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USP7 activates TP53. 128 / 141
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"Consequently, USP7 has emerged as an attractive oncology target because its inhibition stabilizes p53, thereby promoting p53 dependent apoptosis in cancer cells."
27386854
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"Notably, USP7 can directly regulate not only the stability of p53, but also the protein stability of the MDM2 protein."
33421376
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"Here, we report that USP7 inhibitor, P22077, potently activates p53 by decreasing HDM2 levels in NB cells with an intact USP7-HDM2-p53 axis and efficiently inhibits tumor growth in vivo ."
24136231
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"Taken together, these findings indicate that TSPY1 can regulate the cell cycle and apoptosis by suppressing Usp7 mediated p53 function, promoting the proliferation of mouse spermatogonia."
29748603
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"Overexpression of USP7 induces p53 activation, leading to growth suppression and apoptosis."
23151129
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"Our finding that USP7 inhibition in vitro and in vivo significantly suppresses leukemic cell growth, alone and in combination with chemotherapy, independently of p53 status supports this notion."
32447346
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"Correspondingly, it is highly possible that the regulation of USP7 mediated p53 function by TSPY1 is an important molecular mechanism underlying its function in human spermatogenesis."
29748603
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"Notably, when simulating TSPY1 function in Tspy1 deficient spermatogonia cells derived from mouse testes, we observed the promotion of spermatogonial proliferation by TSPY1 along with signaling changes in the Usp7 mediated p53 pathway."
29748603
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"Inactivation of HAUSP in vivo modulates p53 function."
29056421
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"These findings strongly support the potential of TSPY1 function in the regulation of human spermatogonial proliferation by suppressing USP7 mediated p53 function."
29748603
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"Although both TSPY1 and TSPYL5 regulate USP7 mediated p53 activity, the influence of TSPY1, compared to TSPYL5, on p53 function may be more dynamic."
29748603
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"The levels of HAUSP increased in time after addition of doxycycline ( Figure 1 D), resulting in an accumulation of endogenous p53, Hdm2, and also of Hdmx."
15916963
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"The role of HAUSP in the p53 pathway appears to be unique : on the one hand, overexpression of HAUSP stabilizes both p53 and MDM2 and, more importantly, activates p53; on the other hand, HAUSP ablation destabilizes MDM2 and activates p53 XREF_BIBR, XREF_BIBR."
29748582
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"In summary, these data indicate that USP7 is of potential to be a marker and therapeutic target in overcoming resistance to treatment.Except for USP7, which modulates the stability of p53, other types of DUBs also participate in controlling the ubiquitination of p53 and its subsequent degradation."
36694209
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"Expression of the apoptosis regulator p53 is governed by minute double minute 2 (MDM2), an E3 enzyme that targets p53 for ubiquitination and proteasomal processing, and by the deubiquitinating enzyme, herpesvirus associated ubiquitin specific protease (HAUSP), which rescues p53 by removing ubiquitin chains from it."
18375498
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"Inhibiting USP7 with the small-molecule inhibitor P22077 attenuates the p53 dependent apoptotic pathway by destabilizing Tip60."
23775119
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"Initially, USP7 was believed to primarily deubiquitinate p53, increasing the level of p53 [XREF_BIBR]."
18793145
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"Expression of USP7 , the target protein of EBNA1 and ICP0 , however , effectively promotes increased levels of p53 by antagonizing proteasomal degradation of p53 through deubiquitination ( Li et al ., 2004 ) ."
17291557
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"Although USP7 has been shown to promote p53 stability via deubiquitination, the USP7-p53 activation mechanism has remained unclear."
38879877
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"Another contrasting possibility is that HAUSP can target both p53 and MDM2 for deubiquitylation and thus may play a dynamic role in the p53-MDM2 pathway [XREF_BIBR]."
16402859
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"As may be expected , partial reduction of USP7 levels by RNA interference ( RNAi ) was shown to destabilize p53 ( Li et al ., 2004 ) ."
17291557
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"Roles of HAUSP mediated p53 regulation in central nervous system development."
21350561
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"Therefore, a new USP7/p53/TFR1 pathway was found in rat hearts after I/R, in which upregulation of USP7 promoted ferroptosis by activating the p53/TFR1 pathway (Tang et al. 2021c)."
38509409
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"These results indicate that HAUSP mediated p53 regulation is crucial for brain development, and also suggest that both the p53 dependent and the p53 independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice."
21350561
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"A novel pathway of ubiquitin-specific protease 7 (USP7)/p53/TfR1 is found in rat hearts after I/R treatment, and the upregulation of USP7 accelerates ferroptosis by activating the p53/TfR1 pathway [74]."
34745412
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"STAT3 and USP7 are upregulated at both RNA and protein levels in response to EZH2 inhibition.To address the questions that if there is resistance mechanism by which DLBCL cells tolerate EZH2 inhibitor treatment, we used EPZ to treat KARPAS-422 cells for 3 days and examined 11 oncogenic genes MYC, MAX, STAT3, KRAS, BCL2, BRAF, SRC, JUN, RAF1, SKI, FOS, MDM2, and a tumor suppression factor p53."
37829803
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"In contrast, miR-205 that can inhibit the expression of USP7 can downregulate p53 and its downstream target protein, thereby promoting cell proliferation (Zhu et al., 2015)."
37251574
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"HAUSP, a nuclear ubiquitin specific protease, targets p53 and Mdm2 as substrates and, in concert with Mdm2, plays a dynamic role in p53 functionality."
20815019
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"These results uncover a new layer of the p53 transcriptional program mediated by USP7, which restrains relaxation of local chromatin conformation at p53 target promoters."
26971997
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"Lastly, we demonstrate, using newly generated thiazole derivatives of HAUSP inhibitors [23], an increased potency of HAUSP inhibition in a p53 independent manner.ResultsHAUSP inhibition stabilizes and activates p53 protein levelsThe dynamic regulation of HAUSP to modulate p53 stability is well established."
29616860
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"Under conditions of genotoxic stress, however, the expression of ABRO1 is rapidly induced by DNA damage, and ABRO1 translocates into the nucleus, thereby promoting USP7 targeting of p53 and antagonizing the ubiquitination modification of MDM2 and p53."
25283148
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"These results further substantiated that USP7 modulates steady-state SUV39H1 levels independent of p53."
26971997
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"Ubiquitin-specific protease 7 (USP7) is the most widely studied DUB that modulates p53 function through Ub clearance."
35563444
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"HAUSP stabilizes p53 and induces p53 dependent cell apoptosis of lung cancer, thus inhibits tumor progression [ 21 ]."
29331416
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"It has been shown previously that ablation of USP7 could increase p53 abundance, which can trigger cell cycle arrest and apoptosis ."
31519875
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"USP7 directly regulates p53 stability or downregulates p53 by stabilizing MDM2."
35563444
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"Inactivation of HAUSP in vivo modulates p53 function."
19946331
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"This is underscored by recent findings showing that HAUSP can be used to therapeutically target p53 independent apoptosis responses in certain tumors."
22056774
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"Unlike previous USPs, USP7 modulates the localization and conformational structure editing of the well-known tumor suppressors p53 and PTEN."
29864543
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"Partial reduction of USP7 activity by RNAi destabilizes p53 through reduced deubiquitination ."
17291557
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"As previously shown, a modest reduction in Hausp by RNA interference decreased p53 stability."
19946331
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"Thus, USP7 positively regulates P53 through multiple molecular mechanisms.Here, we show that mRNA and protein levels of USP7 are markedly decreased in colon cancers."
22750444
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"USP7 stabilizes the E3 ligase MDM2 due to its deubiquitinating activity, and hence indirectly leads to enhanced p53 proteasomal degradation."
26415220
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"The USP7 deubiquitinase is known to modulate the p53 pathway both by protecting p53 from MDM2 mediated degradation and MDM2 from auto-ubiquitination."
26971997
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"Furthermore, this feedback regulation is specific to Mdm2; in HeLa cells, where p53 is preferentially degraded by viral E6 dependent ubiquitination, depletion of HAUSP fails to activate p53."
15053880
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"Inhibition of USP7 could degradate oncogenic E3 Ub-ligase MDM2, and reactivate tumor suppressor p53."
37795365
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"The results of these experiments showed that in the presence or absence of cabozantinib, USP7 knockdown could reduce the half-life of p53 protein, but had no effect on p53 protein, suggesting that silencing USP7 in p53  cells can produce a similar effect to cabozantinib (Fig. S4, D and E)."
39793887
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"Overexpression of USP7 significantly prolonged the half-life of p53 protein (Fig. S5A) and effectively counteracted the degradation and ubiquitination of p53 induced by cabozantinib (Fig. 4, C and D)."
39793887
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"Accordingly, overexpression of USP7 induces p53-dependent cell growth repression and apoptosis (in H460 lung carcinoma and MEF) suggesting that USP7 may thereby act as a tumor suppressor."
17961905
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"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
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"Chemical inhibition of USP7 and Wip1 impairs the viability of TP53 wild-type Ewing sarcoma cells."
30045945
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"As USP7 participates in regulating the P53-murine double minute-2 (MDM2) axis XREF_BIBR, abrogation of USP7 is considered to inactivate MDM2 and subsequently reactivate P53, leading to cell cycle arrest and apoptosis XREF_BIBR."
33777676
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"USP7 as a context specific modulator mediates p53 dependent apoptosis via controlling MDM2 stability."
33869052
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"In addition, overexpression of USP7, Mdm2 and p53 in H1299 lung carcinoma (p53 −/− ) resulted in p53 rescue by USP7 from Mdm2-mediated degradation [25] ."
17961905
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"This has been described for deubiquitinating enzymes such as HAUSP, which rescues the tumor suppressor p53 by removing ubiquitin moieties that would otherwise target it for degradation by the proteasome."
15037600
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"In theory, USP7 inhibition should therefore trigger HDM2 degradation, p53 stabilization and ultimately activation of apoptotic pathways in tumour cells ."
28959952
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"In fact, USP7 was identified initially as a DUB for p53, although it was later discovered that MDM2 is a more efficient substrate of USP7 that modulates p53 stability."
37740002
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"Specifically, HAUSP inhibition drives the proteolysis of both negative regulators of p53, Mdm2 and Mdmx, which subsequently decreases the ubiquitinated-p53forms leading to a total increase in p53 protein levels."
29616860
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"HAUSP was originally reported as an MDM2 antagonist because overexpression of HAUSP promotes stability of p53."
25808808
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"The fact that STIP is involved in two different ternary complexes raises the possibility that this interaction may facilitate the USP7 mediated the stabilization of Mdm2 and p53."
26460617
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"Interestingly, a study by Reddy et al 22 demonstrated that GMPS is required for ubiquitin-specific protease 7 (USP7)–mediated p53 stabilization."
27939741
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"These results demonstrate the critical roles of both USP7 and CHIP in regulating the cabozantinib-induced alteration of p53 stability.Targeting mutant p53 proteins through promoting their degradation is an attractive strategy for the development of anticancer drugs."
39793887
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"Furthermore, the effect of USP7 on Mdm2 and p53 was significantly diminished when STIP was knocked down by shRNA, indicating that STIP plays a significant facilitating role in USP7 mediated stabilization of Mdm2 and P53."
26460617
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"Here, we show that guanosine 5 '-monophosphate synthase (GMPS) is required for USP7 mediated stabilization of p53."
24462112
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"In contrast, a more modest reduction in HAUSP causes a decrease in both MDM2 and p53 stability, suggesting that, under these conditions, sufficient MDM2 remains to degrade p53."
24143256
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"Although future investigations are required to identify the key substrates for HAUSP mediated p53 independent function, our study provides strong evidence that the HAUSP/Mdm2/p53 interplay represents the major role for HAUSP in vivo."
21350561
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"The herpesvirus associated ubiquitin specific protease (also named as USP7) can be activated by ATM to stabilize p53 response to DNA damage."
27893708
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"Inhibiting USP7 with the small-molecule inhibitor P22077 attenuates the p53-dependent apoptotic pathway by destabilizing Tip60 [105] ."
25911240
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"Our previous study showed that USP7-mediated WNT activation is P53 independent (Novellasdemunt et al., 2017)."
36669491
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"Indeed, USP7 overexpression increases the steady-state levels of the Mdm2 and p53 protein."
26460617
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"ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage."
22361354
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"Collectively, our study identified a novel mechanism by which USP7, through catalyzing the SMAD3 de-monoubiquitination, facilitates the positive autoregulation of SMAD3, and represses the cancer progression of p53-deficient lung cancer."
34580281
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"USP7 promotes positive self-regulation of SMAD3 by catalysing SMAD3 deubiquitination and inhibits the progression of p53-deficient lung cancer, suggesting that SMAD3 can play an anti-cancer role in lung cancer [95]."
37685308
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"Alternatively, strategies to enhance the activity of the p53 deubiquitinating enzyme, HAUSP, may have a similar impact on p53 function [112,113]."
17097911
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"Roles of HAUSP mediated p53 regulation in central nervous system development."
29616860
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"However, USP7 deficiency paradoxically promotes p53 stabilization."
20531303
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"From a functional perspective, we speculate that, WDR79, a scaffold protein with multiple WD-repeat domains, may form a platform to actively recruit or tether USP7 and its targets Mdm2 and/or p53 from the nucleoplasm, which facilitates the USP7 mediated stabilization of Mdm2 and p53."
28406480
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"HAUSP, which is localized in the nucleus, can prevent the degradation of p53 by deubiquitinating even under the circumstance of highly expressed Mdm2."
32140262
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"Although numerous studies indicate that inhibition of USP7 suppresses tumor growth by activating p53, the precise mechanism by which USP7 contributes to tumor growth through the p53-independent manner is not well understood."
37291217
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"However, somatic knockout of HAUSP or embryonic knockout of HAUSP causes p53 stabilization rather than destabilization."
22673503
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"There also seems to be a delicate balance between these proteins, as a modest reduction of HAUSP levels prevents p53 deubiquitination but complete ablation of HAUSP causes robust p53 stabilization."
20404858
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"We also find that ING1 physically interacts with herpesvirus associated ubiquitin specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53."
21731648
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"It will be interesting to discover whether overexpression of USP7 could also rescue the diminished DNA damage induced p53 response caused by USP10 depletion."
20144755
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"USP7 promotes the deubiquitination of : i) p53, increasing its stability via MDM2; ii) PTEN, favoring its shuttling from the nucleus into the cytoplasm; iii) FOXOs, favoring changes in cellular compartmentalization."
28418900
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"USP7 Inhibition Decreases Cell Growth and Viability in TP53 Wild-Type Neuroblastoma Cells."
37762082
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"The expression of USP7/HAUSP prevents p53 ubiquitination from Mdm2 as a p53-specific E3 ligase and increases the p53 protein stability [25]."
| PMC
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"HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53 dependent cell growth repression and apoptosis."
11923872
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"USP7 can Stimulate p53 Function Independent of its Catalytic Activity."
20885946
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"First, we tested whether USP7 could stimulate p53 function in a ubiquitin independent manner during conditions of cellular stress such as DNA damage."
20885946
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"Strikingly, USP7 deletion perturbs the synaptic proteome and dendritic spinogenesis independent of p53."
39862434
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"Next we tested whether USP7 enhanced p53 function by examining the induction of p21 in H1299 cells after transfection of a p53 expressing plasmid alone or in combination with a plasmid expressing either WT USP7 or a USP7 mutant (XREF_FIG)."
20885946
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"However coexpression of USP7-CTD with p53 resulted in a 5-fold increase in luciferase activity, indicating that the USP7-CTD can stimulate p53 transactivation from the p21 promoter."
20885946
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"Taken together, our results show that USP7 can promote p53 function in a manner that is independent of the interaction through the USP7-NTD and deubiquitylation by the catalytic domain."
20885946
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"For instance, USP47 has been shown to promote apoptosis in rat cardiomyocytes following I/R injury by activating NF‐κB. 7 Additionally, USP7 enhances ferroptosis by activating the p53/TfR1 pathway after I/R in the rat heart."
39985261
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"It is also possible that HAUSP mediated p53 effects could be tissue specific, and more recently it was shown that neural cell specific inactivation of HAUSP in mice caused p53 dependent hypoplasia and brain development deficiencies [XREF_BIBR]."
21624367
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"As previous reports have alluded to an additional binding site (other than TRAF) for the USP7 targets p53 and MDM2 in the C-terminal domains of USP7 50, we first assessed the binding of the peptide to USP7 constructs in a FP assay."
30651545
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"Overexpression of HAUSP stabilises Mdm2 and prevents p53 degradation."
19897040
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"USP7 Stimulates p53 DNA Binding Through Interactions with the p53 C-terminal Regulatory Region."
20885946
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"25 USP7 deficiency in mouse embryonic fibroblasts (MEFs) greatly reduces the half-life of MDM2 and activates p53."
24136231
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"Still, the USP7-MDM2-p53 axis remains the paradigm of USP7 interactions in the nucleus, and new research continues to show how USP7 promotes p53 dependent apoptosis in disease."
30897496
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"TSPY1 suppresses USP7 mediated p53 function and promotes spermatogonial proliferation."
29748603
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"In chronic lymphocytic leukemia (CLL), USP7 inhibition arrests cell growth and induces p53 independent apoptosis by restoring PTEN in the nucleus [XREF_BIBR]."
30897496
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"Inactivation of HAUSP in vivo modulates p53 function."
29616860
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"Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions; however, USP7 targets p53 in response to DNA damage."
25605410
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"The data obtained from the present study did not demonstrate whether p53 upregulation is directly regulated by HAUSP activity or is dependent on the more complex BCR, ABL, HAUSP, MDM2, and p53 network, but the upregulation in p53 levels supports the assessment of HAUSP inhibitors in the clinical setting."
27899971
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"USP7 promotes colorectal cancer cell apoptosis by directly stabilizing p53 ."
39341821
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"Although we cannot exclude the possibility that a HAUSP-independent mechanism for RORα and/or a RORα-independent mechanism for HAUSP which is responsible for p53 stabilization might exist, both HAUSP [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22152482
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"However, knockdown of RORα led to a diminished recruitment of CBP coactivator and RNA polymerase II to the promoters ( Figure 5 G), suggesting that RORα regulates transcriptional activation of p53 wit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22152482
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"The ubiquitin-specific protease USP7-mediated pathway is thought to mediate TfR1 regulation, and the inhibited USP7 activates the transcription factor P53 protein by inhibiting deubiquitination, leadi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
38278348
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"For example, USP2 and USP7 modulate p53 and MDM2, impacting cell survival and tumor development, while USP22 stabilizes c-Myc, driving cancer proliferation and metastasis [9–13]."
40188027
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"In addition to the ability of HAUSP to deubiquitinate PTEN and the relevance of the BCR-ABL/HAUSP/PTEN network in CML, HAUSP is also able to target p53."
27899971
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"Taken together, the observations reveal the significance of TSPY1 as a suppressor of USP7 mediated p53 function in inhibiting p53 dependent cell proliferation arrest."
29748603
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"The findings suggest an additional mechanism underlying the regulation of spermatogonial p53 function, indicating the significance of TSPY1 in germline homeostasis maintenance and the potential of TSPY1 in regulating human spermatogonial proliferation via the USP7 mediated p53 signaling pathway."
29748603
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"In addition, HBX 41,108 (11) was proven to regulate the deubiquitination of USP7-mediated p53 both in vitro and in vivo ."
38262120
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"They evaluated the influences of the two compounds on deubiquitination of USP7-mediated p53."
38262120
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"Knockdown of USP7 could inhibit ferroptosis by deubiquitinased p53."
38525836
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"These results indicate that the knockdown of USP7 inhibits the ERK1/2 signaling pathway via a p53-dependent mechanism."
35948545
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"Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53."
37961719
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"When a decrease in USP7 levels leads to MDM2 degradation, the available MDM2 levels become insufficient for ubiquitination, which stabilizes p53.The USP7/p53/MDM2 axis remains one of the cornerstones of the USP7 pathway in the nucleus, and fresh studies continue to illustrate how USP7 promotes p53-dependent apoptosis in disease."
36428632
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"Mechanisms of action underlying the regulation of USP7 mediated p53 function by TSPY1."
29748603
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"Therefore, identification of both E3 ligase and deubiquitinating/deneddylating enzymes for HAUSP will help to elucidate the precise regulatory mechanism of HAUSP-mediated p53 regulation.A number of pr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16111684
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"These findings provide the first evidence that TSPY1, in addition to TSPYL5, can promote the ubiquitin mediated degradation of USP7, suggesting TSPYL5 independent regulation of USP7 mediated p53 function by TSPY1."
29748603
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"In addition, EBNA1 can interact with USP7 that modulates p53 and Mdm2 by preventing their degradation [115, 116]."
34536980
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"The stability of p53 mediated by USP7 is essential for brain development, where KO of USP7 causes neonatal lethality, hypoplasia, and deficiencies in neuronal development (37)."
38952059
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"Impact of TSPY1 on mouse spermatogonia by regulating Usp7 mediated p53 function."
29748603
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"Previous studies showed that USP7 inhibition promotes the degradation of MDM2 and reactivates p53 signaling [ 31 ]."
38555840
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"This inhibition mechanism was shown to play an important role in breast cancers where TRAF4 overexpression prevents USP7 mediated p53 stabilization and diminishes cytotoxic stress response."
30807924
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"However, the phosphorylation is counterbalanced by ATM-dependent protein phosphatase PPMG1, and USP7 dephosphorylation causes MDM2 degradation and p53 stabilization (Figure 3d) [95]."
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