IndraLab

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USP7 inhibits TP53. 94 / 103
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"The inhibition of USP7 can reactivate p53 (90)."
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"USP7 directly regulates p53 stability or downregulates p53 by stabilizing MDM2."
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"Overexpression of USP7 and HDM2 inactivates P53 signaling in tumor cells and facilitates their progression, but suppression of these targets by conventional strategies to reactivate P53 function remains a challenge."
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"The inhibition of USP7 with HBX 41,108, a DUB to Hdm2 has shown to induce p53 dependent apoptosis with an IC in sub-micro-molar concentrations."
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"On the other hand, by ubiquitinating itself, MDM2 targets itself for destruction and promotes the p53 tumor suppressor pathway, a process that can be antagonized by the deubiquitinase herpesvirus associated ubiquitin specific protease (HAUSP)."
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"45 The aberrant activities of USP7 and HDM2 suppress the normal function of P53 and thereby disrupt the natural processes of apoptosis and cell-cycle progression in cells, which may contribute to cancer initiation."
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"Partial reductions in HAUSP levels lead to destabilization of p53, whereas more complete reductions may cause MDM2 destabilization and p53 accumulation."
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"In addition, USP7 is suppressed by various DUB inhibitors including HBX41108 and P22077, thereby regulating p53 [94-96]."
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"USP7 counteracts autoubiquitylation of MDM2 , thereby promoting p53 degradation ."
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"Inhibition of USP7 activated p53 via suppressing deubiquitination, which led to down-regulation of TfR1, accompanied by the decreased ferroptosis and myocardial I/R injury."
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"A class of dual small molecule inhibitors of USP7 and USP47 has been identified to promote p53 activity and apoptosis in MM and B-cell leukemia cells in vitro and xenograft models."
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"Moreover, TSPYL5 overexpression suppresses the function of p53 and by regulating USP7, which causes the degradation of p53, its target genes [87]."
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"A similar situation is observed in the rescue of Hdm2-induced degradation of p53 by HAUSP ( Li et al., 2004 )."
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"Hence, inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53, resulting in inhibition of cell cycle progression and tumor cell apoptosis."
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"Together, these data show that inhibition of USP7 by UbV.7.2 induces MDM2 depletion and p53 stabilization, which in turn increases sensitivity to cisplatin treatment and consequently leads to greater [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"USP7, for example, antagonized p53 stabilization and hence has been screened for small molecule inhibitors ( Colland, Formstecher et al. 2009 )."
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"During the deubiquitination process of USP7 towards these two proteins, USP7 overexpression causes MDM2 to be deubiquitinated more thoroughly than p53, accelerating the degradation of p53."
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"Specifically, USP7 overexpression has been shown to enhance the stability of E3 ligase murine double minute 2 (MDM2) while promoting the degradation of p53, leading to dysregulation of the MDM2-p53 pathway in tumorigenesis ."
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"Moreover, USP7 overexpression rescues p53 degradation in DOPEY1-silenced cells."
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"The essential role of USP7 during cell cycle progression and apoptosis has been reported by other groups: i) USP7 knockdown leads to increased p53 expression and arrest of cell cycle (Cummins et al., 2004), ii) USP7 regulated various tumor-related factors expression (p53, Ki-67) in bladder cancer and prostate cancer (Song et al., 2008; Morra et al., 2019)."
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"This is significantly different from USP2a, USP4, USP2 and USP7-mediated p53 inhibition through stabilization of E3 ligases, including MDM2 and ARF-BP1 [ 63–66 ]."
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"Upon cellular stresses, such as DNA damage or oncogene activation, the TP53 degradation process is attenuated by USP7 and USP10, two deubiquitinating enzymes."
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"As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [XREF_BIBR], USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53."
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"Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway."
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"Furthermore, the abnormal embryos showed p53 staining in the remaining cells, suggesting loss of HAUSP caused accumulation of p53 (XREF_FIG)."
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"To avoid complications associated USP7 inhibition-induced p53 accumulation, we knocked out p53 in both C3H10T1/2 and ST2 cells using CRISPR."
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"For example, expression of EBNA1 but not a USP7 binding mutant of EBNA1 was shown to reduce the accumulation of p53 in response to DNA damage in U2OS cells [XREF_BIBR]."
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"Increased ARF-BP1 and Mule degradation causes p53 stabilization, which is antagonized by the DUBs USP7 and USP4."
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"Our results support a new role for vIRF1 through deregulation of the deubiquitinating enzyme USP7 to inhibit p53 mediated antiviral responses."
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"For example, expression of EBNA1 but not a USP7 binding mutant of EBNA1 in U2OS cells was shown to reduce the accumulation of p53 in response to DNA damage and subsequent apoptosis [XREF_BIBR]."
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"USP7 inhibited the radio-sensitivity of p53-mutated LSCC cells, while it promoted radio-sensitivity of p53-wild type LSCC cells."
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"As shown in Fig. 1, USP47 and USP7 inhibit cancer cell growth in a p53-dependent manner."
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"USP7 disrupts the equilibrium of the p53-dependent MDM2 axis, leading to the proteasomal degradation of p53 and ultimately decreasing the expression of PD-L1 on the surface of tumor cells.120, 121, 122 Several USP7 inhibitors are currently in preclinical trials and further studies are required."
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"By either mechanism, our results establish that USP7 modulates the repressive H3K9me3 mark by protecting SUV39H1 from MDM2 mediated degradation and blocking aberrant p53 transactivation of target genes in unstressed p53 wt cells."
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"Moreover, we showed that CHIP knockdown abrogated the downregulation of p53 caused by USP7 knockdown (Fig. S5D), and simultaneous knockdown of CHIP and USP7 attenuated the enhanced ubiquitination of p53 in the cells subjected to USP7 knockdown (Fig. S5E)."
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"These results suggest that USP7 knockdown elicited similar effects to cabozantinib on p53 and validated the crucial role of USP7 in the cabozantinib-induced, CHIP-mediated degradation of p53 protein."
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"In addition, HAUSP dependent stabilization of Mdm2 and Mdmx might enhance degradation of p53 by the Mdm2 and Mdmx heterodimer."
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"Since MDM2 can make p53 inactivated, inhibition of USP7 can trigger degradation of MDM2 and reactivate the p53 pathway in cancer cells, the study of USP7 inhibitors has become one of the hot topics in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Therefore, we confirm that USP7 also as an oncogene inhibits p53 dependent apoptosis in melanoma, as in colon cancer."
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"Although several Daxx interacting proteins are involved in critical cellular pathways regarding P53 degradation, such as ubiquitin-specific-processing protease 7 (USP7) and mouse double minute 2 (Mdm2) [XREF_BIBR, XREF_BIBR], it is still unclear whether Daxx has any role in tumorigenicity of OSCC."
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"Additionally, knockdown of CHIP completely abolishes the downregulation of p53 caused by USP7 knockdown (Fig. S5, D and E)."
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"Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes."
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"Meanwhile, the abrogation of USP7 suppressed GC cell proliferation by stabilizing p53 and promoting cell cycle arrest both in vitro and in vivo."
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"Inhibition of USP7 has been shown to increase p53 stability, thus promoting cancer cell apoptosis [ 12–14 ]."
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"In fact, several small-molecule inhibitors of USP7 have been recently shown to activate p53 by down-regulating Mdm2 activities without inducing genotoxic stress."
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"Typically , USP7 could stabilize MDM2 by deubiquitination and subsequently promotes the degradation of p53 , causing the inhibition of apoptosis in cancer cells ( Bhattacharya et al. 2018 ) ."
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"Thus, we examined the role of USP7 in the cabozantinib-induced p53 degradation."
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"That is , by knocking down USP7 expression through targeted homologous recombination , Vogelstein and colleagues found that rather than stabilizing p53 , USP7 instead protects Mdm2 from auto-ubiquitination , thus indirectly triggering p53 degradation ."
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"Compound 1, a selective inhibitor of USP7 and USP47 with moderate potency, demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines."
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"Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53 dependent apoptosis in human cancer cells."
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"Previous studies have established that PPM1G can dephosphorylate USP7 and consequently lead to the degradation of Mdm2 as well as the degradation of p53.26 Therefore, the disruption of USP7 and Mdm2 phosphorylation caused the accumulation of p53."
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"Inhibition of USP7 deubiquitinating activity using HBX 41108 could activate and stabilize p53 to inhibit the proliferation of cancer cells [34]."
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"In accordance, partial knockdown of USP7 was shown to cause the destabilization of TP53,39 and the TP53 expression level were by far the lowest in CK2-Mut, which also showed mutation in 1 allele of TP53."
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"USP7 promotes the stability of MDM2, thus maintaining the key tumor suppressor protein p53 at low levels [28,29]."
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"USP7 inhibition triggers p53-dependent apoptosis in cancer cells ( Mungamuri et al., 2016 ; Zhou et al., 2018 ; Gao et al., 2021 ) as well as in senescent fibroblasts ( He et al., 2020 ), mainly in re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"We can propose a scenario shared by melanomas with different genetic backgrounds and phenotypic features, where loss of USP7 induces p53- and p16-independent senescence through p21 upregulation and Cy[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In cancer , USP7 could stabilize MDM2 by de-ubiquitination and subsequently promotes degradation of P53 specifically [ 12 ] ."
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"USP7 Inhibition Induces Cell Apoptosis in TP53 Wild-Type Neuroblastoma Cells."
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"Notably, TSPYL5 interacts with USP7 (ubiquitin specific peptidase 7) to reduce the tumor suppressor activity of p53, overriding p53-dependent proliferation arrest [12], promoting endothelial cell proliferation and angiogenesis [15], and protecting POT1 (protection of telomeres 1) from proteasomal degradation in ALT (alternative lengthening of telomeres)-positive cells [16]."
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"In a xenograft mouse model, USP7 inhibition mediated p53‐dependent cell‐cycle arrest and apoptosis."
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"Thus, inhibiting HAUSP by small compound interference has been proposed as a rational therapeutic strategy to activate p53 in p53 wild type tumors."
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"Knockdown of USP7 can also activate p53 signaling and lead to cell cycle arrest [20], which makes USP7 as a therapeutic target due to its activation of p53 [26]."
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"Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response."
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"More recently, it has been shown that a small molecule inhibitor of HAUSP, HBX41108, stabilizes p53 and induces p53 dependent apoptosis in cancer cell lines that retain wild-type p53 [XREF_BIBR]."
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"Indeed, recent studies have shown that the USP7-specific inhibitor, P22077, induces apoptosis in a p53-dependent manner in colon carcinoma and neuroblastoma [3,4] ."
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"Notably, selective dual inhibitors of USP7 and USP47 have been synthesized and induced accumulation of p53 and apoptosis in human cancer cell lines [XREF_BIBR]."
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"The USP7-TP53-TFRC axis was implicated in ferroptosis in a rat model of myocardial IRI and H9c2 cells subjected to hypoxia/reoxygenation (H/R), whereby inhibition of USP7 activated TP53, which then do[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"However, the neuropathogenesis of HAFOUS has remained poorly understood.Studies in cancer biology have revealed that USP7 induces turnover of the tumor suppressor protein p53, and, thus, inhibition of USP7 may hold therapeutic promise for suppressing tumor growth."
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"These findings suggested that USP7 downregulated by I3MO triggers p53 and p65 degradation and suppresses its downstream signaling transduction.Our previous study indicated that USP7/NEK2/NF-κB pathway activation plays pivotal roles in bortezomib resistance in MM.7 39 Since the stabilization of NEK2 by USP7 is required for the release of p65 into the nucleus, we further investigate whether downregulation of USP7 involved in I3MO efficacy via triggering NEK2 degradation and suppresses its downstream signaling transduction."
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"A study has shown that USP7 deubiquitinates and stabilizes E3 ubiquitin ligase MDM2, and thereby promotes MDM2-mediated ubiquitinated degradation of p53 and cell growth in ovarian cancer cells."
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"26 Taken together, these studies suggest that USP7-MDM2-p53 is a critical axis that functions to limit the level of p53 in cells and that USP7 inhibition can result in p53 activation and cell death."
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"In cancer, USP7 could stabilize MDM2 by de-ubiquitination and subsequently promotes degradation of P53 specifically [12]."
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"Moreover, inhibition of USP7 activated p53 and decreased TfR1, and then attenuates ferroptosis and protects the heart from myocardial I/R injury (Tang et al., 2021), suggesting that inhibition of USP7 may be a potential therapy for cardiovascular disease."
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"Thus, our results indicate that USP7 overexpression inhibits the ERK1/2 signaling pathway by deubiquitination of Raf-1 and independently of p53."
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"We explored whether the distinct p53 induction profiles induced by USP7 and MDM2 inhibitors lead to differential downstream effects in cells."
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"In our study, we confirmed that USP7 overexpression inhibits the ERK1/2 signaling pathway in a p53-independent manner in LUAD cell lines."
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"This indicates that MDM2 inhibitor activity in the RKO cell line is on target and related to the induction of p53, and that the more modest induction of p53 elicited by USP7 inhibition is insufficient to inhibit proliferation in this cell line.These findings highlight significant mechanistic differences between the effects of MDM2 inhibitors and USP7 inhibitors in healthy and neoplastic cells."
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"In addition, we showed that p53 induced by USP7 inhibition in SnCs localized partially to mitochondria, where it might induce SnC apoptosis by interacting with BCL‐XL and displacing BAK."
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"Knockdown of USP7 expression increases p53 expression and inhibits colon cancer cells proliferation ( Colland et al ., 2009 ) ."
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"Collectively, we have demonstrated that inhibition of USP7 by a small-molecule inhibitor P22077 can result in reactivation of p53 and consequently inhibit tumor growth."
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"This hypothesis is supported by our finding that proteasome inhibition with MG132 abrogated USP7 inhibition‐induced downregulation of MDM2 and upregulation of p53 in SnCs."
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"Notably, USP7 overexpression has been demonstrated to stabilize MDM2 and destabilize p53, promoting p53 proteasomal degradation and diminishing p53 tumor suppressor downstream networks (Li et al., 2004)."
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"Our results confirm that downregulation of USP7 potentiates the proteasomal degradation of p53 and dictates cell fate via cell cycle modulation."
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"USP7 impairs the balance of the p53/MDM2 axis resulting in the proteasomal degradation of the p53 tumor suppressor, a process that can be reversed by small-molecule inhibitors of USP7."
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"Inhibition of USP7 induces p53-independent tumor growth suppression in triple-negative breast cancers by destabilizing FOXM1."
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"The essential role of USP7 during cell cycle progression and apoptosis has been reported by other groups : i ) USP7 knockdown leads to increased p53 expression and arrest of cell cycle ( Cummins et al ., 2004 ) , ii ) USP7 regulated various tumor-related factors expression ( p53 , Ki-67 ) in bladder cancer and prostate cancer ( Song et al ., 2008 ; Morra et al ., 2019 ) ."
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"Overexpression of TSPYL5 suppresses p53 function and its target genes by regulating ubiquitin specific protease 7 (USP7) that cause p53 degradation."
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"However, USP7 also prevents genetic alterations in various ways independent of p53."
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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 Mdm2.120 ,218 Unlike HAUSP , USP10 is generally located in the cytoplasm ."
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"It seems that EBNA1 could strongly upregulate p53-inhibiting genes including HDAC1, MDM2, MDM4 , and USP7 ."
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"The results also demonstrated that USP7 can upregulate MDM2 , and inhibit the expression of p53 ."
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"These findings suggest that loss of USP7 function in glutamatergic neurons in the forebrain might be relevant to HAFOUS.In developmental studies, USP7 deletion causes p53-dependent apoptosis in post-mitotic glutamatergic neurons."
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"As p53 is activated by genotoxic stress and has a key role in genotoxic stress induced cell death, we reasoned that pharmacological inhibition of USP7 activity would potentiate p53 activity and result in increased chemosensitivity."
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"For instance, viral interferon regulatory factor 1 (vIRF1) encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV) interacts with ubiquitin-specific protease 7 (USP7) to repress the p53 enzymatic activities, thus inhibiting p53-mediated antiviral responses [8]."
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