IndraLab

Statements

USP7 activates MDM2. 67 / 73
1 | 9 58
eidos
"Therefore , inhibition of USP7 should cause degradation of MDM2 , which , in turn , should increase the stability of p53 and suppress cancer progression in tumors with wild-type p53 ( Figure 2a ) ."
30913483
reach
"Accumulated studies have suggested that USP7, through modulating the MDM2/MDMX-p53 pathway, is a promising target for cancer treatment; however, little is known about the function of USP7 in p53-deficient tumors."
34580281
reach
"In this study, we have shown that PDGF-stimulated PASMCs proliferation by USP7-mediated MDM2 up-regulation and further MDM2-mediated FoxO4 ubiquitinated degradation, and finally CyclinD1 elevation."
34552711
reach
"Notably, USP7 can directly regulate not only the stability of p53, but also the protein stability of the MDM2 protein."
33421376
reach
"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]"
36113266
reach
"Indeed, USP7 overexpression increases the steady-state levels of the Mdm2 and p53 protein."
26460617
reach
"USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy."
32300595
reach
"However, USP7 induces fibroblast activation and myocardial fibrosis by binding to and stabilizing MDM2, leading to p53 degradation ."
39341821
reach
"USP10 directly interacts with p53 to remove Ub, while USP7 seems to preferentially target MDM2 [2,7,8]."
28284458
reach
"However, coexpression of USP10 or HAUSP, but not USP10 CA or USP10Delta1-100, significantly reversed the inhibitory effect of Mdm2 on p53 mediated apoptosis."
20096447
eidos
"In theory , USP7 inhibition should therefore trigger HDM2 degradation , p53 stabilization and ultimately activation of apoptotic pathways in tumour cells93 ."
28959952
reach
"Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2, and thereby elevate levels of the p53 protein, with associated therapeutic benefits in cancer and potentially other diseases."
21468692
eidos
"Importantly , around the same time , the Gu lab , who initially identified USP7 , similarly reported that USP7 loss destabilizes Mdm2 , and this is concomitant with an accumulation of p53 and an induction of cell cycle arrest in G1 through subsequent upregulation of the CKI p2175 ."
32201366
reach
"However, the ability of USP7 to prevent proteasomal degradation of HdmX (as well as Hdm2) was abolished following DNA damage."
20713061
reach
"In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling."
39880128
reach
"Both USP2 and USP7 and HAUSP target MDM2 and lead to its degradation XREF_BIBR."
27665737
reach
"The stability of p53 and its ubiquitin E3 ligases HDM2 and HDMX is modulated by USP7, the de-ubiquitinase of a number of protein targets linked to tumorigenesis [19,23,27] including phosphatase and te[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
27372520
reach
"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
reach
"This can be explained in part by the fact that USP7 also binds to polyubiquitinated Mdm2 and promotes Mdm2 stability."
20531303
reach
"In theory, USP7 inhibition should therefore trigger HDM2 degradation, p53 stabilization and ultimately activation of apoptotic pathways in tumour cells ."
28959952
reach
"This study provides an example of an ubiquitin ligase (Mdm2) that is directly regulated by a deubiquitinase (HAUSP) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway."
15053880
reach
"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
eidos
"As Hdm2-induced autoubiquitylation leads to its destruction , inhibitors of Usp7 promote the degradation of Hdm2 , which in turn stabilizes Hdm2 substrates , particularly p53 ."
25325686
reach
"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
reach
"However, others [66] and we have not been able to confirm a direct interaction between p14ARF and Hdmx.Lastly, Li et al. [62] mentioned that HAUSP co-expression could not rescue the Mdm2 mediated degr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15865931
reach
"Because HAUSP rescues Hdm2-mediated degradation of Hdmx, we wondered whether an increase in HAUSP expression would also prevent the degradation of Hdmx after DNA damage."
15916963
reach
"USP7 promotes the stability of MDM2, thus maintaining the key tumor suppressor protein p53 at low levels [28,29]."
40006058
reach
"This observation suggests that the absence of USP7 promotes MDM2 downregulation, which in turn eliminates the activity of MDM2 as the Ub ligase for p53."
24239534
reach
"However, it was later shown that depletion of HAUSP promotes MDM2 destabilization and leads to p53 activation."
25808808
reach
"However, it is unclear whether up-regulation of USP7 elevates MDM2 and subsequently promotes cell proliferation in PDGF-stimulated PASMCs."
34552711
reach
"Examples of MDM2 regulators are : ARF4 that may dampen the p53 pathway by releasing MDM2; HAUSP that targets MDM2 resulting in its stabilization and negative regulation of the p53 pathway; and WIP1, a phosphatase that dephosphorylates MDM2 preventing prolonged p53-pathway activation [XREF_BIBR]."
27916892
reach
"This interference is first evidenced by the response to oxidative DNA damage and modulation of DNA accessibility to base excision repair (BER) machinery, which is an indirect effect due to HAUSP mediated MDM2 regulation."
29967688
reach
"However, it is unclear whether up-regulation of MDM2 by USP7 facilitates FoxO4 ubiquitinated degradation and subsequently up-regulates CyclinD1 to promote PDGF-induced PASMCs proliferation."
34552711
reach
"HAUSP enhances Mdm2 stability by removing ubiquitin moieties from Mdm2 ( Li et al., 2004; Meulmeester et al., 2005 )."
17936559
reach
"In unstressed cells, SUV39H1 is deubiquitinated and protected from MDM2 mediated degradation by HAUSP, promoting the repression of p53 responsive gene transcription."
29967688
reach
"Hence, inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53, resulting in inhibition of cell cycle progression and tumor cell apoptosis."
27769803
reach
"The results also demonstrated that USP7 can upregulate MDM2, and inhibit the expression of p53."
33869052
reach
"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
reach
"Another example highlights a deubiquitinase (Usp7) docking motif that negatively regulates Mdm2 degradation ."
35545699
reach
"USP7 mediates PDGF-induced up-regulation of MDM2, down-regulation of FoxO4 and elevation of CyclinD1 in PASMCs."
34552711
reach
"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]"
28587923
reach
"As Hdm2-induced autoubiquitylation leads to its destruction, inhibitors of Usp7 promote the degradation of Hdm2, which in turn stabilizes Hdm2 substrates, particularly p53."
25325686
reach
"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."
37658402
reach
"Inhibition of USP7 could degradate oncogenic E3 Ub-ligase MDM2, and reactivate tumor suppressor p53."
37795365
reach
"In addition to P5091, a dual inhibitor of USP7 and USP47, compound 1 ( Table 2 ) (IC 50 = 4.2 μM for USP7 and IC 50 = 4.3 μM for USP47) [86] accelerated MDM2 degradation in human cancer cell lines and[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
33157193
reach
"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
eidos
"Our study suggests that USP7 up-regulates MDM2 , which facilitates FoxO4 ubiquitinated degradation , and subsequently increases the expression of CyclinD1 to mediate PDGF-induced PASMCs proliferation ."
34552711
eidos
"47 In an earlier study , USP7 removed PTEN monoubiquitination , enhanced its nuclear export , and abolished its nuclear function.21 MDM2 is also a substrate of USP7 , and inhibition of USP7 resulted in degradation of MDM2 ."
30370059
reach
"Although USP7, like all DUBS, deconjugates ubiquitin from several target proteins, inhibition of USP7 promotes the degradation of its primary cellular target, HDM2, resulting in net p53 stabilization and activation [30], [42], [43]."
22610084
reach
"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
reach
"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
reach
"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
reach
"In addition, EBNA1 can interact with USP7 that modulates p53 and Mdm2 by preventing their degradation [115, 116]."
34536980
eidos
"USP7 inhibition causes degradation of MDM2 due to stabilisation of proteasome-targeting ubiquitin chains , which in turn stabilises the tumour suppressor p53 ."
33080838
reach
"In this light, it is interesting that HAUSP (USP7), a DUB originally proposed to counteract MDM2 dependent p53 ubiquination, has since been found to target MDM2 as its prime substrate, reconciling contradictory observations that p53 was stabilized in cells of diminished HAUSP."
27546791
reach
"Some inhibitors of DUBs have been discovered, such as P5091, a potent and specific inhibitor of USP7 that promotes the degradation of MDM2 and thereby stabilizes p53 ."
30250021
reach
"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
reach
"This observation indicates that Mdm2 may recruit nucleolin to HAUSP, and that HAUSP then increases the stability of both Mdm2 and nucleolin via its deubiquitinating enzyme activity."
26238070
eidos
"The results also demonstrated that USP7 can upregulate MDM2 , and inhibit the expression of p53 ."
33869052
reach
"Therefore, inhibition of USP7 should cause degradation of MDM2, which, in turn, should increase the stability of p53 and suppress cancer progression in tumors with wild-type p53 (XREF_FIG)."
30913483
reach
"Our study indicated that MDM2 was up-regulated; this was accompanied with down-regulation of FoxO4, elevation of CyclinD1 and cell proliferation in PASMCs stimulated with PDGF, while knockdown of USP7 attenuated the changes of MDM2, FoxO4 and CyclinD1 as well as PASMCs proliferation caused by PDGF."
34552711
reach
"Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions; however, USP7 targets p53 in response to DNA damage."
25605410
reach
"It has also been shown that the inhibition USP7 and USP2a which are de-ubiquitinases of Hdm2, increases Hdm2 proteolysis and stabilizes p53 levels in multiple myeloma cells enabling the initiation of apoptosis."
24756373
reach
"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
reach
"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
eidos
"The stabilized USP7 / HAUSP can enhance Mdm2 and decrease p53 protein expression ."
| PMC
reach
"P22077 downregulated USP7 targets MDM2, claspin, and Chk1 [XREF_BIBR] and inhibited neuroblastoma growth [XREF_BIBR], and P50429 inhibited HCT116 proliferation [XREF_BIBR, XREF_BIBR]."
30897496