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USP7 binds MDM2. 238 / 294
32 4 | 1 106 131
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"Previous reports have indicated that MDM2 binds USP7 through interactions mediated by MDM2 aa147-159, while aa200-262 are involved in MDM2 binding to SUV39H1."
26971997
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"USP7 can bind directly to Mdm2 or p53 in a mutually exclusive manner."
26460617
sparser
"Conversely, the dynamic acetylation of MDM2 on lysine 182 and lysine 185 induced by acetyltransferase p300 enables the binding of HAUSP to the acidic domain of MDM2 and the subsequent deubiquitination[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34998788
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"USP7 plays a critical role in cellular processes; it interacts with HDM2 and enhances its stability through the deubiquitination pathway.33 34 Considering the interaction between USP7 and HDM2, we further examined whether the polyQ-IRF fusions could sequester endogenous HDM2 together with USP7."
40104064
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"In unstressed cells, MDM2 interacts with DAXX and HAUSP and is stabilized in the MDM2, DAXX, and HAUSP complex, which leads to persistent ubiquitination and degradation of the tumor suppressor p53."
20935220
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"For example, by interacting with ubiquitin specific protease USP7 (as discussed below), it has been suggested that EBNA1 could interfere with p53 's or MDM2 's own binding to USP7, leading in particular to lower levels of the p53 transcriptional activator, thereby promoting cell survival in response to cellular stress [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."
29642420
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"USP7 also binds the tumour suppressor protein p53 and the ubiquitin ligase MDM2 (amongst other proteins, including MDMX and FoxO4A) and in so doing, removes ubiquitin moieties that would otherwise target these substrate proteins for degradation by the proteasome (XREF_FIG)."
29642420
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"The results that HAUSP binds to both GST-Hdmx and to GST-Mdm2, but not GST only, suggest a direct interaction."
15916963
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"Thus USP7 is able to stabilise both p53 and MDM2 [XREF_BIBR, XREF_BIBR, XREF_BIBR] and it has been hypothesised that EBNA1 can compete for the binding of USP7 to MDM2 and thereby affect the p53 pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
29642420
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"In the presence of intact DAXX and HAUSP, the newly synthesized MDM2 could associate with DAXX and HAUSP again, leading to stabilization of MDM2 and new ubiquitination and degradation of p53."
20935220
sparser
"The recent biochemical and structural analyses have characterized four USP7-binding sites on MDM2, including 147 PSSS HLVSR PSTS 159 , 226 AGVS 229 , and 397 PSTS 400 , and Ser150 and Ser229 are critical for the MDM2-USP7 binding ( xref ; xref ; xref )."
32300595
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"Incubation with MG132 alone does not affect the interaction between HAUSP and Hdmx/Hdm2 (data not shown)."
15916963
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"HAUSP preferentially forms a stable HAUSP and MDM2 complex even in the presence of excess p53."
16402859
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"These results indicate that upon DNA damage, the interaction between HAUSP and Hdm2/Hdmx is weakened, most likely caused by ATM/ATR-dependent phosphorylation of Hdmx, resulting in impaired deubiquitin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15916963
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"This is because, in addition to deubiquitination of p53, USP7 also binds to MDM2."
25283148
sparser
"RASSF1A associates with Daxx and the C-terminal region of Mdm2 and interferes with the formation of a ternary complex between Mdm2, Daxx and the ubiquitin hydrolase HAUSP resulting in increased auto-ubiquitination and degradation of Mdm2."
19929178
sparser
"Moreover, under steady-state conditions, Daxx can form a ternary complex with MDM2 and the deubiquitinating enzyme HAUSP (herpesvirus associated ubiquitin-specific protease), enhancing MDM2 stability."
18680765
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"The observation that HAUSP can directly interact with and deubiquitylate both p53 and MDM2 creates a conundrum : how can HAUSP stabilize p53 while at the same time being able to stabilize MDM2, which is primarily responsible for the destruction of p53?"
16402859
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"This finding led us to wonder whether HAUSP interaction and nuclear translocation of MDM2 are linked or separately regulated."
28196907
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"As we expected, wild-type MDM2 and the KRKR MDM2 mutant, both of which dominantly express in the nucleus, interacted with HAUSP largely in the nucleus (XREF_SUPPLEMENTARY)."
28196907
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"On the contrary, compared to wild-type and the KRKR mutant, the KQKQ mutant exhibited increased interaction with HAUSP in both the nucleus and the cytoplasm, suggesting that nuclear translocation of MDM2 is not required for HAUSP interaction with MDM2, at least in this experimental setting (XREF_SUPPLEMENTARY)."
28196907
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"We found that DNA damage induced HAUSP dissociation from MDM2 was largely diminished in SIRT1 depleted U2OS cells (XREF_FIG), supporting our model that MDM2 acetylation triggers a stable interaction of MDM2 and HAUSP."
28196907
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"This result suggests that MDM2 binds to HAUSP with a higher affinity than does p53."
16402859
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"MDM2 acetylation and HAUSP interaction in U2OS cells declined 4 hours after treatment with ETO (XREF_FIG), supporting a model in which HAUSP associates with MDM2 possibly in an MDM2 acetylation dependent manner."
28196907
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"Compared to p53, the more extensive interactions between MDM2 and HAUSP provide a mechanistic explanation to our biochemical observation that MDM2 out competed excess p53 for binding to HAUSP."
16402859
sparser
"The proteasome has both ubiquitin ligases and DUBs that associate with it (Crosas et al., 2006) , and several DUB-ligase pairs interact directly, including BRCC36-BRCA1, BAP1-BRCA1, USP4-Ro52, USP7-MDM2, USP8-GRAIL, USP20-pVHL, USP33-pVHL and USP44-APC (Kee and Huibregtse, 2007; Marfany and Denuc, 2008; Ventii and Wilkinson, 2008) ."
19571111
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"Second, MDM2 binding to HAUSP was found to be mutually exclusive with p53 binding to HAUSP."
16402859
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"However, under genotoxic stress conditions, binding of Mdm2 to USP7 is impaired as a result of ATM mediated phosphorylation of Mdm2, shifting the balance towards stabilization of p53 [XREF_BIBR, XREF_BIBR]."
27844253
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"The deubiquitinase USP7 binds Mdm2 or p53 via its N-terminal TRAF-domain or C-terminal region in a mutually exclusive manner to remove ubiquitins and stabilize the two proteins [XREF_BIBR - XREF_BIBR]."
26460617
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"A minimal HAUSP binding peptide derived from MDM2 efficiently displaced p53 from the p53 and HAUSP complex in a competition assay and formed a stable HAUSP and MDM2 complex."
16402859
sparser
"Hu et al. found that the short peptides before the acidic region of MDM2 can specifically recognize and bind to the TRAF domain at the N-terminal of USP7, and USP7 in cells preferentially forms a stab[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
35114313
sparser
"A previous study suggested that the interaction between HAUSP and Mdm2 is significantly decreased in response to DNA damage xref ."
26238070
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"For example, USP7 (HAUSP) interacts with MDM2 to regulate the turnover of p53 together, and it is also able to increase the stability of MDM2 XREF_BIBR."
24714733
sparser
"USP7 protein (also known as HAUSP) plays a central role in Mdm2 regulation since self-ubiquitylation of Mdm2 promotes its own degradation ( xref ) that is rescued by formation of a complex between Mdm2 and USP7 proteins ( xref )."
22361354
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"The interactions between HAUSP and p53 or MDM2 are likely to be more complex in vivo, not only due to the presence of multiple binding sites in MDM2 but also because of the oligomeric nature of p53 and possibly HAUSP."
16402859
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"On the other hand, USP7 also can bind to and stabilize E3 ubiquitin ligase MDM2, a negative regulator of p53 [63]."
37658402
sparser
"Upon stress signals such as DNA damage, the USP7-Mdm2 interaction is compromised through ataxia telangiectasia mutated (ATM)-mediated phosphorylation, and USP7 becomes preferentially associated with p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
36952348
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"Our current structural studies identify differential features for HAUSP binding by MDM2 and by p53."
16402859
sparser
"DAXX has been shown form a ternary complex with HDM2 and USP7 and facilitate the stabilization of both itself and HDM2 by USP7 ( Tang et al., 2006 , 2010 )."
32603670
sparser
"USP7 binds to and stabilizes MDM2 under stress-free conditions, resulting in p53 turnover in an MDM2-dependent manner ( xref )."
32300595
sparser
"HAUSP preferentially forms a stable HAUSP HDM2 complex, even in the presence of excess p53 [ xref ]."
23822887
sparser
"Under normal conditions, USP7 preferentially interacts with HDM2 and prevents its degradation ( xref )."
30807924
sparser
"In addition, the death domain-associated protein DAXX was shown to bind simultaneously to Mdm2 and USP7 and to mediate the stabilizing effect of USP7 on Mdm2 [12] ."
17961905
reach
"Therefore, these inhibitors, by binding to USP7, successively blocked the protein–protein interaction between USP7 and MDM2 and induced apoptosis in wild-type p53 cancer cells and suppressed the growt[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34474304
sparser
"On the other side of this molecular switch are proteins that affect the MDM2–USP7 interaction."
28591556
sparser
"Ras association domain-containing protein RASSF1A is a potential tumour suppressor that disrupts the association of USP7 to MDM2, allowing the latter to self-ubiquitinate and stabilising p53 [54] ."
28591556
reach
"Intriguingly, HAUSP also binds and deubiquitinates Mdm2, thereby stabilizing Mdm2 and consequently destabilizing p53."
15865930
sparser
"A positive regulator of the MDM2–USP7 complex, and thus p53 degradation, is the aforementioned DAXX [45] , a protein that also has been found to sequester USP7 away from the target PTEN, resulting in [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28591556
sparser
"USP7 associates with Mdm2 to regulate the turnover of p53 and plays a role in viral gene expression ( Li et al., 2004 )."
16109378
sparser
"USP7 plays a critical role in cellular processes; it interacts with HDM2 and enhances its stability through the deubiquitination pathway. xref , xref Considering the interaction between USP7 and HDM2, we further examined whether the polyQ-IRF fusions could sequester endogenous HDM2 together with USP7."
40104064
sparser
"Alternatively they may coordinately regulate the stability of a third partner as exemplified by the association of MDM2 with USP7 (HAUSP), both regulators of p53 ( xref )."
23105109
sparser
"A previous study suggested that Mdm2 mediates p53 stabilization through HAUSP expression, and Mdm2 and HAUSP can interact in a p53-independent manner xref ."
26238070
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"Thus, we tested the nature of the interactions, if any, between USP7, SUV39H1 and MDM2."
26971997
reach
"Previous studies have shown that MDM2 physically interacts with USP7, and also forms a complex with SUV39H1."
26971997
trips
"Here, we show that HAUSP also interacts with Hdmx, resulting in its direct deubiquitination and stabilization."
15916963
sparser
"Previous studies have shown that MDM2 physically interacts with USP7 ( xref ), and also forms a complex with SUV39H1 ( xref )."
26971997
sparser
"The death domain-associated protein (DAXX) also plays an important role in the stabilisation of MDM2, because it can bind to MDM2 and USP7."
32092586
sparser
"Under normal circumstances, USP7 associates with MDM2, possibly with help of adaptor protein DAXX [45] and/or acetylation of MDM2 [46] , to protect the E3 Ub ligase from auto-ubiquitination."
28591556
sparser
"The TRAF-like domain of HAUSP is regarded as the necessary region to bind to p53, and HAUSP interacts with MDM2 both in vivo and in vitro. xref , xref "
32532965
sparser
"Although USP7 can interact with both Mdm2 and p53 depending on the cellular context, USP7 preferentially forms a stable USP7-Mdm2 complex even in the presence of excess p53 [ xref ], indicating that USP7 predominantly functions to stabilize Mdm2."
33207738
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"Since USP7 forms a complex with Mdm2 and is required for Mdm2 stability, a knockout of USP7 in cells leads to Mdm2 self ubiquitination and proteasomal degradation, which in turn results in Poleta accumulation."
25435364
sparser
"Coordinates have been deposited at the Protein Data Bank with accession codes 3MQR for USP7:HdmX AHSS and 3MQS for USP7:Hdm2 PSTS ."
20713061
sparser
"If the cell is subjected to stress, activation of ATM signaling promotes the PPM1G-mediated dephosphorylation of USP7 and its subsequent inactivation, resulting in the destabilization of the USP7-HDM2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
32603670
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"For example, MDM2 interacts USP7 to maintain the protein stability [57], and USP7 deubiquitinates FOXO4, leading to its nuclear localization and attenuation of transcriptional activity [58]."
38725075
sparser
"Considering that USP7 binds to MDM2 via the TRAF domain instead of the catalytic core domain, berberine may block the USP7-MDM2 binding via interacting with the TRAF domain."
32300595
sparser
"A number of proteins have been reported to interact with USP7 and regulate its activity toward Mdm2 or p53. [ xref ] For instance, death domain associated protein (Daxx) promotes the binding of USP7 to Mdm2 and enhances Mdm2‐dependent p53 degradation. [ xref ] In addition, testis‐specific protein Y‐encoded like 5 (TSPYL5) and Epstein‐Barr virus nuclear antigen 1 (EBNA1) compete with p53 for binding to the TRAF‐like domain of USP7, thereby suppressing the function of p53. [ xref , xref ] Moreover, Abraxas brother 1 (ABRO1) stabilizes p53 by facilitating the interaction of p53 with USP7. [ xref ] In this study, we show that MLF2 binds to both N‐terminal TRAF‐like domain and C‐terminal UBL4‐5 of USP7."
37438558
sparser
"Previous reports have indicated that MDM2 binds USP7 through interactions mediated by MDM2 aa147–159 ( xref ), while aa200–262 are involved in MDM2 binding to SUV39H1 ( xref )."
26971997
sparser
"On the other hand, USP7 interacts with MDM2 to improve its stability by deleting ubiquitin on MDM2 and protecting it from proteasome destruction [ xref ] ."
36624687
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"Interestingly, STIP knock down seem to have a more profound impact on the interaction between USP7 and Mdm2 than the interaction between USP7 and p53."
26460617
sparser
"For instance, EBNA1 can inhibit p53 accumulation by blocking its interaction with MDM2 and a cellular ubiquitin-specific protease USP7."
31521748
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"Consistent with this, our results reveal that STIP knock down have a more profound impact on the interaction between USP7 and Mdm2 than the interaction between USP7 and p53."
26460617
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"Other different residues of TRAF like domain also interact with MDM2, but not with p53, and vice versa, accounting for USP7 binding to MDM2 and p53 with the different affinities."
27893708
sparser
"Expression of RASSF1 , the product of which disrupts the interaction between MDM2 and HAUSP was significantly up-regulated in the clinical PNI samples."
27665737
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"USP7 can bind p53 and Mdm2 (an E3 ubiquitin ligase for p53) and stabilize these proteins by removing the polyubiquitin chains that normally signal degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
23170171
sparser
"Neither overexpression nor knockdown of RALY affected the interaction between USP7 and Mdm2 at both exogenous and endogenous levels ( Figures 5 I, 5J, S4 E, and S4F)."
36952348
sparser
"USP7 can directly bind Mdm2 in vitro [ xref ]."
18687060
reach
"However, EBNA1 binds this pocket with higher affinity than either p53 or Mdm2 and therefore interferes with p53 or Mdm2 binding to USP7 at least in vitro [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
23170171
reach
"As a result, MDM2 and USP7 form a complex circuit to finely regulate p53 stability and activity."
38275873
sparser
"Importantly, it has been reported that the MDM2-USP7 binding is much stronger than the p53-USP7 binding ( xref ; xref ), which provides a rationale for developing selective inhibitors of MDM2-USP7 interaction without affecting the deubiquitinating effects of USP7 on p53."
32300595
reach
"After DNA damage, however, phosphorylation of the HDM2-HDMX ligase disrupts interactions between HDM2 and USP7, leading to degradation of the ligase and activation of p53-dependent transcription [205]."
35608338
sparser
"To determine whether HAUSP-mediated stabilization of Mdm2 is a direct effect, we first examined whether HAUSP can bind Mdm2 in the absence of p53."
15053880
sparser
"HAUSP, a deubiquitinase, can bind to MDM2 [ xref ]."
29789718
sparser
"42 , 43 , 44 , 45 In addition, Daxx functions as an adaptor protein to facilitate binding of USP7 to Mdm2, preventing Mdm2 degradation."
36952348
sparser
"We further show that this phenomenon occurs because HAUSP binds, deubiquitinates, and stabilizes Mdm2 in a p53-independent manner."
15053880
sparser
"However, under genotoxic stress conditions, binding of Mdm2 to USP7 is impaired as a result of ATM-mediated phosphorylation of Mdm2, shifting the balance towards stabilization of p53 [ xref , xref ]."
27844253
sparser
"46 Unlike Daxx, RALY does not modulate the USP7-Mdm2 interaction, although these three proteins are able to form a ternary complex in cells."
36952348
sparser
"Interactions between the USP7–NTD and p53 have been shown to occur through two closely spaced peptides in the p53 regulatory region and, similarly USP7–Mdm2 interactions also involve two closely space[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21411309
reach
"We next verified that HAUSP and nucleolin could form a complex with p53 and Mdm2 by examining the interaction between HAUSP and nucleolin in p53- and Mdm2 depleted cells."
26238070
sparser
"Concomitantly, RASSF1A binds to the DR associated protein DAXX, which results in the disruption of the interaction between MDM2 and HAUSP, resulting in MDM2 auto-ubiquitination and degradation inducing p53 stabilisation, which leads to cell cycle arrest and apoptosis."
31963420
sparser
"To demonstrate that the interaction between HAUSP and Hdmx is independent of p53, the same experiment was performed with a point mutant of Mdmx (G57A), which is unable to bind p53 ( Danovi et al., 200[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15916963
sparser
"The association of endogenously expressed HAUSP and Hdmx proteins was investigated by immunoprecipitations on extracts of three cell lines (MCF-7, C33A, and U2OS)."
15916963
reach
"A previous study suggested that the interaction between HAUSP and Mdm2 is significantly decreased in response to DNA damage XREF_BIBR."
26238070
sparser
"These data provide evidence that Hdmx associates with HAUSP in vitro and in vivo, independent of p53."
15916963
reach
"USP7 binds to p53 and mdm2, stabilizing the proteins."
34888589
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"This model has been consolidated by structural and biochemical data which revealed that while both Mdm2 and p53 associate with USP7 in a mutually exclusive manner, USP7 has a higher binding affinity f[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
17961905
reach
"In addition, the tumor suppressor RASSF1A, by disrupting the interaction between Mdm2, DAXX and HAUSP, enhances Mdm2 auto-ubiquitination, thus favoring p53 stabilization during the DNA damage response[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
19217357
sparser
"A proposed mechanism for the dissociation of Mdm2 from HAUSP involves ATM phosphorylation of Daxx (death domain-associated protein 6) triggering its dissociation from Mdm2, and relieving Daxx mediated promotion of Mdm2-HAUSP interaction ( xref , xref )."
28690977
sparser
"It should be noted that the HAUSP (C223S) mutant interacted with Hdmx comparable to wild-type (wt) HAUSP (data not shown)."
15916963
sparser
"To examine whether regulation of Hdmx protein levels by HAUSP was the result of an interaction between HAUSP and Hdmx, we expressed HA-Hdmx and Myc-HAUSP in U2OS cells and immunoprecipitated protein c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15916963
sparser
"To obtain more insight into the interaction between HAUSP and Hdmx, GST-Hdmx pull-downs were carried out on 35 S-labeled, in vitro-translated HAUSP ( Figure 3 B)."
15916963
sparser
"Moreover, using a HAUSP-specific antibody, we also verified the interaction between endogenous HAUSP and Mdm2 proteins in U20S cells."
15053880
sparser
"Daxx promotes the binding of MDM2 to HAUSP and thus increases MDM2 stability ( xref )."
25808808
sparser
"Indeed, we find that the interaction between HAUSP and Hdmx is not significantly impaired after DNA damage in the presence of caffeine ( Figure S6 ), indicating that ATM/ATR-dependent phosphorylation [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15916963
reach
"Dissociation of either of these proteins disrupts the stability of the Mdm2 and HAUSP complex and promotes Mdm2 auto-ubiquitination and degradation."
20404858
sparser
"To provide further evidence for a role of Hdmx phosphorylation in the reduction of interaction between Hdmx and HAUSP, Hdmx was immunoprecipitated from mock-treated or NCS-treated cells."
15916963
sparser
"This is because, in addition to deubiquitination of p53, USP7 also binds to MDM2."
25283148
sparser
"Since USP7 forms a complex with Mdm2 and is required for Mdm2 stability ( xref , xref ), a knockdown of USP7 employed in our experiments, leads to Mdm2 self-ubiquitylation and proteasomal degradation ( xref , pathway 2)."
21138959
reach
"Expression of RASSF1, the product of which disrupts the interaction between MDM2 and HAUSP was significantly up-regulated in the clinical PNI samples."
27665737
sparser
"Acetylation at Lys 182 and Lys 185 in MDM2 by p300 promoted the interaction of MDM2 with the deubiquitinase HAUSP, thereby suppressing self-ubiquitination, as well as altered the conformation of MDM2, thereby enhancing its functional interaction with p53."
28196907
sparser
"Nonetheless, MDM2 has more extensive interactions with USP7 than p53 71 ; the excessive pooling of poly-ubiquitinated p53 could affect the equilibrium of the USP7-MDM2 interaction."
37552992
reach
"If the cell is subjected to stress, activation of ATM signaling promotes the PPM1G-mediated dephosphorylation of USP7 and its subsequent inactivation, resulting in the destabilization of the USP7-HDM2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
32603670
sparser
"It is possible that specific HAUSP mutants may be present in tumor cells that only abrogate the p53-HAUSP interaction but not the Mdm2-HAUSP interaction."
15053880
sparser
"Concurrently, it was found that HAUSP interacted with Mdm2 and exhibited strong deubiquitinase activity and stabilization toward the protein."
16455486
reach
"It is not surprising that HAUSP also forms a complex with Mdm2 [79] ."
22673503
reach
"Analysis of the molecular basis of their differential binding revealed that MDM2 binds HAUSP with a much higher affinity, and suggests how HAUSP may regulate the critically important p53-MDM2 pathway."
20076526
reach
"RASSF1A disrupts the interaction between Mdm2, DAXX, and HAUSP, thereby promoting Mdm2 ubiquitination, and consequently resulting in p53 stabilization."
19450511
reach
"Daxx promotes the binding of MDM2 to HAUSP and thus increases MDM2 stability."
25808808
reach
"Since USP7 forms a complex with Mdm2 and is required for Mdm2 stability, a knockdown of USP7 employed in our experiments, leads to Mdm2 self ubiquitylation and proteasomal degradation (XREF_FIG, pathway 2)."
21138959
sparser
"However, the deubiquitinase HAUSP interacted with acetylation-mimetic mutants of MDM2 with greater affinity than it did with wild-type MDM2 in 293T cells ( xref ), which might in part explain the reduced autoubiquitination status for the acetylation-mimetic MDM2 mutants."
28196907
sparser
"Because the KQKQ-MDM2 mutant bound HAUSP more strongly than did the wild-type MDM2 ( xref ), we hypothesized that acetylation within the NLS may promote HAUSP recruitment on the acidic domain."
28196907
reach
"Previous studies had indicated that Daxx plays a role in regulating posttranslational stability of the p53 tumor suppressor through interaction with the Mdm2 and Hausp complex [XREF_BIBR]."
28301594
sparser
"HAUSP interacts with p53 and p53 regulator MDM2 and regulates the degradation of both proteins under certain cellular conditions ( xref – xref )."
35572598
reach
"In addition, an interesting feedback loop exists in p53 regulation because USP7 also binds, deubiquitinates and stabilizes Mdm2 more potently under physiologic conditions [14, 15] and stabilizes p53 under genotoxic stress conditions [16, 17]."
32571254
sparser
"Intriguingly, HAUSP also binds and deubiquitinates Mdm2, thereby stabilizing Mdm2 and consequently destabilizing p53."
15865930
reach
"Further insight into the mechanism by which ATM switches the interactions between HAUSP, Mdmx, Mdm2 and p53, to favor p53 activation may offer new tools for therapeutic intervention in the p53 pathway for cancer treatment."
16082221
reach
"Thus, Wip1 promotes Mdm2 stabilization through inhibition of Mdm2 autoubiquitination.To assess the effects of Wip1 on Mdm2 deubiquitination, we examined binding of Mdm2 to HAUSP in U2OS cells."
17936559
reach
"While the levels of HAUSP remained constant before and after ionizing radiation, the relative amounts of Mdm2 bound to HAUSP were increased by overexpressed Wip1 ( Figure 6 C)."
17936559
reach
"This result suggests that Wip1 enhances binding of HAUSP to Mdm2 and contributes to Mdm2 stability by facilitating its deubiquitination.In Figure 5 C, when ATM-deficient human A-T cells were treated w[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
17936559
reach
"These data are consistent with the observation that HAUSP binds to Mdm2 with a higher affinity than p53 [163] ."
19897040
reach
"The DNA damaging agent NCS prevents binding of HAUSP to Mdm2 and MdmX as a result of ATM-dependent phosphorylation [57] ."
19897040
sparser
"HAUSP interaction with MDM2 was enhanced by Lys 182 acetylation ( xref )."
28196907
reach
"They find that, before stress signaling, USP7 binds and deubiquitylates MDM2, thus stabilizing MDM2 and promoting p53 degradation."
24507714
sparser
"To this end, we conducted cell fractionation assays to determine the subcellular localization where HAUSP interacts with MDM2 in 293T cells."
28196907
sparser
"On the contrary, compared to wild-type and the KRKR mutant, the KQKQ mutant exhibited increased interaction with HAUSP in both the nucleus and the cytoplasm, suggesting that nuclear translocation of MDM2 is not required for HAUSP interaction with MDM2, at least in this experimental setting ( xref )."
28196907
reach
"Current evidence is that USP7 preferentially binds and deubiquitinates MDM2, thereby leading to increased degradation of p53, and consequent anti‐apoptotic functions."
20073038
sparser
"In addition, an interesting feedback loop exists in p53 regulation because USP7 also binds, deubiquitinates and stabilizes Mdm2 more potently under physiologic conditions [ xref , xref ] and stabilizes p53 under genotoxic stress conditions [ xref , xref ]."
32571254
reach
"Neither overexpression nor knockdown of RALY affected the interaction between USP7 and Mdm2 at both exogenous and endogenous levels ( Figures 5 I, 5J, S4 E, and S4F)."
36952348
sparser
"We found that DNA damage–induced HAUSP dissociation from MDM2 was largely diminished in SIRT1 -depleted U2OS cells ( xref ), supporting our model that MDM2 acetylation triggers a stable interaction of MDM2 and HAUSP."
28196907
reach
"42 , 43 , 44 , 45 In addition, Daxx functions as an adaptor protein to facilitate binding of USP7 to Mdm2, preventing Mdm2 degradation."
36952348
sparser
"Mapping HAUSP–MDM2 Interactions."
16402859
sparser
"Later studies showed that HAUSP also forms a complex with Mdm2 and stabilizes Mdm2 by its de-ubiquitinase activity."
15865931
sparser
"After DNA damage, however, phosphorylation of the HDM2-HDMX ligase disrupts interactions between HDM2 and USP7, leading to degradation of the ligase and activation of p53-dependent transcription [ xref ]."
35608338
sparser
"MDM2 acetylation and HAUSP interaction in U2OS cells declined 4 hours after treatment with ETO ( xref ), supporting a model in which HAUSP associates with MDM2 possibly in an MDM2 acetylation–dependent manner."
28196907
reach
"Under non stressed conditions, for example, the MDM2 and MDMX complex also binds to the deubiquitinating protein HAUSP, which stabilizes both MDM2 and MDMX."
23002429
sparser
"These data are consistent with the observation that HAUSP binds to Mdm2 with a higher affinity than p53 [163] ."
19897040
reach
"USP7 can directly bind Mdm2 in vitro [XREF_BIBR]."
18687060
sparser
"The fact that both a p53 C-terminal peptide fragment and a short-peptide sequence preceding the acidic domain of MDM2 bind to the N-terminal TRAF-like domain of HAUSP raised an intriguing possibility: HAUSP binding by p53 and by MDM2 might be mutually exclusive."
16402859
sparser
"For example, interaction between USP7 and MDM2 results in USP7-mediated deubiquitylation of MDM2 and enhanced stability of the latter [ xref , xref ]."
36342772
sparser
"This result suggests that MDM2 binds to HAUSP with a higher affinity than does p53."
16402859
sparser
"While the MDM2–USP7 interaction is best known in the context of p53 stability, it may also regulate p53 targets epigenetically through the SUV39H1 H3K9 methyltransferase [ xref ]."
30897496
reach
"For example, a previous review from Pfoh et al. (2015) (190) proposed the development of a drug that would block interaction between MDM2 and USP7 in patients with cancer caused by hyperactivation of MDM2, thereby targeting MDM2 for degradation and stabilizing p53.By studying the DUBs and the pathways that are affected by their redox regulation, the upstream and downstream effectors that are deregulated due to DUB inactivity can be identified, and those can also become targets of therapeutic development."
34391779
sparser
"Under identical experimental conditions, the MDM2 peptide bound to the HAUSP TRAF-like domain with a dissociation constant of 3 μM, 7-fold tighter than that of the p53 peptide ( xref D)."
16402859
sparser
"USP7 interacts with MDM2, the E3 ligase of the P53 tumor suppressor, to precisely regulate the abundance of P53 and further pairs with TRIM27 to balance the K63 ubiquitination of Wiskott-Aldrich syndrome protein and suppressor of cAR (SCAR) homolog (WASH) to promote WASH-dependent endosomal protein recycling, which might correlate with human neurodevelopment ( xref )."
35385312
sparser
"To elucidate the mechanism by which MDM2 recognizes HAUSP, we sought to determine the structure of HAUSP TRAF-like domain bound to the minimal MDM2 fragment."
16402859
sparser
"Several proteins have been reported to regulate the deubiquitination of p53 by affecting the interaction between USP7 and MDM2, or that between USP7 and p53."
25283148
reach
"USP7 can bind Mdm2 or p53 via its N-terminal and C-terminal regions in a mutually exclusive manner, which consequently stabilizes the two proteins by removing ubiquitin."
28406480
sparser
"In the structure of the HAUSP–MDM2 fusion protein, the MDM2 peptide (residues 223–230) is bound to the shallow surface groove on one side of the β-sandwich in the TRAF-like domain, the same site where p53 binds."
16402859
sparser
"Comparison of HAUSP Binding by MDM2 and by p53."
16402859
sparser
"DUBs are known to bind to ubiquitin ligases; for example, USP7 binds to MDM2 and RNF2/RING2, while UBP12/13 has been shown to interact with ZTL. xref , xref , xref Interestingly, USP7 deubiquitinated MDM2 and its target p53, likewise, our data indicated that UBP12/13 interact with CRY2 and COP1 simultaneously."
35700731
reach
"There are several examples of Ub ligase-DUB pairs where a DUB either regulates substrate ubiquitination or auto-ubiquitination of the Ub ligase, notably the Mdm2 and USP7 complex that regulates p53 stability and the DUB A20, which also harbors Ub ligase activity."
26997266
reach
"The binding between MDM2 and HAUSP or DAXX and that between HAUSP and DAXX were decreased in S100A6-transfected cells (Fig. 4C)."
37217945
reach
"A positive regulator of the MDM2–USP7 complex, and thus p53 degradation, is the aforementioned DAXX [45] , a protein that also has been found to sequester USP7 away from the target PTEN, resulting in [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28591556
reach
"Previous studies demonstrated that EBNA1 regulates USP7 interactions with MDM2 and p53 to control of cell cycle [47]."
39821265
sparser
"The herpesvirus-associated ubiquitin-specific protease (HAUSP) and death domain-associated protein (DAXX) interact with MDM2, forming a tertiary complex to weaken the MDM2 self-ubiquitination [ xref ]."
37217945
sparser
"DAXX mediates the stabilizing effect of USP7 on MDM2 by promoting the binding of USP7 and MDM2 (refs xref , xref )."
25283148
sparser
"Compared to p53, the more extensive interactions between MDM2 and HAUSP provide a mechanistic explanation to our biochemical observation that MDM2 out-competed excess p53 for binding to HAUSP."
16402859
sparser
"Since USP7 forms a complex with Mdm2 and is required for Mdm2 stability, a knockout of USP7 in cells leads to Mdm2 self-ubiquitination and proteasomal degradation, which in turn results in Polη accumulation."
25435364
reach
"Therefore, a drug that prevents the formation of the Hdm2 and USP7 complex or inhibits its catalytic activity will benefit patients with cancer associated with a dysregulated Hdm2 protein."
25605410
reach
"31 However, upon DNA damage, ataxia telangiectasia mutated dependent phosphorylation of Mdm2 decreased the binding affinity between USP7 and Mdm2, tilting the balance towards p53 stabilization."
28406480
reach
"Indeed, the binding affinity between HAUSP and Mdm2 as well as MdmX is greatly reduced after treatment with NCS due to ATM-mediated phosphorylation ( Meulmeester et al., 2005 )."
16455486
sparser
"USP7 also binds and stabilizes MDM2 under normal conditions, resulting in p53 turnover in an MDM2-dependent manner."
36428632
reach
"It is likely that Mdm2 is the preferred substrate for HAUSP in unstressed cells, while genotoxic stress decreases HAUSP 's binding to Mdm2 and MdmX through ATM dependent phosphorylation, tilting the balance toward p53 stabilization."
20096447
sparser
"A minimal HAUSP-binding peptide derived from MDM2 efficiently displaced p53 from the p53–HAUSP complex in a competition assay and formed a stable HAUSP–MDM2 complex."
16402859
sparser
"Analysis of the molecular basis of their differential binding revealed that MDM2 binds HAUSP with a much higher affinity, and suggests how HAUSP may regulate the critically important p53–MDM2 pathway. xref "
20076526
sparser
"Hu et al. followed the same approach to reveal the mechanism of HAUSP–MDM2 interactions, and identified a ten–amino acid fragment in MDM2 as key to HAUSP recognition."
20076526
sparser
"Our current structural studies identify differential features for HAUSP binding by MDM2 and by p53."
16402859
sparser
"And because MDM2 consistently formed stable complexes with HAUSP despite the presence of ten times more p53 peptides, it was clear that MDM2 binds to the deubiquitylating enzyme with a higher affinity."
20076526
sparser
"Strategies can be devised to screen for specific inhibitors that target this interface, thus destabilizing HAUSP–MDM2 interactions."
16402859
reach
"In the normal state, HAUSP specifically binds to and deubiquitinates Mdm2, thereby stabilizing Mdm2 and subsequently inducing the proteasomal degradation of p53 through Mdm2 activity."
25695607
sparser
"It appeared that USP7 binds MDM2 and counteracts its autoubiquitylation, thereby promoting the degradation of p53."
24462112
sparser
"In terms of USP7-MDM2-p53 pathway, the current strategies for p53 reactivation include (i) inhibition of p53-MDM2 interaction by developing MDM2 inhibitors, and (ii) inhibition of USP7 activity and US[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34474304
sparser
"Continuing with our investigation to delineate USP7–NTD substrate binding, we identified the regions of HdmX that interact with USP7, co-crystallized a peptide corresponding to one of these regions wi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
20713061
reach
"Later studies showed that HAUSP also forms a complex with Mdm2 and stabilizes Mdm2 by its de-ubiquitinase activity."
15865931
reach
"The phosphorylation of HdmX and Hdm2 can cause either association/dissociation of adaptor proteins that regulate USP7-mediated deubiquitination or dissociation of the USP7/Hdm2 complex."
20713061
sparser
"The interaction between USP7 and this Hdm2 peptide was further characterized by fluorescence assays and structural studies."
20713061
reach
"Under normal conditions, USP7 interacts with and stabilizes MDM2, resulting in enhanced ubiquitin-mediated degradation of its target, p53 [22, 26]."
36342772
reach
"In addition, USP7(208–880) binds mdm2, but not p53."
20816748
reach
"Our results showed that both full-length USP7 and USP7(208–1102), lacking the previously identified N-terminal p53/mdm2 binding domain, can bind to full-length mdm2, mdm2-S211 (a.a."
20816748
reach
"Targeting the USP7 deubiquitinating activity or the mdm2 interaction with USP7 could be effective ways to treat cancer by activating wild type p53."
20816748
reach
"Several proteins have been reported to regulate the deubiquitination of p53 by affecting the interaction between USP7 and MDM2, or that between USP7 and p53."
25283148
reach
"DAXX mediates the stabilizing effect of USP7 on MDM2 by promoting the binding of USP7 and MDM2."
25283148
sparser
"The interaction between USP7 and Mdm2 is also enhanced by DAXX, which simultaneously binds both proteins and enhances the E3 ubiquitin ligase activity of Mdm2 towards p53 ( xref )."
32850836
sparser
"In addition, USP7(208–880) binds mdm2, but not p53."
20816748
sparser
"To assess the effects of Wip1 on Mdm2 deubiquitination, we examined binding of Mdm2 to HAUSP in U2OS cells."
17936559
sparser
"Interestingly, STIP knock down seem to have a more profound impact on the interaction between USP7 and Mdm2 than the interaction between USP7 and p53."
26460617
reach
"Some DUBs have additional binding sites with affinity for the target protein that is ubiquitylated (Ventii and Wilkinson, 2008) ; for example, USP7 binds to a peptide sequence present in its substrates p53, MDM2 (murine double minute 2, an oncoprotein) and the Epstein Barr nuclear antigen-1 (Hu et al., 2006) ."
19571111
sparser
"To further understand the molecular mechanism of the USP7–Hdmx interaction, we co-crystallized USP7–NTD and the HdmX peptide (acetyl- 395 LDL AHSS ESQ 404 -amide), and the structure was determined usi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
20713061
sparser
"While the levels of HAUSP remained constant before and after ionizing radiation, the relative amounts of Mdm2 bound to HAUSP were increased by overexpressed Wip1 ( Figure 6 C)."
17936559
sparser
"However, not only does depletion of HAUSP fail to decrease p53 levels, but it actually increases its levels since HAUSP binds to MDM2 and deubiquitinates it."
33906413
reach
"We then employed co-immunoprecipitation to identify possible changes in the binding of USP7 to Mdm2 and p53."
28406480
sparser
"Targeting the USP7 deubiquitinating activity or the mdm2 interaction with USP7 could be effective ways to treat cancer by activating wild type p53."
20816748
reach
"Mdm2 seems to be the preferred substrate for USP7 in unstressed cells, and genotoxic stress decreases USP7 binding to Mdm2 through ATM dependent phosphorylation, shifting the balance toward p53 stabilization XREF_BIBR XREF_BIBR."
28233861
sparser
"This result suggests that Wip1 enhances binding of HAUSP to Mdm2 and contributes to Mdm2 stability by facilitating its deubiquitination."
17936559
reach
"HAUSP, a deubiquitinase, can bind to MDM2 [21]."
29789718
sparser
"USP7 (previously known as HAUSP), a deubiquitinase, interacts with MDM2 [ xref ]."
35008383
sparser
"Consistent with this, our results reveal that STIP knock down have a more profound impact on the interaction between USP7 and Mdm2 than the interaction between USP7 and p53 (Figure xref )."
26460617
sparser
"Normally, p53 is predominantly associated with MDM2, but also with USP7, most likely through the interaction of USP7 with MDM2 ( Figure 1 G)."
24462112
reach
"In unstressed cells, USP7 preferably interacts with and stabilizes HDM2, an E3 ligase responsible for ubiquitinating p53 and targeting it for proteasomal degradation."
29056420
reach
"Intriguingly, WDR79 knockdown seemed to have a more profound impact on the interaction between USP7 and Mdm2 than the interaction between USP7 and p53."
28406480
reach
"DAXX and HAUSP interact with MDM2 to form a tertiary complex, which reduces self ubiqitination of MDM2 [XREF_BIBR]."
25888903
reach
"The best known such example is provided by the association between USP7 and MDM2, which has rendered USP7 a prominent drug target, as a means to regulate levels of p53."
33507233
reach
"However, we found that full-length USP7 binds MDM2 with nanomolar affinity, although no direct interaction of USP7CD-UBL12345 with MDM2 was observed at concentrations of USP7 up to 500 nM."
27452404
sparser
"This result is consistent with the notion that USP7 binds and deubiquitylates MDM2, thereby promoting p53 degradation in these cells ( Cummins et al., 2004; Li et al., 2004 )."
24462112
reach
"However, since we are able to activate the catalytic domain with the addition of peptide, trans activation is certainly possible and could be employed as a regulatory mechanism of USP7 on some substra[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
27452404
reach
"USP7 also binds and stabilizes MDM2 under normal conditions, resulting in p53 turnover in an MDM2-dependent manner."
36428632
sparser
"They find that, before stress signaling, USP7 binds and deubiquitylates MDM2, thus stabilizing MDM2 and promoting p53 degradation."
24507714
reach
"20 , 22 Complete ablation of USP7 results in Mdm2 destabilization and subsequent p53 stabilization, possibly because USP7 binds to Mdm2 with a higher affinity than p53."
37438558
sparser
"Thus USP7 is able to stabilise both p53 and MDM2 [ xref , xref , xref ] and it has been hypothesised that EBNA1 can compete for the binding of USP7 to MDM2 and thereby affect the p53 pathway [ xref , xref , xref ]."
29642420
sparser
"Consistent with the previous reports of peptide binding to the USP7-NTD domain alone, we observed a weak interaction of full-length MDM2 with a USP7 construct containing NTD-USP7CD ( Figure 5 B )."
27452404
sparser
"However, we found that full-length USP7 binds MDM2 with nanomolar affinity ( Figure 5 A), although no direct interaction of USP7CD-UBL12345 with MDM2 was observed at concentrations of USP7 up to 500 n[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
27452404
sparser
"Although both the individual NTD and UBL domains have previously been reported to have some interaction with MDM2, it is clear from the SPR data that both the NTD and the UBL domains are necessary for[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
27452404
sparser
"The affinities we measured for the USP7-MDM2 interaction are, however, consistent with MDM2 as a specific substrate of USP7, and the affinity of USP7 for MDM2 is similar to the binding affinity of UBL[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
27452404
reach
"Upon DNA damage the interaction between MDM2 and MDMX and USP7 decreases in an ATM dependent manner [XREF_BIBR]."
23151129
sparser
"The viral interferon regulatory factor protein (vIRF4)-derived short vif1 and vif2 peptides were reported to be able to disrupt the MDM2-USP7 binding [30] ."
34474304
sparser
"Therefore, these inhibitors, by binding to USP7, successively blocked the protein–protein interaction between USP7 and MDM2 and induced apoptosis in wild-type p53 cancer cells and suppressed the growt[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34474304
sparser
"The GST pull down established that USP7 and HdmX interact directly and that USP7–NTD is sufficient to interact with HdmX."
20713061
reach
"Under normal conditions, USP7 preferentially interacts with HDM2 and prevents its degradation."
30807924
sparser
"Intriguingly, WDR79 knockdown seemed to have a more profound impact on the interaction between USP7 and Mdm2 than the interaction between USP7 and p53."
28406480
sparser
"Studies have found that the binding of USP7 with MDM2 is much stronger than that with p53 [ xref ]."
| PMC
sparser
"Moreover, Misawa and colleagues [31] mapped a large number of compounds that could target the USP7-MDM2 interaction without any effect on USP7 activity."
34474304
reach
"37 For instance, death domain associated protein (Daxx) promotes the binding of USP7 to Mdm2 and enhances Mdm2‐dependent p53 degradation."
37438558
reach
"One study showed that MDM2 interaction with the scaffold protein Daxx and deubiquiting enzyme HAUSP is stimulated by DNA damage, which promote p53 de-ubiquitination."
20081365
reach
"The knockdown of WDR79 not only abolished the effect of USP7 on Mdm2 and p53 but also decreased the binding of USP7 to Mdm2 and p53."
28406480
sparser
"By performing a 3D pharmacophore-based virtual screening, two compounds, NS-03113866 and NS-01893308, were identified as promising drug candidates to disrupt the USP7-MDM2 interaction by binding to th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34474304
sparser
"On the other hand, USP7 also can bind to and stabilize E3 ubiquitin ligase MDM2, a negative regulator of p53 [ xref ]."
37658402
reach
"DUBs are known to bind to ubiquitin ligases; for example, USP7 binds to MDM2 and RNF2/RING2, while UBP12/13 has been shown to interact with ZTL."
35700731
sparser
"However, the interactions between USP7–NTD and HdmX are consistently weaker based on the K d values for the individual peptides binding to USP7–NTD, suggesting that USP7 would preferentially interact [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
20713061
sparser
"21 However, an HdmX construct lacking residues 27–124 also bound USP7, suggesting that HdmX interacts with USP7 through a second site."
20713061