Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herpes simplex virus type 1 regulatory protein ICP0 contains a zinc-binding RING finger and has been shown to induce the proteasome-dependent degradation of a number of cellular proteins in a RING finger-dependent manner during infection. This domain of ICP0 is also required to induce the formation of unanchored polyubiquitin chains in vitro in the presence of ubiquitin-conjugating enzymes UbcH5a and UbcH6. These data indicate that ICP0 has the potential to act as a RING finger ubiquitin ubiquitin-protein isopeptide ligase (E3) and to induce the degradation of certain cellular proteins through ubiquitination and proteasome-mediated degradation. Here we demonstrate that ICP0 is a genuine RING finger ubiquitin E3 ligase that can interact with and mediate the ubiquitination of the major oncoprotein p53 both in vitro and in vivo. Ubiquitination of p53 requires ICP0 to have an intact RING finger domain and occurs independently of its ability to bind to the ubiquitin-specific protease USP7.
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PMID:The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53. 1285 95

USP7 or HAUSP is a ubiquitin-specific protease in human cells that regulates the turnover of p53 and is bound by at least two viral proteins, the ICP0 protein of herpes simplex type 1 and the EBNA1 protein of Epstein-Barr virus. We have overexpressed and purified USP7 and shown that the purified protein is monomeric and is active for cleaving both a linear ubiquitin substrate and conjugated ubiquitin on EBNA1. Using partial proteolysis of USP7 coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry, we showed that USP7 comprises four structural domains; an N-terminal domain known to bind p53, a catalytic domain, and two C-terminal domains. By passing a mixture of USP7 domains over EBNA1 and ICP0 affinity columns, we showed that the N-terminal p53 binding domain was also responsible for the EBNA1 interaction, while the ICP0 binding domain mapped to a C-terminal domain between amino acids 599-801. Tryptophan fluorescence assays showed that an EBNA1 peptide mapping to residues 395-450 was sufficient to bind the USP7 N-terminal domain and did so with a dissociation constant of 0.9-2 microM, whereas p53 peptides spanning the USP7-binding region gave dissociation constants of 9-17 microM in the same assay. In keeping with these relative affinities, gel filtration analyses of the complexes showed that the EBNA1 peptide efficiently competed with the p53 peptide for USP7 binding, suggesting that EBNA1 could affect p53 function in vivo by competing for USP7.
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PMID:Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP. 1450 83

p53 ubiquitination is the principal mechanism by which p53 levels are regulated in the cell. HAUSP (also known as USP7) has been proposed to serve as a substrate-specific deubiquitinase of p53, and an increase in p53 levels was reported upon overexpression of HAUSP. We have disrupted the HAUSP genomic locus by homologous recombination and shown that HAUSP ablation results in a phenotype opposite to that predicted. Rather than decreasing p53 levels associated with increased p53 ubiquitination, the absence of HAUSP resulted in p53 accumulation accompanied by decreased p53 ubiquitination. The p53 protein in HAUSP-deficient cells was active, as assessed by the induction of its transcriptional targets and growth arrest. The basis for this phenotype was traced to the increased ubiquitination of MDM2, a negative regulator of p53 levels. These results demonstrate that MDM2, rather than p53, is the substrate for HAUSP under physiologic conditions and document a fascinating and unexpected twist to the regulation of the p53/MDM2 axis.
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PMID:HAUSP is required for p53 destabilization. 1511 11

The major oncoprotein p53 regulates several cellular antiproliferation pathways that can be triggered in response to a variety of cellular stresses, including viral infection. The stabilization of p53 is a key factor in the ability of cells to initiate an efficient transcriptional response after cellular stress. Here we present data demonstrating that herpes simplex virus type 1 (HSV-1) infection of HFFF-2 cells, a low-passage-number nontransformed human primary cell line, results in the stabilization of p53. This process required viral immediate-early gene expression but occurred independently of the viral regulatory protein ICP0 and viral DNA replication. No specific viral protein could be identified as being solely responsible for the effect, which appears to be a cellular response to developing HSV-1 infections. HSV-1 infection also induced the phosphorylation of p53 at residues Ser15 and Ser20, which have previously been implicated in its stabilization in response to DNA damage. However, an HSV-1 infection of ATM(-/-) cells, which lack a kinase implicated in these phosphorylation events, did not lead to the phosphorylation of p53 at these residues, but nonetheless p53 was stabilized. We also show that the wild-type p53 expressed by osteosarcoma U2OS cells can be stabilized in response to DNA damage induced by UV irradiation, but not in response to HSV-1 infection. These data suggest that multiple cellular mechanisms are initiated to stabilize p53 during an HSV-1 infection. These mechanisms occur independently of ICP0 and its ability to sequester USP7 and may differ from those initiated in response to DNA damage.
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PMID:Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner. 1525 78

USP7 (also called HAUSP) is a de-ubiquitinating enzyme recently identified as a key regulator of the p53-mdm2 pathway, which stabilizes both p53 and mdm2. We have discovered that the Epstein-Barr nuclear antigen 1 protein of Epstein-Barr virus binds with high affinity to USP7 and disrupts the USP7-p53 interaction. The results have important implications for the role of Epstein-Barr nuclear antigen 1 in the cellular immortalization that is typical of an Epstein-Barr virus latent infection.
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PMID:HAUSP/USP7 as an Epstein-Barr virus target. 1549

USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.
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PMID:Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. 1580 6

Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), a deubiquitylating enzyme of the ubiquitin-specific processing protease family, specifically deubiquitylates both p53 and MDM2, hence playing an important yet enigmatic role in the p53-MDM2 pathway. Here we demonstrate that both p53 and MDM2 specifically recognize the N-terminal tumor necrosis factor-receptor associated factor (TRAF)-like domain of HAUSP in a mutually exclusive manner. HAUSP preferentially forms a stable HAUSP-MDM2 complex even in the presence of excess p53. The HAUSP-binding elements were mapped to a peptide fragment in the carboxy-terminus of p53 and to a short-peptide region preceding the acidic domain of MDM2. The crystal structures of the HAUSP TRAF-like domain in complex with p53 and MDM2 peptides, determined at 2.3-A and 1.7-A resolutions, respectively, reveal that the MDM2 peptide recognizes the same surface groove in HAUSP as that recognized by p53 but mediates more extensive interactions. Structural comparison led to the identification of a consensus peptide-recognition sequence by HAUSP. These results, together with the structure of a combined substrate-binding-and-deubiquitylation domain of HAUSP, provide important insights into regulation of the p53-MDM2 pathway by HAUSP.
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PMID:Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway. 2007 26

Herpesvirus-associated ubiquitin-specific protease (HAUSP) directly stabilizes the tumour suppressor p53 by de-ubiquitination. Therefore, the HAUSP gene might play an important role in carcinogenesis. In this paper, HAUSP expression and p53 gene status have been studied in relation to the expression of p53 target genes in 131 patients with non-small cell lung cancer (NSCLC). p53 gene status was evaluated by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by sequencing. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) was performed to evaluate the gene expression of HAUSP, p21, and bax. Immunohistochemistry was performed to evaluate the protein expression of p53, HAUSP, mdm2, p21, and bax. Fifty-nine carcinomas (45.0%) showed reduced expression of HAUSP, and 58 carcinomas (44.3%) had mutations of p53. Concerning tumour histology, HAUSP mRNA expression was significantly lower in adenocarcinomas than in squamous cell carcinomas (p = 0.0038), while the frequency of p53 mutation was significantly higher in squamous cell carcinomas than in adenocarcinomas (p = 0.0461). There was no significant difference in HAUSP mRNA expression according to p53 gene status. In total, 93 carcinomas (71.0%) showed either mutant p53 or reduced HAUSP expression. The down-regulation of HAUSP was associated with reduced p53 protein expression (p = 0.0593 in tumours with wild-type p53 and p = 0.0004 in tumours with mutant p53). Furthermore, p21 and bax protein expression was significantly lower in tumours with either mutant p53 or reduced HAUSP expression than in tumours with both wild-type p53 and positive HAUSP expression (p = 0.0440 and p = 0.0046, respectively). In addition, the simultaneous evaluation of both HAUSP expression and p53 gene status was a significant indicator of poor prognosis in adenocarcinoma patients (hazard ratio 4.840, p = 0.0357). These results suggest that reduction of HAUSP gene expression may play an important role in NSCLC carcinogenesis, especially in adenocarcinomas, through p53-dependent pathways.
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PMID:The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways. 1645 Mar 35

The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby it stabilizes both p53 and MDM2. 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. Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide. These peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1, explaining the competitive nature of the interactions. The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7. Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway.
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PMID:Molecular recognition of p53 and MDM2 by USP7/HAUSP. 1647 2

Latent Epstein-Barr virus (EBV) infection is strongly associated with several cancers, including nasopharyngeal carcinoma (NPC), a tumor that is endemic in several parts of the world. We have investigated the molecular basis for how EBV latent infection promotes the development of NPC. We show that the viral EBNA1 protein, previously known to be required to maintain the EBV episomes, also causes the disruption of the cellular PML (promyelocytic leukemia) nuclear bodies (or ND10s). This disruption occurs both in the context of a native latent infection and when exogenously expressed in EBV-negative NPC cells and involves loss of the PML proteins. We also show that EBNA1 is partially localized to PML nuclear bodies in NPC cells and interacts with a specific PML isoform. PML disruption by EBNA1 requires binding to the cellular ubiquitin specific protease, USP7 or HAUSP, but is independent of p53. We further observed that p53 activation, DNA repair and apoptosis, all of which depend on PML nuclear bodies, were impaired by EBNA1 expression and that cells expressing EBNA1 were more likely to survive after induction of DNA damage. The results point to an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.
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PMID:Epstein-Barr nuclear antigen 1 contributes to nasopharyngeal carcinoma through disruption of PML nuclear bodies. 1883 93


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