IndraLab

Statements

USP7 activates MDM2. 48 / 53
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"The stabilized USP7 / HAUSP can enhance Mdm2 and decrease p53 protein expression ."
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"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
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"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 ."
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"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."
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"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
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"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 ."
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"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]."
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"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."
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"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
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"USP10 directly interacts with p53 to remove Ub, while USP7 seems to preferentially target MDM2 [2,7,8]."
28284458
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"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."
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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."
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"In theory, USP7 inhibition should therefore trigger HDM2 degradation, p53 stabilization and ultimately activation of apoptotic pathways in tumour cells 93 ."
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"The results also demonstrated that USP7 can upregulate MDM2, and inhibit the expression of p53."
33869052
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"Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins."
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"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
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"Indeed, USP7 overexpression increases the steady-state levels of the Mdm2 and p53 protein."
26460617
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"Both USP2 and USP7 and HAUSP target MDM2 and lead to its degradation XREF_BIBR."
27665737
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"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 ."
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"In fact, a genetic knockout of USP7 caused depletion of MDM2 and, despite the aforementioned rescue effect of USP7 on p53, effectively stabilized p53 (Cummins et al., 2004, Li et al., 2004)."
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"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
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"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
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"USP7 inhibition causes degradation of MDM2 due to stabilisation of proteasome-targeting ubiquitin chains , which in turn stabilises the tumour suppressor p53 ."
33080838
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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."
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"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
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"The results also demonstrated that USP7 can upregulate MDM2 , and inhibit the expression of p53 ."
33869052
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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."
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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]."
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"In theory , USP7 inhibition should therefore trigger HDM2 degradation , p53 stabilization and ultimately activation of apoptotic pathways in tumour cells93 ."
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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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"In unstressed cells, SUV39H1 is deubiquitinated and protected from MDM2 mediated degradation by HAUSP, promoting the repression of p53 responsive gene transcription."
29967688
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"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
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"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."
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"This can be explained in part by the fact that USP7 also binds to polyubiquitinated Mdm2 and promotes Mdm2 stability."
20531303
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"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
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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."
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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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"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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"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
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"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
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"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
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"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
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"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
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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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"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 ."
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"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] ."
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"However, it was later shown that depletion of HAUSP promotes MDM2 destabilization and leads to p53 activation."
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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."
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