - XREF_BIBR], but TP53 function can also be disrupted by deregulated MDM2 expression."
"Cre mediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90MDM2 constitutively regulates both the activity and the level of p53 in homeostatic tissues."
"Taken together, these results indicate that in thyroid cancer cells, TAp73alpha is able to increase p53 protein level and function by interfering with Mdm2 mediated p53 degradation."
"Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53."
"P53 and MDM-2 form a feedback control loop : while P53 can transactivate the MDM-2 gene, high levels of MDM-2 inhibit P53 transactivation as well as promote rapid degradation of P53."
"While both MDM2 and MDM4 inhibits p53 by direct binding and masking of its transactivation domain [ xref – xref ], only MDM2 possesses E3 ubiquitin ligase activity and may downregulate p53 by targeting it for ubiquitin-proteasome-dependent degradation [ xref – xref ]."
"In Skp2B overexpressing cells (XREF_FIG), native p53 is rapidly degraded by Mdm2 and the denatured p53 fraction contributes to the elevated level of total p53 observed in these cells."
"p53 inhibition by MDM2 in human pterygium."
"The INK4a and ARF locus sits at the nexus of these two growth-control pathways, by virtue of its ability to generate two distinct products : the p16INK4a protein, a cyclin dependent kinase inhibitor that functions upstream of RB; and the p19ARF protein, which blocks MDM2 inhibition of p53 activity."
"Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome dependent degradation."
"The pRb-Mdm2 interaction is able to inhibit Mdm2 mediated p53 degradation, but does not remove the ability of Mdm2 to inhibit p53 transactivation of its target genes [XREF_BIBR]."
"For instance, a rapid onset of aneuploidy is observed when the adenovirus oncoprotein E1A or oncogenic H-RasV12 are expressed either in p53-null cells or in cells in which p53 is inactivated by overexpression of Mdm2."
"The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation."
"Because MDM2 plays a primary role in inhibition of the p53 tumor suppressor function and antagonizes p53 through their direct interaction, blockade of the MDM2-p53 protein protein interaction would liberate p53 from MDM2, thus restoring the tumor suppressor function of wild-type p53."
"Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53."
"The reduction of phosphorylated p53 might be involved in MYR induced cytotoxicity, as phosphorylated p53 inhibits the interaction of p53 with MDM2, a negative regulator of p53, thereby preventing degradation of p53 protein."
"Not surprisingly, impairment of the p53 pathway is a hallmark of almost all human cancers, where either the TP53 gene is mutated or wild-type p53 is functionally inactivated by the E3 ubiquitin ligase MDM2 and its homolog MDMX [ xref , xref ]."
"AKT mediated phosphorylation of MDM2 promotes its nuclear localization and enhanced p53 degradation, and represents an important pro survival effect of AKT."
"Mdm4 p53 binding protein homolog (MDM4) which structurally has homology with MDM2, can collaborate with MDM2 to inhibit p53 activity when cell responses to DNA damage (Wade et al., 2010)."
"Inhibition of MDM2 can restore p53 activity in cancers containing wild-type p53, leading to anti-tumor effects with apoptosis and growth inhibition [XREF_BIBR - XREF_BIBR]."
"XREF_BIBR, XREF_BIBR Other functions include the phosphorylation and degradation of the inhibitor of kappaB (IkappaB), and which results in increased nuclear factor kappa B (NF-kappabeta) activity and transcriptional stimulation of pro survival genes, 91 it also modulates MDM2, which inhibits P53 (an activator of cell-cycle arrest)."
"In this study, we first investigated the ability of HDM2 (MDM2 human homologue) to degrade endogenous p53 in neuroblastoma (NB)."
"Two anti-apoptotic genes, Mdm2 (antagonist of p53) and Bcl-2 (inhibitor of Bax), were down-regulated, and the activity of capspase-9 and caspase-3 was significantly increased."
"XREF_BIBR In addition, Mdm2 has been recently reported to complex with Nbs1, a component of the Mre11 and Rad50 / Nbs1 DNA repair complex and can inhibit DNA break repair in p53 deficient cells."
"Overall, MDM2 and MDMX deletion models have suggested the following notions about MDM2- and MDMX mediated p53 regulation : (i) MDM2 is the master regulator of p53 and is necessary to prevent p53 dependent cell death at all stages following embryonic day 5; (ii) MDMX may serve to enhance MDM2 mediated p53 inhibition and/or degradation in a developmental and tissue specific manner."
"The main oncogenic function of MDM2 is to inhibit the tumor suppressor p53 [XREF_BIBR - XREF_BIBR]; thus, p53 function becomes inactivated in MDM2 overexpressing cells, resulting in cancer cell growth and disease progression."
"Here we demonstrate that, using nonphosphorylatable mutants of Mdmx, the cooperative inhibition of p53 by Mdmx and Mdm2 was associated with cytoplasmic localization of p53, and with an increase of the interaction of Mdmx to p53 and Mdm2 in the cytoplasm."
"These results demonstrate that an additional mechanism of p53 inactivation by MDM2 is to inhibit p53 acetylation by p300."
"Overexpression of p76 (MDM2) antagonizes the ability of p90 (MDM2) to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53."
"Cyclin dependent kinase inhibitor 2A blocks MDM2 mediated degradation of p53."
"Amplification of the p53 antagonists MDM2 and MDM4have also been found in distinct subsets of Tp53 intactGBMs, as well as mutations and/or deletions inthe CDKN2A second locus that encodes p14ARF which is a regulator of p53."
"The discovery of Mdm2 as both a target of p53 transcriptional activation and a factor that inhibits p53 transactivation led to the definition of a novel negative feedback loop in the signaling pathway and another level of regulation on p53 functions."
"We propose a model in which these miRNAs are : 1) regulators of the auto-regulatory loop, increasing the window of time between p53 apoptotic action and p53 degradation by MDM2; and 2) at the same time targeting the IGF axis, antagonizing the MDM2 ubiquitin ligase function on IGF-1R (XREF_FIG)."
"MDM2 is a known inhibitor of the tumor suppressor p53; it acts as an E3 ligase that promotes p53 degradation through a ubiquitin dependent pathway XREF_BIBR."
"MDM2 is a pivotal E3 ubiquitin ligase and suppresses p53 by proteasomal degradation and transcriptional inactivation [XREF_BIBR]."
"We found that the small molecules Nutlin and RITA could both relieve the MDM2 dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions."
"Preventing the central domain of MDM2 from folding would likely interfere with MDM2 mediated p53 degradation."
"MDM2 not only rapidly degrades p53 through its E3 ubiquitin ligase activity but is also up-regulated by p53 at the transcriptional level as a negative feedback loop of p53 activity."
"One prominent example is that, in response to oncogene activation, p14ARF activates p53 by inhibiting the ubiquitin ligase activity of HDM2 and relieving HDM2-dependent inhibition of p53 ( xref )."
"Mechanisticly, impairment of any step of ribosome biogenesis leads to redirection of the nascent IRBC from the assembly into pre-60S ribosomes towards inhibition of MDM2, the E3 ligase that negatively regulates p53 [XREF_BIBR - XREF_BIBR]."
"ARF activates p53 by sequestering Mdm2, an E3 ubiquitin ligase, to the nucleolus, thereby inhibiting the Mdm2 mediated proteasomal degradation of p53."
"Because the cleft in mdm2 is contacted by only three amino acids in p53 (Phe19, Leu26 and Trp23), it was reasoned that small molecules that mimicked these amino acids might be able to disrupt the p53 and mdm2 complex in tumor cells where overexpression of mdm2 inactivates p53."
"MDM2 inhibits p53 by preventing its interaction with the general transcription machinery and targeting it for ubiquitin-mediated degradation."
"p14 stabilises p53 by preventing MDM2 mediated degradation of p53 (XREF_FIG)."
"However, it remains possible that increased DNA damage-induced p53 activity in WT thymi is caused not only by reduced Mdm2-mediated p53 degradation (due to destabilization of Mdm2) but also by reduced Mdm2 steric inhibition of p53."
"In turn, MDM2 protein binds to the N-terminal transactivation domain of p53 and inhibits p53, primarily by promoting its ubiquitination and subsequent degradation by the proteasome [XREF_BIBR]."
"In this case, MDM2 acts as an oncogene, degrade p53 by ubiquitinylation, and blocks the normal cell cycle."
"Mdm-2 failed to induce p53 degradation under these conditions."
"The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53."
"HDM2 blocks p53 by binding to its transcription domain and reduces its levels acting as an E3 ubiquitin ligase polyubiquitinating p53 and targeting it for degradation XREF_BIBR XREF_BIBR."
"Therefore, only wild type p53 can be inhibited by the MDM2."
"It is known that caspase cleaved c-Abl can phosphorylate the p53 E3 ligase, Mdm2, to inhibit Mdm2 dependent degradation of p53 and allow it to accumulate XREF_BIBR."
"Moreover, MDM2 acts like a E3 ubiquitin ligase, mediating p53 degradation in a proteasome dependent manner."
"However, p53 target genes were not activated in the infected cells, although p53 phosphorylation did occur and the p53 antagonists Mdm2 and deltaNp73 did not accumulate."
"XREF_BIBR The elevated levels of MDM2 protein in carriers of the G-allele will inhibit the p53 induced apoptotic responses to DNA-damage, thereby resulting in genetic instability (such as gene mutations in the cells) and eventually leading to tumorigenesis at a young age."
"Other studies in non Nigerian patients have shown that p53 in ameloblastoma are mostly suppressed by MDM2 and not mutated."
"MDM2 promotes degradation of TP53, thus inhibiting this interaction with Nutlin-3a effectively stabilizes TP53."
"One prominent example is that, in response to oncogene activation, p14ARF activates p53 by inhibiting the ubiquitin ligase activity of HDM2 and relieving HDM2 dependent inhibition of p53."
"Insulin like growth factor I induces MDM2 dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage."
"To our best knowledge, HDM2 could inhibit p53 function and increase p53 ubiquination, and p53 could induce proteins of caspase family to increase cell apoptosis."
"Recent evidence has established that MDM2, a RING oncoprotein and a negative regulator of p53 [XREF_BIBR], modulates the proteasomal degradation of p53 via a RING-finger-dependent manner [XREF_BIBR - XREF_BIBR]."
"Interestingly, the p53 mutation found in this LFS family is localized to the p53 region that we have recently identified as necessary for Mdm2 mediated p53 degradation."
"Mechanistically, by occupying the p53 pocket in MDM2 (XREF_FIG), an MDM2 inhibitor blocks p53-MDM2 interaction and consequently the MDM2 mediated p53 protein degradation, leading to p53 accumulation and transcriptional activation in cells with wild-type p53 but not in cells with mutated or deleted p53."
"In view of these results, we further examined the inhibitory activity of Nutlin-3, a small-molecule antagonist of MDM2 that inhibits MDM2 mediated degradation of p53 [XREF_BIBR, XREF_BIBR], against K562 and K562G cell lines."
"Thus, Mdm2 negatively regulates p53 by both suppression of transactivation and post-translational destabilization."
"Mdm2 inhibition of p53 induces E2F1 transactivation via p21."
"In epithelial cells exposed to high score PSF, RYBP levels are low leading to elevated levels of Mdm2, which then degrades wild type p53 (XREF_FIG)."
"Wild-type (WT) p53 activity can also be abrogated by endogenous MDM2 or viral proteins; the human papilloma virus E6 protein, SV-40 large T antigen and adenovirus E1B-55kDa proteins can bind and attenuate p53 activity resulting in cellular transformation."
"Inhibition of MDM2 in response to stress underlies the activation of wild-type p53, but is also thought to lead to the overexpression of mutant p53 seen in cancer cells."
"Although wild-type p53 is expressed in approximately 50% of patients with cancer, it remains dysfunctional in these tumor cells because of abnormally elevated levels of p53 suppressors such as MDM2, MDMX, SIRT1, and HDACs [XREF_BIBR - XREF_BIBR]."
"Moreover, the half-life of p53 in p19 Arf-/-; Pten Delta and Delta cells was similar to that in Wt cells (XREF_FIG), further supporting the notion that p53 increase induced by Pten deletion is independent from the inhibition of Mdm2 mediated p53 degradation by p19 Arf."
"We have observed that isoproterenol infusion leads to lowering of p53 levels, and have elucidated a molecular mechanism whereby ARRB1 regulates MDM2 dependent degradation of p53 upon beta 2 -adrenoreceptor stimulation."
"HDM2 is an important negative regulator of p53 (promotes degradation of p53) and small-molecule inhibitors of HDM2 can trigger apoptosis in cells with intact p53 function by activating p53."
"It is intriguing that in this negative feedback loop Mdm2 downregulates p53 through a post-translational mechanism (protein degradation), which is not as energy efficient as transcriptional repression because p53 is being produced and actively degraded simultaneously."
"In addition, results of biochemical studies have suggested that MDMX inhibits MDM2 mediated p53 degradation, thus contradicting its role as defined in gene knockout experiments."
"We demonstrate that p53 and p73 are inhibited by both MDM2 and MDMX, but p63 does not interact with MDM2 or MDMX."
"Thus, we conclude that p53 protein is activated after IL-3 deprivation by loss of MDM2."
"Consequently, even if some cancer cells have wild-type TP53, the overexpressing MDM2 prevents activation of TP53 mediated apoptotic program."
"The oncoprotein MDM2 suppresses p53 activity by direct inhibition of its transcriptional activity and enhances the degradation of p53 via the ubiquitin-proteosome pathway."
"The enhanced rRNA transcription stimulated the MDM2 mediated proteasomal degradation of p53, by reducing the availability of ribosome proteins for MDM2 binding."
"As RPL26 binds to the 5 ' UTR of p53 mRNA and effects the translation of p53, we examined overexpression of RPL26 's effect on HDM2 mediated p53 degradation by introducing exogenous proteins into p53 deficient human non-small-cell carcinoma H1299 cells."
"Although it is known that the MDM2-p53 interaction is controlled by an autoregulatory loop and that the MDM2 mediated degradation of p53 is dependent upon the cellular level of MDM2, the mechanisms regulating this interaction appear to be complex and are poorly understood."
"MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome dependent p53 degradation."
"Given that suppression of P53 increases the efficiency of hiPSC generation up to 10-20 fold [XREF_BIBR], inactivation of P53 by Mdm2 in healthy hPSCs may be crucial for their survival and maintenance."
"Fascinatingly, this suggests that while Mdm2 negatively regulates p53 on the protein level, it is a positive regulator of p53 on the mRNA level."
"Several strategies have been designed to restore p53 function in human tumors, including p53 gene therapy, reactivation of mutant p53, and activation of wild type p53 by inhibition of the p53 antagonist MDM2."
"The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, and are important molecular targets for anticancer therapy."
"The activated AKT phosphorylated MDM2 at Ser (166) and promoted degradation of the tumor suppressor p53."
"On the basis of our study, it is easy to comprehend that Mdm2 might be required to inhibit p53 activity in stem cells after DNA damage."
"It has been hypothesized that the MDM4-A protein can act as an oncogene by enhancing the MDM2 mediated degradation of p53 XREF_BIBR."
"Deacetylation could serve as an important step to allow Mdm2 mediated p53 degradation, given that acetylation of p53 inhibits p53 ubiquitination by Mdm2 in vivo and in vitro."
"Of note, MDM2 accumulation does not cause p53 degradation in the context of (-)-Nutlin-3 treatment because this drug interferes with the binding of MDM2 to p53."
"The MDM2 rs2279744 polymorphism has been reported to suppress the p53 pathway via the modulation of MDM2 expression."
"There has been extensive validation of MDM2 and MDMX as a target showing that even a small reduction in MDM2 is significant enough to increase p53 activity."
"In mouse embryo fibroblasts and lymphoblasts, this DNA-PKc/Akt/GSK3a/Mdm2 signaling pathway prevented Mdm2 mediated p53 degradation."
"As a key protein involved in the process of DNA damage response, inhibition of p53 by MDM2 and MDM4 can result in delayed DNA repair [ xref – xref ]."
"An increase in MDM2 impairs p53 mediated arrest of the cell cycle allowing DNA replication and mitosis to proceed despite induced DNA damage [XREF_BIBR]."
"After ubiquitination by Mdm2, p53 is rapidly degraded by the proteasome."
"MDM2 protein negatively regulates p53 and is found to be elevated in cancer cells."
"Human cancers over-expressing mdm2, through a T to G variation at a single nucleotide polymorphism at position 309 (mdm2 SNP309), have functionally inactivated p53 that is not effectively degraded."
"The mRNA levels of murine double minute-2 (Mdm2), which mediates p53 degradation, Cu/Zn-superoxide dismutase (Sod1), and Mn-superoxide dismutase (Sod2), were also elevated and the antioxidant gene glutathione-S-transferase murine type-1 (Gstm1) was suppressed."
"However, differences in the requirements of E6/E6AP and Mdm2 to promote the degradation of p53, both in vivo and in vitro, suggest that these two E3 ligases may promote p53 degradation by distinct pathways."
"For example, overexpression of MDM2 promotes degradation of p53 [XREF_BIBR] while overexpression of TCTP (fortilin) blocks the binding of p53 with Bax and inhibits p53 dependent apoptosis [XREF_BIBR]."
"HDM2 binds to and inhibits the transcriptional activity of both p53 and p73; however, it only promotes ubiquitination and degradation of p53, and instead results in increased steady state levels of p73 XREF_BIBR."
"Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus, where Mdm2 decreases p53 transcriptional activity and hence diminishes cellular levels of p53 [XREF_BIBR]."
"Our findings suggest that p53 accumulation could be due to a decrease in full-length MDM2 isoform together with an increase of the 57-kDa MDM2 isoform that was unable to stimulate p53 degradation."
"In normal unstressed cells, these upstream pathways predominantly include the binding by proteins such as Mdm2 that promote p53 degradation via the ubiquitin-26S proteasome pathway [XREF_BIBR]."
"MDM2 inhibits TP53 in an ubiquitin-dependent manner [ xref ]."
"Furthermore, MDM2 can function as an E3 ligase to ubiquitinate p53 [XREF_BIBR] and degrade wild type p53."
"In line with the critical role for Mdm2 mediated degradation of p53 in favoring tumorigenesis, a specific Mdm2 inhibitor (MI-219) has been reported to synergize with oxaliplatin, which inhibits DNA synthesis, to exhibit superior anti-cancer effects in solid tumors types bearing wild-type p53 [XREF_BIBR]."
"Previous study showed that inhibition of P53 suppression by MDM2 in cancer cells promotes growth arrest, apoptosis and senescence in vitro and in vivo."
"Homozygotic SNP309 G/G carriers express higher levels of MDM2, which can subsequently attenuate the p53 pathway [XREF_BIBR]."
"MDM2 expression is induced by TP53, promoting p53 degradation and limiting its activity [XREF_BIBR]."
"These small molecule compounds disrupt Mdm2 mediated p53 degradation and thus lead to tumor regression by inducing p53 mediated cell cycle arrest and cell death [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
"MDM2 also directly represses p53 activity."
"In contrast, expression of HDM2 inhibited the exogenous p53 transcriptional activity, and co-expression of RPL26 alleviated exogenous HDM2 mediated p53 suppression in the MEF (p53 - / - / mdm2 - / -) cells (XREF_FIG C, lane 6 and 7)."
"Importantly, WIP1 suppresses p53 by multiple mechanisms, including dephosphorylation of p53 kinases (ATM, CHK1, CHK2), p53 itself (at serine 15), and MDM2, which facilitates MDM2 mediated degradation of p53."
"XREF_BIBR - XREF_BIBR MDM2 not only inhibits p53 dependent apoptosis, but also has p53 independent effects on apoptosis by affecting both pro apoptotic and anti-apoptotic proteins."
"In the latter case, TAp73alpha inhibits MDM2 mediated p53 protein degradation by reducing MDM2 binding to p53 and by directly antagonizing p53 activity on the MDM2 promoter (XREF_FIG B)."
"Third, mammary gland specific overexpression of Mdm2 in mice abrogated normal mammary gland development in a p53 independent manner and led to the formation of mammary tumours."
"[XREF_BIBR] The interaction of FHIT with MDM2 could interfere with the association of MDM2 and p53 and subsequently interrupting MDM2 mediated p53 degradation."
"We previously reported that RASSF6 blocks MDM2 mediated p53 degradation.17 We hypothesized that UNC119A regulates apoptosis and cell-cycle progression through RASSF6-MDM2-p53."
"The cellular MDM2 protein, for example, is able to inhibit p53 tumor suppressor function by concealing its transactivation domain."
"The prime goal of p53 based cancer therapy has been to increase levels of functional p53 and/or inhibit MDM2 levels to prevent further p53 degradation."
"From oncogenic point of view extremely important appears to be that action of these two genes is interrelated : Protein product of TP53 gene -- p53 protein -- has the ability to activate (a number of genes including) MDM2 gene, resulting in an increased production of mdm2 protein, which in turn inhibits p53 protein activity and by reducing its suppressor properties may initiate the process of carcinogenesis, including EC as well [XREF_BIBR]."
"Why would mammalian cells need so many proteins to overcome the negation of p53 by MDM2?"
"Since Mdm2 negatively regulates p53 ( xref ), and p53 inhibits the development of tetraploidy ( xref , xref , xref , xref , xref ), the polyploidy we observed in Mdm2 transgenic cells is likely due at least in part to inhibition of p53 by Mdm2."
"In the absence of stress, expression of Mdm2 is required to negatively regulate p53 activity in order to avoid p53 induced cell death."
"Therefore, increases in p53 levels are tightly regulated, mainly by its transcriptional target, mdm2, that downregulates p53."
"TP53 is degraded by MDM2, a ubiquitin ligase for TP53, and the MDM2 function is augmented by the kinase activity of Akt."
"Therefore, dysregulation of MDM2 is thought to decrease p53 activity, and in vitro studies with the MDM2 inhibitor nutlin showed that it could stabilize p53 and induce G 1 cell cycle arrest and apoptosis."
"Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest."
"This hypothesis is supported by recent studies showing that nutlin, a small molecule inhibitor of MDM2, can reactivate p53 function and induce cell death of retinoblastoma cells [XREF_BIBR, XREF_BIBR]."
"In normal unstressed cells, p53 protein is kept at a low level by its negative regulators, such as Mdm2, COP1 and Pirh2, which are E3 ubiquitin ligases for p53 and degrade p53 through the proteasome degradation pathway [XREF_BIBR, XREF_BIBR]."
"In our previous studies [XREF_BIBR], we demonstrated that (a) the basal level of endogenous p53 protein is much higher in mouse Ube4b null MEFs than in parental wild-type MEFs; indicating Ube4b plays a critical role in regulating basal level of p53 in unstressed conditions; (b) overexpression of mouse Ube4b decreased the level of p53 in Mdm2 null MEFs, suggesting that the Ube4b dependent Mdm2 mediated p53 degradation is not absolute."
"MDM2 isoform B (MDM2-B), the MDM2 isoform most frequently over-expressed in human tumors, interacts with full-length MDM2 to inhibit MDM2 mediated mutp53 degradation, promoting mutp53 accumulation and GOF in tumorigenesis."
"UBE4B promotes Hdm2 mediated degradation of the tumor suppressor p53."
"p53 and MDM2 form a negative feedback loop - p53 transcriptionally activates MDM2, while MDM2 degrades p53 via ubiquitination XREF_BIBR."
"In a non lethal stress response, Mdm2 also limits the duration and intensity of p53 activation."
"MDM2 was reported to inhibit p53 transcription function by blocking p53 surface that interact with the basal transcription factors such as TFIIE [XREF_BIBR]."
"p14ARF, on the other hand, by accumulating evidence is suggested to act as a tumour suppressor by neutralising MDM2 mediated degradation of p53 (Pomerantz et al, 1998; Stott et al, 1998; Zhang et al, 1998)."
"In response to stress, the MDM2 mediated p53 degradation is unleashed through various mechanisms, leading to p53 stabilization and activation."
"As MDM2 suppresses p53, it is not surprising that it should exhibit oncogenic activity and show over-expression in many primary tumors [XREF_BIBR, XREF_BIBR]."
"For example, a two-fold increase in Mdm2 expression due to a polymorphism in the Mdm2 gene reduces p53 activation enough to significantly increase the risk and decrease the age of onset for hormone dependent breast cancer in women [XREF_BIBR, XREF_BIBR]."
"ATM phosphorylates both p53 at Ser 15 (mouse Ser 18) and MDM2, an endogenous E3-ligase for p53, at Ser 395, resulting in an impairment of MDM2 mediated p53 degradation [XREF_BIBR]."
"Nevertheless, p19 Ink-4d has been shown to inhibit the MDM2 protein activity, leading to an increase in p53 activity since MDM2 inhibits p53 ( Chin et al., 1998; Pomerantz et al., 1998; Weber et al.,[MISSING/INVALID API KEY: limited to 200 char for Elsevier]"
"MDM2, a ubiquitin ligase, suppresses wild type TP53 via proteasome mediated degradation."
"This might indicate that Mdm2 can effectively antagonize p53 in some tissues."
"Our western blot data indicate that Bcl2 expression is up-regulated upon Mdm2 overexpression alone, likely due to Mdm2 mediated p53 degradation and transcriptional inhibition."
"MDM2 also acts as E3 ubiquitin ligase, promoting proteasome dependent p53 degradation; therefore, p53 and MDM2 regulate each other in an autoregulatory loop."
"BC cells with wild-type p53 often have high Mdm2 oncogenic expressions, which may block the p53 function."
"We found that Panx3 overexpression increased phosphorylation of Akt and Akt-downstream MDM2, and promoted the degradation of p53 in both C2C12 and calvarial cells (XREF_FIG, a and b)."
"First, when combined with the p53 neo allele, which expresses ~ 15% of wild type p53 levels, MEFs containing MDMX DeltaRING appear to display greater p53 activity with no difference in p53 stabilization compared to MEFs containing wild type MDMX, suggesting that MDMX does not necessarily contribute to MDM2 mediated p53 degradation."
"We confirmed that, by pharmacologically inhibiting Mdm2 mediated p53 degradation or genetically reducing Nedd4-2 in a mouse model, the GluA1 ubiquitination and down-regulation induced by chronically elevated neuronal activity are both attenuated."
"Repeat shRNA experiments confirmed the effect of YEATS4 knockdown seen in the arrayed screen (XREF_FIG), consistent with the hypothesis that YEATS4 and MDM2 amplification may cooperatively repress the p53 network in dedifferentiated liposarcoma, as recently suggested XREF_BIBR."
"To determine whether USP49 affects p53 degradation, we transfected HCT116 cells with p53 and MDM2 in the presence or absence of USP49 and found that USP49 drastically reduced MDM2 mediated p53 degradation."
"These results demonstrate that p53 is still subjected to Mdm2 mediated degradation in SMG7 knockout cells under DNA damage condition, indicating that SMG7 has an inhibitory effect on Mdm2 degradation of p53."
"Although TP53 and MDM2 often form a negative feedback loop by MDM2 inhibiting TP53 activity which results in transcriptional up-regulation of MDM2 expression, functions of MDM2 independent of TP53 have also been identified."
"The inhibition of Nrf2 also suppresses the expression of murine double minute (Mdm2), an oncogene which promotes p53 degradation, resulting in p53 pathway activation."
"Moreover, p53 is negatively regulated by MDM2 and the overexpression of MDM2 causes proliferation and survival of myeloma cells [XREF_BIBR, XREF_BIBR]."
"It is also unlikely that AKT signaling pathway promotes the p53 transactivation, since AKT is shown to enhance MDM2 mediated degradation of p53."
"Abnormal expression of MDM2 in tumors may attenuate the p53 mediated growth arrest and apoptosis response, resulting in increased cell proliferation and resistance to chemotherapy."
"Mdm2 is required to negatively regulate p53 activity at the peri implantation stage of early mouse development."
"28 Over-expression of hDM2 prevents p53 from exerting its pro apoptotic activity and so this PPI is a major target for cancer chemotherapy, with several examples of small molecule inhibitors reported."
"MDM2, an E3 ubiquitin ligase, inhibits p53 via poly-ubiquitination [ xref ] and by binding to p53's N-terminus, thereby shielding its transcription activation domain."
"Given that Mdm2 and Mdm4 inhibit p53 activities to promote tumor development, small molecules and peptides were developed to abrogate the inhibition of p53 by Mdm proteins."
"In the absence of HDM2-induction after the high dose of UV radiation p53-HDM2-interaction was promoted, but HDM2 failed to downregulate p53."
"Restriction of Mdm2 to the cytoplasm promotes p53 function and thereby sustains the sensitivity of cancer cells to chemotherapy."
"An important regulator of the p53 pathway is the MDM2 protein which is an E3 ubiquitin ligase that can inhibit p53 activity by promoting ubiquitination and degradation of p53 protein [XREF_BIBR]."
"Dual inhibition of MDM2 and MDM4 in virus positive Merkel cell carcinoma enhances the p53 response."
"This Mdm2 mediated degradation of p53 is absent in both Mdm2-null MEFs and those with the C462A mutation, which renders Mdm2 incapable of degrading p53."
"Because Mdm2 is a major physiological regulator of p53 function, we tested whether GIPC acts through Akt mediated Mdm2 phosphorylation to inhibit the apoptotic effects of p53 activity and subsequently increase cell survival."
"MDM2 can inhibit p53 activity by a variety of means."
"p14 AFR blocks MDM2 induced p53 degradation and p16 Ink4a inhibits CDK4 (6) which in turn prevents cells with functional Rb from entering S phase."
"While Mdm2 negatively regulates p53, Mdm2 also has p53 independent functions that negatively impact genome stability."
"Similarly, siRNA mediated knockdown of Mdm2 and Mdm4 in SMCs failed to induce p53 activity (XREF_SUPPLEMENTARY), which suggests that cultured SMCs do not require Mdm2/Mdm4 to restrain p53 activity."
"P53 and MDM2 form an autoregulatory feedback loop in which p53 transcriptionally activates the expression of MDM2 and MDM2 stimulates the degradation of p53, thereby controlling the levels of both proteins."
"p53 is strongly increased following the inhibition of CDK9 by reduced expression of MDM2, an ubiquitin-ligase which prevents accumulation of p53 [XREF_BIBR, XREF_BIBR]."
"Thereby, MDM2 impairs the transactivation function of p53 and targets it for proteasomal degradation."
"Taken together, our data support a model by which Mdm2 inhibition of p53 and p73 cooperate in lymphomagenesis via inhibition of apoptosis."
"However Mdm2 does not induce a significant degradation of p53 in yeast, but can bind to its transactivation domain."
"MDM2 and Flag-NIR individually were able to suppress p53 induced transactivation, as expected."
"The tumor suppressor ARF (murine p19 ARF and human p14 ARF) inhibits the p53 suppressor Mdm2, thus causing activation of p53."
"USF1 associates with p53 and inhibits MDM2 mediated p53 degradation."
"Interestingly, it was also shown that p300 can form a complex with Mdm2 in vitro and in vivo XREF_BIBR, XREF_BIBR and this complex (Mdm2-p300) facilitate Mdm2 mediated p53 degradation."
"Moreover, MDM2 inhibits p53 by binding to and concealing its N-terminal transcription activating domain."
"E3 ubiquitin protein ligase (MDM2) endogenously inhibits p53, and the disruption of an interaction between the p53 transactivation domain and MDM2 leads to the activation of p53."
"Degradation of MDM2 drives p53 stabilization and activation."
"MDM2 and p53 form a negative feedback loop, in which p53 as a transcription factor positively regulates MDM2 and MDM2 negatively regulates tumor suppressor p53 through promoting its degradation."
"Mdm2 also suppresses p53 transcriptional activity and shuttles p53 out of the nucleus."
"Dual Roles of MDM2 in the Regulation of p53 : Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity."
"This inhibition of p53 by MDM2 has been gracefully verified by TP53 and mdm2 double knockout studies ( xref , xref )."
"It also dephosphorylates MDM2 at Ser395 to stabilize MDM2 and enhances MDM2 mediated p53 degradation."
"Indeed, in the Bcl-2-sensitive pathway, transactivation dependent signalling is activated leading to a rapid MDM2 mediated degradation of p53."
"Because MDM2 is an inhibitor of p53, we investigated the consequences of nilotinib mediated downregulation of MDM2 on p53 expression."
"Persistent p53 expression in the presence of mdm-2 suggests that in testicular germ cell tumors, while mdm-2 can block the transactivation potential of p53, it can no longer target p53 for degradation."
"The importance of the C-terminal oligomerization domain to Mdm2 targeted degradation of p53 is likely to reflect the importance of oligomerization of the full-length p53 protein for interaction with Mdm2, as previously shown in vitro."
"Recent reports show that KSHV targets Mdm2 to deregulate the p53 tumor suppressor pathway XREF_BIBR, XREF_BIBR."
"DNA damage results in phosphorylation of p53, which is constitutively inhibited by Mdm2."
"This is consistent with the previous reports that activation of p53 by MDM2 and MDMX inhibitors inhibit cell growth [XREF_BIBR - XREF_BIBR]."
"The MDM2 oncogene is frequently amplified in many tumor tissues to functionally inactivate p53, suggesting that inhibition of MDM2 activity might provide a robust method for cancer prevention."
"Parallel experiments performed in H1299 cells transfected with suboptimal amounts of HEY1 and RPL11 expression plasmids allowed us to observe that HEY1 and RPL11 cooperate in preventing MDM2 mediated p53 degradation (XREF_FIG B)."
"The released Mdm2 may stimulate the proteasomal degradation of p53 leading to an attenuated apoptotic response to stresses."
"MDM2 negatively regulates p53, and recent studies have shown that the ability of MDM2 to act as a ubiquitin ligase targeting p53 for degradation by the proteasomes is essential for this."
"The difference in hepatic injury is likely unattributable to diminished DEN cytotoxity in p53 +/- rats as expression of CYP2E1, which is responsible for DEN bioactivation in hepatocytes, 14 did not differ between wild-type and p53 +/- rats, whereas the induction of p53 target gene, Mdm2 by DEN, was significantly suppressed in p53 +/- and p53 - / - rats (XREF_SUPPLEMENTARY."
"In addition to the association of p53 aggregation and chemoresistance in HGSOC cells, we further demonstrated that the overexpression of a p53 positive regulator, p14ARF, inhibited MDM2 mediated p53 degradation and led to the imbalance of p53 turnover that promoted the formation of p53 aggregates."
"The activation of p53 by PAHs alleviates MDM2 dependent inhibition of p53 activity XREF_BIBR and further controls the cell cycle and regulated apoptosis in mammalian cells XREF_BIBR, XREF_BIBR."
"Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis."
"RPL26 was found to increase the translational rate of p53 mRNA by binding to its 5 ' untranslated region (UTR) and, in this case, MDM2 acts as a ubiquitin E3 ligase for ubiquitylation and degradation of RPL26, hence inhibiting p53 translation."
"Our finding that lenalidomide not only disrupts RPS14 association with MDM2, but also stabilizes MDM2 to promote p53 proteasomal degradation in del (5q) progenitors, suggests that strategies to induce or enhance MDM2 activity may restore effective erythropoiesis in disorders affecting integrity of ribosomal biogenesis."
"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."
"MDM2 inhibits P53 transcriptional activity and thereby results in accelerated tumor formation."
"Although several in vitro studies suggest that MDMX may facilitate MDM2 mediated p53 degradation, we still do not have a clear understanding of whether this occurs in vivo."
"p53 can upregulate the Mdm2 gene, while elevated levels of p53 can signal Mdm2 downregulation of p53 via ubiquitination and proteosomal degradation maintaining normal p53 steady state levels through a negative feedback loop [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."
"The Mdm2 protein inactivates p53 by binding to its transcription activation domain [ xref ]."
"Although the major function of Mdm2 is to suppress p53 activities, emerging evidence has identified p53 independent roles of Mdm2 in tumor formation and progression."
"N-terminal 130 amino acids of MDM2 are sufficient to inhibit p53 mediated transcriptional activation."
"Together, these experiments show that ARF functions through Tp53 dependent mechanisms to inhibit fin regeneration, and also demonstrate the importance of active suppression of Tp53 by Mdm2."
"Furthermore PI3K and Akt, via the mTOR kinase, promote the translation and nuclear import of Mdm2, which inhibits TP53 activity both in vitro and in vivo [XREF_BIBR]."
"Previous studies employing latently KSHV infected cells have shown that inhibition of MDM2 by Nutlin-3, as well as genetic knockdown of MDM2 [XREF_BIBR], result in activation of the tumor suppressor p53 pathway and stabilization of K-Rta leading to cell cycle arrest, massive cell death and disruption of viral latency."
"It has therefore been suggested that MDM2 acts to inhibit p53 by concealing its activation domain from the basal machinery."
"Mdm2 reduces the physical association of p53 with the ApoCIII promoter, which may contribute to its efficient antagonism of p53 's inhibition."
"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 )."
"As described above, p14 ARF restrains cell growth by binding and abrogating MDM2 inhibition of p53 activity, and therefore facilitates p53 mediated cell cycle arrest and apoptosis [XREF_BIBR]."
"For instance, MDM2 promotes p53 degradation, XREF_BIBR and p53 also regulates Smad protein activities, XREF_BIBR, XREF_BIBR suggesting a role for p53 as a link between MDM2 and Smad signaling in LAC."
"MDM2 suppresses the transcriptional activity of p53 by binding to the transactivation domain of p53 [XREF_BIBR]."
"MDM2 inactivates p53 via direct binding or its E3 ubiquitin ligase activity, which targets p53 for proteasomal degradation."
"Overexpressed LRF suppresses the transcription of p14ARF so that Mdm2 is no longer deactivated by p14ARF, leaving p53 to continue the cellular growth process."
"Thus, oncogene induced replication stress and genotoxic insults ensue DNA damage responses that impair the nucleolar interaction of ARF with NPM, leading to the release of ARF to the nucleoplasm where it binds HDM2 and inhibits HDM2 mediated degradation of p53 [XREF_BIBR]."
"Conversely, phosphorylation of MDM2 at several serine residues within its central acidic domain (Ser 240, Ser 242, Ser 246, and Ser 383) results in increased MDM2-p53-binding and subsequent degradation of p53 under non stress conditions."
"P53 is inhibited during normal cell growth by MDM2 a proto-oncogene through either ubiquitin dependent p53 degradation in the cytoplasm or repression of the transcriptional activity of p53 in the nucleus [XREF_BIBR]."
"46 Genotoxic stress has been shown to inhibit Mdm2 mediated p53 degradation and increase the stability and, consequently, protein levels of p53."
"37 The modest induction of p53 in response to MDM2 and/or MDM4 depletion contrasted with the dramatic induction of p53 and p53 mediated cell death in response to Nutlin-3a, 20 most likely because residual MDM2 mediates p53 degradation after MDM2 knockdown whereas Nutlin-3a effectively blocks MDM2 mediated p53 degradation."
"Recently, in mouse models carrying either the polymorphic MDM2 SNP309G or MDM2 SNP309T allele [XREF_BIBR], Post et al. found that MDM2 SNP309G/G cells exhibit elevated MDM2 levels, reduced p53 levels, and decreased p53 dependent apoptosis in response to DNA damage; importantly, those mice with two MDM2 SNP309G alleles have an attenuation of the p53 pathway resulting in a decreased latency to tumor formation and decreased survival."
"Mdm2 functionally inhibits p53 and targets the tumor suppressor protein for degradation."
"p14ARF, an alternate transcript of the INK4A tumor suppressor locus, prevents hdm2 induced transcriptional silencing of p53 by binding hdm2."
"In addition, the binding of Mdm2 to L26 attenuates the association of L26 with p53 mRNA and represses L26 mediated augmentation of p53 protein synthesis."
"Since wild-type p53 is quickly degraded by MDM2, extensive efforts have been performed to identify the small compound (s), which could inhibit the interaction between p53 and MDM2."
"In an autoregulatory feedback loop, Hdm2 maintains low levels of p53 in normal non stressed cells and inhibits nuclear p53 through multiple and diverse mechanisms."
"As expected, the presence of Nutlin-3 almost completely counteracted the MDM2 mediated degradation of p53 and led to accumulation of p53 in the nucleus."
"These results suggest that MDM2 negatively regulates NFATc2 activation and cytokine induction in naive CD4 + T cells in a p53 independent manner."
"In this study, we show that clinorotation induces HDM2 mediated degradation of p53, which subsequently inactivates mTOR and induces autophagy in HUVEC."
"RPL26 activates p53 by overcoming HDM2 mediated p53 degradation through the proteasome."
"The subsequent inhibition of Mdm2 by L5, L11, and L23 causes activation of p53."
"This p53 mediated increase in MDM2 expression will begin to degrade p53 and repress its function."
"As Mdm2 can have an impact on p53 function both catalytically, by promoting its ubiquitination, or noncatalytically, by blocking its transcriptional activation domain, we first assessed whether the variant forms of Mdm2 could suppress p53 activity in promoter assays."
"Pitx2a does not regulate Hdm2 mediated p53 degradation, because Pitx2a does not affect p53 protein levels in HPV negative cells, such as HCT116, U2OS, and C33A cells."
"As a consequence, CDKNA2 deletion (ARF loss) and MDM2 (12q15) amplification both increase the ubiquitylation and subsequent degradation of p53 (XREF_FIG)."
"XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR 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."
"HDM2 inhibition is hypothesized to increase p53 stability by reducing HDM2 mediated degradation."
"The absence of detectable p14 ARF protein in our samples suggests that MDM2 protein in retinoblastoma may be unsuppressed and thereby constitutively block p53 tumor surveillance and promote retinoblastoma development."
"p90 (MDM2) inhibits p53 by blocking the transcriptional activation domain of p53 as well as by stimulating its degradation."
"However, our study raises the question of primary mutation in the p53 tumor suppressor protein in Nigerian ameloblastoma cases and not p53 inhibition by MDM2."
"One of its transcriptional targets is MDM2, which in turn down-regulates p53."
"The results show that p53 could still inhibit GR under conditions where MDM2 levels were decreased by siRNA, though knockdown of MDM2 diminished p53 inhibition of GR slightly."
"MDM2 ubiquitinates and promotes proteasomal degradation of p53 and inhibits p53 's tumor suppressor function [XREF_BIBR]."
"Another example of edgetic anti-cancer therapy options is that of nutlins, which block the interaction between p53 and its negative modulator MDM2 activating the tumor suppressor effect of p53."
"To determine whether such degradation is involved in the regulation of neural network synchrony, we applied a small-molecule inhibitor, Nutlin-3 (1muM), that specifically inhibits Mdm2-p53 interaction and Mdm2 mediated p53 degradation [XREF_BIBR]."
"When concentration of Hdm2 increases, Hdmx can reverse its p53 preserving function by augmenting the Hdm2 mediated degradation of p53 through the formation of a heterodimeric Hdmx and Hdm2 complex capable of enhanced trans-ubiquitination."
"The perturbation of ribosome biogenesis caused by aspirin was responsible for the reduction of the Mdm2 mediated proteasomal digestion of p53 throughout the RPs-Mdm2-p53 pathway [XREF_BIBR - XREF_BIBR]."
"Wild-type and cancer related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers."
"Phosphorylation at Ser15 in human p53 has been shown to relieve the inhibition or degradation of p53 by MDM2 ( xref ), whereas the mouse equivalent pSer18 has been implicated in the pro-apoptotic function of p53 ( xref )."
"Since MDM2 is an inhibitor of p53, we tested whether activation of p53 plays a role in MX69 induced cancer cell death following inhibition of MDM2."
"When the balance between MDM2 and p53 is disrupted, MDM2 upregulation inhibits the function of p53 as a tumour suppressor (Chen et al, 1995; Taylor et al, 2000; Takahashi et al, 2004; Tovar et al, 2006)."
"MDM2 oncoprotein negatively regulates p53 activity through the ubiquitination and proteasomal degradation of p53."
"In vitro, HER-2 promotes Hdm2 mediated p53 degradation through the inactivation of ARF, and HER-2 further enhances mammary tumorigenesis in ARF heterozygous mice [XREF_BIBR, XREF_BIBR]."
"For example, CK1-delta phosphorylation of the Mdm2 acidic domain blocks Mdm2 dependent p53 degradation [XREF_BIBR]."
"p53 inactivation by MDM2 and MDMX negative feedback loops in testicular germ cell tumors."
"For instance, it is known that E1A can bind to MDM4 to inhibit MDM2 induced degradation of p53."
"MDM2 binds and inhibits P53 protein."
"The selective deubiquitination of MDM2 by USP2a promotes p53 degradation in prostate cancer cells, resulting in a reduction of expression of microRNAs targeting MYC mRNA."