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phosphosite cbn pc11 biopax bel_lc signor biogrid tas lincs_drug hprd trrust | geneways tees isi trips rlimsp medscan sparser reach
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MDM2 activates TP53. 10 / 1292
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"XREF_BIBR XREF_BIBR Mdm2 antagonizes the indirect inhibition of p53 and SHP on ApoC-III, which is probably the underlying mechanism for the involvement of ApoC-III in tumorigenesis and cancer progression."
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"MDM2 inhibitors that activate p53 and induce apoptosis are currently being developed for potential treatment of acute leukemia."
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"The tumor suppressor p53 is inactivated by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4."
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"The Drosophila genome does not have an obvious ortholog of the ubiquitin ligase MDM2, which targets p53 for degradation in mammalian cells XREF_BIBR - XREF_BIBR."
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"Nutlin-3 is a small-molecule inhibitor of MDM2, which can activate the p53 pathway."
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"The ATM dependent phosphorylation of MDM2 and MDMX allow them to bind p53 mRNA, these interactions promote p53 translation."
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"This substantiates the notion that MDM2 mediated P53 inactivation may benefit from inactivation of P14 and ARF."
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"Besides regulating p53, recent reports have shown that MDM2 could also promote cell proliferation and tumorigenesis in a p53 independent manner, raising the possibility that XBP1-u and MDM2 might also contribute to tumorigenesis in a p53 independent manner."
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"There is also evidence to suggest that Mdm2 mediates diverse non ubiquitin modifications of p53 (Box 2)."
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"Unlike p53 +/- tumors which lose their wild-type allele, the tumors which retain an intact p53 allele express p53 protein that induces apoptosis following gamma irradiation, activates p21 (WAF1 and CIP1) and Mdm2 expression, represses PCNA expression (a negatively regulated target of wild-type p53), shows high levels of binding to oligonucleotides containing a wild-type p53 response element and prevents chromosomal instability as measured by comparative genomic hybridization."
MDM2 bound to TP53 activates TP53. 10 / 23
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"MDM2 may bind P53 and promote P53 degradation at baseline but stimulate P53 translation under stress XREF_BIBR."
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"MDM2 binds NS independently of p53, and mediates association of NS and p53."
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"Many anticancer drug development efforts in the past decade have therefore been devoted to the discovery and optimization of small molecules that selectively disrupt the interaction between MDM2 and p53, which could provide, in principle, a potent means to restore p53 function in tumor cells with wild-type p53."
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"A quite recent study showed that the RING finger domain of MDM2 binds to p53 mRNA in vivo, which increases p53 synthesis."
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"In addition, HDM2 binding to p53 blocks its transactivation domain preventing p53 transcriptional activation of its target genes."
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"The binding of hdm2 to p53 induces the suppression and degradation of p53, as well as export p53 from the nucleus, thus hdm2 function as a negative regulator of p53."
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"Nutlin-3 inhibits the physical interaction between p53 and its inhibitor MDM2, and activates p53 responses in p53 wild-type cancer cells."
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"Nutlin-3a, a small molecule inhibitor of the p53 and MDM2 interaction, which promotes p53 reactivation, kills PEL cells in culture and has potent anti-tumor activity in mice bearing PEL tumors [XREF_BIBR, XREF_BIBR]."
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"The protein MDM2 binds to p53, inhibits its transcriptional activation, causes nuclear export and acts as an E3 ligase to target p53 for proteasomal degradation."
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"HDM2 binds p53 at the transactivation domain of p53 and blocks its ability to activate transcription, serves as a ubiquitin ligase that promotes p53 degradation, and mediates the nuclear export of p53."
MDM2 activates mutated TP53. 10 / 19
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"We show for the first time that in the presence of activated DNA damage checkpoint signaling, MDM2 acts to increase mutant p53 abundance, by facilitating monoubiquitination of mutant p53, and inactivation of checkpoint signaling serves as a switch that turns MDM2 from an activator of mutant p53 abundance to facilitating its degradation."
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"Although mutant p53 can be targeted by MDM2 in normal cells, MDM2 can not polyubiquitinate mutant p53 in cancer cells XREF_BIBR."
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"Persistence of chemotherapy induced DNA damage has been observed in wild-type p53 glioblastoma cells [XREF_BIBR] as well as p53 deleted or mutant p53 ovarian cells [XREF_BIBR] treated with the first generation MDM2 antagonist Nutlin3a and this correlated with increases in MDM2 expression and cell death."
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"Moreover, since MDM2-FL and other isoforms can modulate mutant p53 stability, it is possible that MDM2 antagonists could promote stabilization of mutant p53."
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"Therefore, MDM2 isoforms inhibit MDM2 mediated mutant p53 protein degradation, which in turn promotes mutant p53 accumulation and GOF in tumorigenesis [XREF_BIBR]."
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"Both wild-type and mutant p53 can be targeted for proteasomal degradation in otherwise normal cells by the ubiquitin ligase MDM2."
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"On the contrary, MDM2 overexpression induced migration in DU-145 cells bearing a p53 mutation; this effect was partially dependent on MDM2 E3 ligase activity (XREF_SUPPLEMENTARY) and suggests that effects of MDM2 modulation on cellular motility are cell type and context specific."
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"XREF_FIG, ectopic expressed Mdm2 could enhance mutant p53 ubiquitination, indicating that Mdm2 could still target mutant p53 to decompose."
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"These results demonstrated that inhibition of HDM2 efficiently leads to decrease of RRM1 and RRM2 via p53-mTORC1 signaling in TP53 wild type Rh18 but not TP53 mutant Rh30 cells."
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"In mutant p53 triple negative breast cancer cells, however, we did not see increased stability of mutant p53 in cells treated with the MDM2 antagonist, Nutlin3a [XREF_BIBR]."
MDM2 bound to CDKN2A activates TP53. 10 / 13
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"p19 Arf binds to Mdm2 and inhibits the degradation of p53, thus p16 Ink4a and the p19 Arf -p53 pathway synergistically downregulate the self-renewal capacity of HSCs [XREF_BIBR]."
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"ARF bound Hdm2 blocks Hdm2 dependent nucleocytoplasmic shuttling of p53, to produce nuclear retention and activation of p53 [XREF_BIBR, XREF_BIBR]."
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"XREF_BIBR p19 Arf (p14 ARF) directly binds to Mdm2 (HDM2), sequesters Mdm2 to the nucleus and neutralizes its activity, and thereby activates p53."
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"p14ARF directly interacts with HDM2 and leads to upregulation of p53 transcriptional response."
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"Oncogene activation and inappropriate mitogenic signaling activate the expression of Arf, which binds to Hdm2 and relieves inhibition of p53, ultimately leading to p53 dependent and -independent cell cycle arrest or apoptosis XREF_BIBR; XREF_BIBR."
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"p14ARF, along with other free, non assembled ribosomal proteins, bind MDM2 and inhibit p53 degradation."
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"p19 Arf (p14 ARF in humans) directly binds to Mdm2 (HDM2), sequesters Mdm2 to the nucleous and neutralize its activity, and thereby activates p53."
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"For example, binding of p14 ARF and pRb to the MDM2 acidic region have been shown to increase p53 stability, while interaction with the chromatin remodeling protein, p300, stimulates MDM2 dependent p53 degradation [XREF_BIBR]."
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"As mentioned above, ARF interaction with MDM2 causes MDM2 to target MDMX for degradation, and in the event of mitogenic stimulation MDMX is often downregulated to allow p53 activation."
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"p14ARF interacts with MDM2, which targets p53 for degradation, thereby inducing p53 dependent cell-cycle arrest in both G1 and G2 phases [XREF_BIBR, XREF_BIBR]."
MDM2 bound to RPL11 activates TP53. 3 / 3
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"RPL11 could also be detected associated with HDM2 after combination of both stresses indicating that p53 stabilisation is at least partially mediated by competition of HDM2 binding by RPL11."
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"These may include RPL11, which then would bind Mdm2 and induce p53 activation."
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"Activation of p53 occurs through interaction of RPL11 with Mdm2 : under conditions of ribosomal biogenesis stress unassembled RPL11 binds Mdm2 and prevents p53 degradation."
MDM2-C462A activates TP53. 3 / 3
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"While both Mdm2 Y487A and Mdm2 C462A disrupt p53 degradation and maintain Mdm2 degradation, the location of the Y487 residue, C-terminal of the Mdm2 RING finger domain, should not disrupt zinc coordination, thus proper folding and the structure of the RING domain should remain intact (XREF_SUPPLEMENTARY)."
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"Mdm2 C462A enhances p53 transcriptional activity."
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"Here, we show in vivo that the Mdm2 C462A protein not only fails to suppress p53, but compared to the complete absence of Mdm2, Mdm2 C462A actually enhances p53 transcriptional activity toward p53 target genes p21 and CDKN1A, MDM2, BAX, NOXA, and 14-3-3sigma."
MDM2 bound to LATS2 activates TP53. 3 / 3
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"For example, LATS1 was found to regulate cytokinesis by inhibiting LIMK1; and LATS2 bound to Mdm2 to activate p53, serving as a novel checkpoint for the maintenance of proper chromosome number."
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"Lats2 binds Mdm2, inhibits its E3 ligase activity, and activates p53."
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"Lats2 binds to Mdm2 and upregulates p53, which in turn upregulates Lats2, thereby constituting a positive feedback loop for p53 activation in HEK293 cells XREF_BIBR."
Mutated MDM2 activates TP53. 3 / 3
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"Thus, ligase dead mutants of Mdm2 did not act in a dominant negative manner to reactivate p53 and they are not oncogenes in MCF10A cells."
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"For example, a point mutation of the Mdm2 RING domain that destroys RING structure (C462A) and blocks Mdm2 ligase activity triggers p53 stabilization and leads to p53 dependent embryonic lethality."
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"Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53."
MDM2 bound to RPs activates TP53. 3 / 3
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"Upon release, the RPs bind MDM2 and cause p53 accumulation via the stabilization of p53 and/or an increase in p53 translation, which ultimately results in cell cycle arrest or apoptosis."
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"Like RPS11, RPS20 is one of the RPs that can also bind to MDM2 and activate p53 [XREF_BIBR] and it was reported that overexpression of RPS20 is associated with an adverse outcome in medulloblastoma [XREF_BIBR]."
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"For example, it is unclear why a redundant number of RPs bind to MDM2 to elicit a seemingly similar p53 response."
MDM2 activates ubiquitinated TP53. 3 / 3
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"It is inhibited by the RING-domain E3 ligase MDM2, which targets ubiquitinated p53 for degradation."
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"Recent studies suggest that Hdm2 mediated ubiquitination reduces Hdm2 and p53 affinity, which enable the mono-ubiquitinated p53 to be localized to the cytoplasm."
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"In contrast, stress mediated modifications of MDM2 and p53 rapidly increase the non ubiquitinated p53 pool, exposing NLS I for efficient importin-alpha3 recognition and enhanced import."
MDM2 bound to MDM4 activates TP53. 2 / 2
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"Together, these data suggest that antagonism of endogenous Mdm2 and Mdmx heterodimers should activate endogenous p53."
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"In response to DNA damage ATM phosphorylates and modulates the function of several E3-Ubiquitin ligases, among which the MDM2 and MDM4 complex, whose activity and stability is downregulated by ATM, allowing in turn the stabilization of p53 (reviewed in)."
MDM2 activates TP53-R175H. 1 / 2
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"HSP70 and MDM2 Enhance p53 R175H Aggregation and Alter its Subcellular Distribution."
MDM2 bound to its activates TP53. 2 / 2
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"Under nonstressed conditions, the redox sensitive transcription factor p53 is repressed through its binding to mdm2, which targets p53 for degradation (XREF_FIG) [XREF_BIBR, XREF_BIBR]."
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"Translocation of Siva1 correlates with its reduced interaction with Mdm2 (an inhibitor of p53 signalling), as well as with its increased interaction with TRAF2 and XIAP (known to enhance pro apoptotic signalling)."
MDM2 bound to ECD activates TP53. 2 / 2
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"A previous study showed that ECD interacts with MDM2 and up-regulates p53 by inhibiting MDM2 mediated degradation of p53 in osteosarcoma [XREF_BIBR]."
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"A previous study demonstrated that ECD interacts with MDM2 and up-regulates p53 by inhibiting the MDM2 mediated degradation of p53 [XREF_BIBR]."
MDM2 bound to p53 tumor suppressor protein activates TP53. 1 / 1
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"Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53 dependent."
MDM2 bound to RPL23 activates TP53. 1 / 1
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"L23 interacted with MDM2, forming a complex independent of the 80S ribosome and polysome. The interaction of L23 with MDM2 was enhanced by treatment with actinomycin D but not by gamma-irradiation, leading to p53 activation."
MDM2 bound to RYBP activates TP53. 1 / 1
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"Furthermore, RybP binds to E3 ligase MDM2, preventing proteasomal degradation of the tumor suppressor p53."
MDM2 bound to p14/19 ARF activates TP53. 1 / 1
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"For example, the p14/19 ARF protein can bind Mdm2 (a nucleocytoplasmic shuttling protein) to inhibit degradation of p53 by Mdm2."
MDM2 activates phosphorylated TP53. 1 / 1
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"This p53 accumulation is reversed by its downregulation mediated by Hdm2, requiring a dephosphorylated p53 and therefore also needs the removal of VRK1 as stabilizer."
MDM2 bound to ribosomal protein L23 activates TP53. 1 / 1
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"One example is ribosomal protein L23 that is released from the nucleolus after actinomycin D treatment and that directly binds and inhibits MDM2 thereby activating p53 XREF_BIBR, XREF_BIBR."
MDM2 bound to TNF activates TP53. 1 / 1
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"Further, a 37-residue intrinsically unstructured N-terminal fragment of p19 Arf (mArf-N37) XREF_BIBR bound to Mdm2 and caused p53 dependent cell cycle arrest in mouse fibroblasts XREF_BIBR; XREF_BIBR."
MDM2 bound to region activates TP53. 1 / 1
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"In the absence of DNA damage, MDM2 binds to the N-terminal region of p53 and inhibits its activity by blocking p53 mediated transactivation, exporting p53 from the nucleus to the cytoplasm, and promoting the proteasomal degradation of p53."
MDM2 bound to RPL26 activates TP53. 1 / 1
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"The interaction of RPL26 and HDM2 was increased and activated p53."
MDM2 bound to RPS27A activates TP53. 1 / 1
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"RPS27a also interacts with MDM2 to suppress MDM2 associated p53 ubiquitination and then leading to the activation of p53 and cell cycle arrest."
MDM2 bound to RAD6 activates TP53. 1 / 1
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"In addition to our previous work showed that the RAD6 and MDM2 complex synergistically targets p53 for turnover [XREF_BIBR - XREF_BIBR], we found that ASF1A is a new and conserved target of the RAD6-MDM2 degradation machine in both Drosophila and Homo sapiens."
MDM2 bound to it activates TP53. 1 / 1
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"In the early stage of nucleolar stress, L11 is deneddylated by NEDD8 specific protease 1 (NEDP1) and translocates from the nucleolus to the nucleoplasm, where it interacts with MDM2 and activates p53."
MDM2 bound to CUL4A activates TP53. 1 / 1
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"The same group also reported that Cul4A, but not Cul4B, associates with Mdm2 to accelerate proteolysis of p53."
MDM2 bound to MIP activates TP53. 1 / 1
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"GFP-MIP interacts with MDM2 and activates the p53 pathway in cultured cells."
MDM2-Y487A activates TP53. 1 / 1
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"While both Mdm2 Y487A and Mdm2 C462A disrupt p53 degradation and maintain Mdm2 degradation, the location of the Y487 residue, C-terminal of the Mdm2 RING finger domain, should not disrupt zinc coordination, thus proper folding and the structure of the RING domain should remain intact (XREF_SUPPLEMENTARY)."
Phosphorylated MDM2 activates TP53. 1 / 1
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"The phosphorylation of MDM2 stimulates the translocation of MDM2 to the nucleus to bind to p53, and then targets p53 for degradation by the proteosome."
MDM2 bound to arginine and SRSF1 activates TP53. 1 / 1
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"For instance, in response to ribosomal disturbances, SFRS1 (arginine and serine rich 1) interacts with MDM2 (murine double minute 2) to inhibit p53 degradation 6."
MDM2 bound to HSPB1 activates TP53. 1 / 1
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"Of interest, HspB1 interacts with HDM2, which serves as ubiquitin ligase (E3) to target p53 for degradation, and modulates its activity [XREF_BIBR, XREF_BIBR]."
MDM2 bound to NUP214 activates TP53. 1 / 1
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"For example, the p14/19 ARF protein can bind Mdm2 (a nucleocytoplasmic shuttling protein) to inhibit degradation of p53 by Mdm2."
MDM2 bound to LATS1 activates TP53. 1 / 1
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"In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis."
MDM2 bound to CSNK1A1 activates TP53. 1 / 1
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"In addition, increased expression of beta catenin, downstream of Csnk1a1 inhibition, has also been shown to induce p53, and Csnk1a1 can regulate p53 by binding to MDM2."
MDM2 bound to ABL1 activates TP53. 1 / 1
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"The nuclear Abl dependent p53 accumulation is consistent with the previous findings that Abl interacts with Mdm2 to block p53 degradation 29 and that the Abl muNLS mutant protein is defective in binding Mdm2."
MDM2 bound to LincRNA-p21 activates TP53. 1 / 1
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"LincRNA-p21 also binds to MDM2 thus enhancing p53 activities XREF_BIBR."
MDM2 bound to GNL3 activates TP53. 1 / 1
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"MDM2 binds NS independently of p53, and mediates association of NS and p53."
MDM2 bound to RPL5 activates TP53. 1 / 1
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"Upon nucleolar stress, ribosomal protein RPL5, RPL11, RP23 and RPS7 is released from the nucleolus, binds MDM2 and activates TP53 [XREF_BIBR - XREF_BIBR]."
MDM2 bound to RB1 activates TP53. 1 / 1
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"For example, binding of p14 ARF and pRb to the MDM2 acidic region have been shown to increase p53 stability, while interaction with the chromatin remodeling protein, p300, stimulates MDM2 dependent p53 degradation [XREF_BIBR]."
MDM2 bound to SRSF1 activates TP53. 1 / 1
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"Similarly, whereas SRSF1-NRS was able to interact with RPL5 and MDM2, SRSF1-AAA, another mutant of SRSF1 that accumulates in the cytoplasm, failed to interact with RPL5, yet weakly interacted with MDM2 and very marginally induced p53 protein (XREF_SUPPLEMENTARY)."
MDM2 bound to serine and SRSF1 activates TP53. 1 / 1
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"For instance, in response to ribosomal disturbances, SFRS1 (arginine and serine rich 1) interacts with MDM2 (murine double minute 2) to inhibit p53 degradation 6."
MDM2 bound to RPL23 activates TP53. 1 / 1
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"However, the MDM2 C305F mutation does not affect MDM2 binding to RPL23; and like RPL11, RPL23 interacts with MDM2 and activates p53."
MDM2 bound to CDKN2A activates TP53. 1 / 1
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"INK4b/ARF/INK4a locus encodes two cyclin dependent kinase inhibitors CDKN2B (p15) and CDKN2A (p16) as well as p19ARF which binds to MDM2 and promotes its degradation resulting in the p53 activation [XREF_BIBR]."
MDM2 bound to CUL4B activates TP53. 1 / 1
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"The same group also reported that Cul4A, but not Cul4B, associates with Mdm2 to accelerate proteolysis of p53."