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TP53 binds USP7 and MDM2. 51 / 51
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sparser
"In addition, USP7 can interact indirectly with p53, using Mdm2 as a bridge, resulting in the formation of USP7-Mdm2-p53 complexes."

reach
"The HAUSP, p53, and Mdm2 complex and p53-nucleolin interplay in DNA damage have been identified XREF_BIBR XREF_BIBR XREF_BIBR; however, the molecular relation between these two findings was poorly understood."

sparser
"Taken together, the activation of USP7-MDM2-p53 interaction can promote the occurrence and development of tumors."

reach
"P53, as a tumour-suppressor, exerts an essential role in signalling associated with the control of cell survival and aberrant p53 signalling results in unchecked cell growth and the initiation of cancer.USP7 interacts with a range of protein targets in the p53 pathway (p53, MDMX, MDM2)39 and MDM2 plays a key role in p53 stabilization by increasing the ubiquitination process.39 USP7 deubiquitinates MDM2 and its functional regulator MdmX and stabilizes p53.39 USP7 apparently has 2 independent p53 regulatory functions, stabilizing p53 through deubiquitylation and regulating the sequence-specific DNA binding of p53.40 Within the USP7, MDM2 and p53 complex, p53 and the MDM2 have been shown to bind USP7 through the TRAF domain.39 Under normal conditions, USP7 prefers MDM2 as a substrate rather than p53 and MDM2 has a higher binding affinity for USP7 compared to p53.41 Reduction of USP7 expression levels leads to p53 stabilisation, and destabilization of MDM2."

reach
"The authors find that genotoxic stress induces a shift in complex formation from a p53, MDM2, and USP7 complex to p53/GMPS/USP7."

sparser
"Binding of HAUSP to either p53 or MDM2 leads to their de-ubiquitination, and binding to MDM2 leads to p53 destabilization due to increased MDM2 stability [ xref ]."

sparser
"USP7 can bind directly to Mdm2 or p53 in a mutually exclusive manner."

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."

reach
"However, the linkage between the DNA damage response machinery and the HAUSP, p53, and Mdm2 complex in DNA damaged cells still remain unresolved."

reach
"Taken together, this study reveals a new component of the HAUSP, p53, and Mdm2 complex that governs dynamic cellular responses to DNA damage."

sparser
"An obstacle to this switch is that while USP7 binds both Mdm2 and p53 via its TRAF-like domain, Mdm2 makes more extensive contacts and thus binds the TRAF-like domain with a higher affinity ( xref ; xref )."

sparser
"A complex between USP7, MDM2, and p53 is formed in the nucleus that results in the ubiquitylation and degradation of p53."

sparser
"We then employed co-immunoprecipitation to identify possible changes in the binding of USP7 to Mdm2 and p53."

reach
"Collectively, these results suggest that nucleolin is involved in the formation of the HAUSP, Mdm2, and p53 complex, and the HAUSP-nucleolin interaction requires the presence of Mdm2 in normal condition."

sparser
"Crystal structure analysis visualized HAUSP-p53 and HAUSP-Mdm2 interactions via HAUSP binding motif P/AXXS xref ."

sparser
"The accumulated evidence regarding the interactions of USP7 and MDM2 with p53 indicates that these interactions are important in regulating the stability of p53 under both physiological and pathological conditions."

sparser
"P53 and Mdm2 bind to the N-terminal TRAF-like domain of HAUSP vgin a mutually exclusive manner, and the balance between the Mdm2-mediated ubiquitination and HAUSP-mediated deubiquitination is considered as the key for p53 homeostasis and activation ( xref )."

sparser
"MDM2 and p53 also interact with USP7 via CTD, which serves as a second site of interaction [ xref , xref , xref , xref ]."

sparser
"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 , xref , xref ]."

reach
"19 The identification of Nucleolin as a substrate of HAUSP and a member of the HAUSP, p53, and MDM2 complex has added to the complexity of its dynamics, implicating cellular adaptations to combat DNA damage stress by upregulating Nucleolin in the presence of ionizing radiation."

sparser
"Recent structural studies have indicated that p53 and Mdm2 bind to the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner."

reach
"Next, we investigated whether nucleolin might be a component of the HAUSP, Mdm2, and p53 complex."

sparser
"The N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2 (p53 residues 359−367 and MDM2 residues 147−159) ( xref )."

sparser
"MDM2 is a major negative regulator of p53 [ xref ], and recent studies have found that p53 and MDM2 both bind to the N-terminal TRAF-like domain of USP7 in a mutually exclusive manner [ xref , xref ]."

sparser
"These structures reveal the molecular basis for the differential binding of p53 and MDM2 to HAUSP, which allows the derivation of a consensus peptide-recognition sequence for HAUSP."

sparser
"As USP7 binds both p53 and Mdm2 with the same N-terminal domain [ xref ], the overall effect of its enzymatic activity is highly dependent on the relative affinity for the two targets."

sparser
"USP7 binds to p53 and mdm2, stabilizing the proteins."

sparser
"Because WDR79 affected the interaction of USP7 with Mdm2 and p53, we hypothesized that WDR79 is involved in USP7-mediated regulation of Mdm2 and p53."

sparser
"The Protein Data Bank () accession numbers for the atomic coordinates of the HAUSP TRAF-like domain alone, the HAUSP TRAF-like domain bound to p53 and MDM2 peptides, and HAUSP (residues 53–560) are 2F1W, 2F1X, 2F1Y, and 2F1Z, respectively."

sparser
"MDM2 and p53 also interact with USP7 via CTD, which serves as a second site of interaction [10,147,149,150]."

sparser
"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 ."

sparser
"USP7 interacts with a range of protein targets in the p53 pathway (p53, MDMX, MDM2) xref and MDM2 plays a key role in p53 stabilization by increasing the ubiquitination process. xref USP7 deubiquitinates MDM2 and its functional regulator MdmX and stabilizes p53. xref USP7 apparently has 2 independent p53 regulatory functions, stabilizing p53 through deubiquitylation and regulating the sequence-specific DNA binding of p53. xref Within the USP7, MDM2 and p53 complex, p53 and the MDM2 have been shown to bind USP7 through the TRAF domain. xref Under normal conditions, USP7 prefers MDM2 as a substrate rather than p53 and MDM2 has a higher binding affinity for USP7 compared to p53. xref Reduction of USP7 expression levels leads to p53 stabilisation, and destabilization of MDM2."

sparser
"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 , xref , xref , xref , xref ]."

sparser
"The binding of HAUSP to either p53 or MDM2 leads to their de-ubiquitination, and its binding to MDM2 leads to p53 destabilization due to increased MDM2 stability [ xref ]."

sparser
"Collectively, these results suggest that nucleolin is involved in the formation of the HAUSP-Mdm2-p53 complex, and the HAUSP-nucleolin interaction requires the presence of Mdm2 in normal condition."

sparser
"HAUSP preferentially forms a stable HAUSPMDM2 complex even in the presence of excess p53."

reach
"Since the discovery of the MDM2, USP7, and p53 complex, similar ' switch ' interactions have been well reviewed for USP [XREF_BIBR] and also discovered for other E3 ligases and DUBs."

sparser
"We show that the N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2, falling between p53 residues 359-367 and MDM2 residues 147-159."

sparser
"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."

sparser
"Moreover, p53 was found to be upregulated in MDM2 −/− p53 −/− double-deficient MEFs after co-transfection of both p53 and ABRO1, indicating that ABRO1-dependent p53 stabilization is made possible by enhanced p53-USP7 interaction without effects on p53-MDM2 interaction and MDM2 stability."

sparser
"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."

sparser
"We found that the USP7-Mdm2 and USP7-p53 interactions were significantly reduced in WDR79 shRNA-treated cells compared with control cells ( xref )."

sparser
"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 )."

sparser
"We found that the USP7-Mdm2 or USP7-p53 interactions were significantly reduced in STIP shRNA-treated U2OS cells by co-IP (Figure xref )."

reach
"And our results provide a line of evidence that nucleolin may regulate the DSB response pathway as a component of a HAUSP, Mdm2, and p53 complex."

reach
"However, the protein substrates that are targeted by HAUSP to mediate DNA damage responses in the context of the HAUSP, p53, and Mdm2 complex are not fully identified."

sparser
"In a similar experiment, alanine substitutions of NTD residues known to be important for interactions of USP7 substrates such as p53 and MDM2 ( xref , xref ) led to loss of (W 149 A and DWGFS 152 A 5 ) or greatly diminished (R 88 A) interaction of the residue 1 to 220 USP7 fragment with vIRF-2 (data not shown), indicating canonical interaction of the vIRF-2 PSTS motif with the USP7 TRAF-like domain despite the additional requirements for vIRF-2 and its binding region (residues 241 to 260) to interact with USP7."

reach
"Our findings that nucleolin is a novel substrate for HAUSP and is a component of the HAUSP, Mdm2, and p53 complex led us to investigate the biological significance of HAUSP and nucleolin interaction in response to DNA damage."

reach
"Nucleolin exists as a component of the HAUSP, p53, and Mdm2 complex, and both Mdm2 and p53 are required for the interaction between HAUSP and nucleolin."

sparser
"Structural studies have shown that p53 and MDM2 interact with the N-terminus of USP7 in a mutually exclusive manner [ xref ]."

sparser
"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."