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)

Infection by high risk papillomavirus causes various forms of anogenital cancer including squamous cell carcinoma of the cervix. A primary step in the carcinogenesis includes formation of a complex of viral E6 protein and a human E3 ubiquitin ligase. This complex is competent to cause degradation and inactivation of several target proteins including human tumor suppressors which contributes to hyperproliferation of infected cells. Great insight on the mechanism by which E6 binds target proteins has recently been provided by determination of structures of interacting peptides and a E6 domain. These data have also provided a basis for the discovery of small molecules that can inhibit E6. However, there is still a need to further solve the structures of additional interacting complexes to identify the structural relationship that exists between proteins that simultaneously bind E6, such as E6AP and p53 or E6AP and PDZ domain-containing proteins, and to provide a clear picture of the interface between E6 and its ubiquitin ligase.
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PMID:Structure and function of the papillomavirus E6 protein and its interacting proteins. 1798 32

The NKX3.1 gene located at 8p21.2 encodes a homeodomain-containing transcription factor that acts as a haploinsufficient tumor suppressor in prostate cancer. Diminished protein expression of NKX3.1 has been observed in prostate cancer precursors and carcinomas. TOPORS is a ubiquitously expressed E3 ubiquitin ligase that can ubiquitinate tumor suppressor p53. Here we report interaction between NKX3.1 and TOPORS. NKX3.1 can be ubiquitinated by TOPORS in vitro and in vivo, and overexpression of TOPORS leads to NKX3.1 proteasomal degradation in prostate cancer cells. Conversely, small interfering RNA-mediated knockdown of TOPORS leads to an increased steady-state level and prolonged half-life of NKX3.1. These data establish TOPORS as a negative regulator of NKX3.1 and implicate TOPORS in prostate cancer progression.
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PMID:Ubiquitination by TOPORS regulates the prostate tumor suppressor NKX3.1. 1807 45

Homeodomain-interacting protein kinase 2 (HIPK2) is a member of the nuclear protein kinase family, which induces both p53- and CtBP-mediated apoptosis. Levels of HIPK2 were increased by UV irradiation and cisplatin treatment, thereby implying the degradation of HIPK2 in cells under normal conditions. Here, we indicate that HIPK2 is ubiquitinated and degraded by the WD40-repeat/SOCS box protein WSB-1, a process that is blocked under DNA damage conditions. Yeast two-hybrid screening was conducted to identify the proteins that interact with HIPK2. WSB-1, an E3 ubiquitin ligase, was characterized as an HIPK2-interacting protein. The coexpression of WSB-1 resulted in the degradation of HIPK2 via its C-terminal region. Domain analysis of WSB-1 showed that WD40-repeats and the SOCS box were required for its interaction with and degradation of HIPK2, respectively. In support of the degradation of HIPK2 by WSB-1, HIPK2 was polyubiquitinated by WSB-1 in vitro and in vivo. The knockdown of endogenous WSB-1 with the expression of short hairpin RNA against WSB-1 increases the stability of endogenous HIPK2 and resulted in the accumulation of HIPK2. The ubiquitination and degradation of HIPK2 by WSB-1 was inhibited completely via the administration of DNA damage reagents, including Adriamycin and cisplatin. These findings effectively illustrate the regulatory mechanisms by which HIPK2 is maintained at a low level, by WSB-1 in cells under normal conditions, and stabilized by genotoxic stresses.
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PMID:Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1. 1809 72

NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family. NUMB is also an endocytic protein, and the NOTCH-NUMB counteraction has been linked to this function. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH. Thus, in these cancers, a single event-loss of NUMB expression-determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry.
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PMID:NUMB controls p53 tumour suppressor activity. 1817 99

During the adenovirus infectious cycle, the early proteins E4orf6 and E1B55K are known to perform several functions. These include nuclear export of late viral mRNAs, a block of nuclear export of the bulk of cellular mRNAs, and the ubiquitin-mediated degradation of selected proteins, including p53 and Mre11. Degradation of these proteins occurs via a cellular E3 ubiquitin ligase complex that is assembled through interactions between elongins B and C and BC boxes present in E4orf6 to form a cullin 5-based ligase complex. E1B55K, which has been known for some time to associate with the E4orf6 protein, is thought to bind to specific substrate proteins to bring them to the complex for ubiquitination. Earlier studies with E4orf6 mutants indicated that the interaction between the E4orf6 and E1B55K proteins is optimal only when E4orf6 is able to form the ligase complex. These and other observations suggested that most if not all of the functions ascribed to E4orf6 and E1B55K during infection, including the control of mRNA export, are achieved through the degradation of specific substrates by the E4orf6 ubiquitin ligase activity. We have tested this hypothesis through the generation of a virus mutant in which the E4orf6 product is unable to form a ligase complex and indeed have found that this mutant behaves identically to an E4orf6(-) virus in production of late viral proteins, growth, and export of the late viral L5 mRNA.
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PMID:Control of mRNA export by adenovirus E4orf6 and E1B55K proteins during productive infection requires E4orf6 ubiquitin ligase activity. 1818 99

Mdm2 has been thought to regulate the tumor suppressor p53 in two ways: by masking p53's access to transcriptional machinery, and by ubiquitinating p53, targeting it for proteasomal degradation. This dogma was recently challenged by data generated from knockin mice in which Mdm2's RING E3 ubiquitin ligase activity was abrogated by a single point mutation. The RING mutant Mdm2 is fully capable of binding with p53, yet cannot suppress p53 activity, suggesting that Mdm2 cannot block p53 by binding alone, without ubiquitination. Data from the RING knockin mice also revealed that endogenous Mdm2 does not, as previously thought, regulate its own stability by self-ubiquitination. In this review, we will discuss these findings and their relevance to the field, including potential reasons for the discrepancies between previous data and that generated by our knockin mice, as well as the feasibility of targeting Mdm2's E3 ubiquitin ligase activity in cancer. We will also discuss additional research questions that may be addressed using our mouse model.
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PMID:Unlocking the Mdm2-p53 loop: ubiquitin is the key. 1823 22

Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.
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PMID:Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. 1825 23

Sensitive to apoptosis gene (SAG)/regulator of cullins-2/RING box protein 2 is a stress-responsive RING component of Skp-1/Cullins/F-box protein E3 ubiquitin ligase. When overexpressed, SAG inhibits apoptosis induced by reactive oxygen species or hypoxia. Here, we report that SAG overexpression inhibits ultraviolet (UV) B-induced apoptosis in mouse JB6 epidermal cells. Using a transgenic mouse model, in which SAG expression was targeted primarily to epidermis by a K14 promoter, we showed that, at the early stage of UVB skin carcinogenesis (10 weeks post-UVB exposure), c-Jun, p27, p53, c-Fos and cyclin D1 were strongly induced. While having no effect on UVB-induced p53, c-Fos and cyclin D1, SAG-transgenic expression reduced the levels of c-Jun and p27 and inhibited AP-1 activity. The net outcome of SAG-mediated inhibition of c-Jun/AP-1 (pro-tumor promotion) and of p27 (antiproliferation) increased skin hyperplasia, with no apparent effect on apoptosis, as evidenced by increased skin thickness, and increased rate of DNA synthesis, but hardly any apoptosis. Although skin hyperplasia was promoted, SAG-transgenic expression had no significant effect on tumor formation in the later stage of UVB carcinogenesis. Thus, by simultaneously targeting c-Jun and p27, SAG accelerates UVB-induced skin hyperplasia, but not carcinogenesis.
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PMID:SAG/ROC2/RBX2 E3 ligase promotes UVB-induced skin hyperplasia, but not skin tumors, by simultaneously targeting c-Jun/AP-1 and p27. 1825 8

The p53 tumor suppressor is essential in maintaining genomic integrity in response to cellular stresses. In response to DNA damage, p53 is activated and stabilized largely through post-translational modifications, including phosphorylation by DNA damage responsive kinases such as ATM and ATR. Activated p53 transactivates a battery of genes that can mediate either cell cycle arrest or apoptosis. In those instances where p53 facilitates cell cycle arrest, a means to return the cell to a pre-stress state with low p53 levels is important. The E3 ubiquitin ligase Mdm2 is one p53 transcriptional target that accumulates after damage and promotes p53 ubiquitination and degradation. Thus, p53 and Mdm2 form a critical negative feedback regulatory loop that helps to maintain appropriate p53 levels in the presence or absence of stress. We propose here that Wip1 (Wildtype p53-Induced Phosphatase 1), also known as PPM1D, plays an important role in the p53-Mdm2 autoregulatory loop. We have recently shown that Wip1, also a p53 target gene, dephosphorylates Mdm2 at Ser395 (an ATM target site), resulting in stabilization of Mdm2, enhanced Mdm2-p53 binding, and enhanced ubiquitination of p53 by Mdm2. Thus, Wip1 facilitates Mdm2-mediated degradation of p53. The p53 inhibitory role of Wip1 implicates it as a potential oncogene and indeed Wip1 is amplified and overexpressed in a number of human cancers. Wip1 may inhibit p53 signaling by multiple mechanisms, but our data suggests that its largest effects are due to dephosphorylation of Mdm2.
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PMID:The Wip1 phosphatase and Mdm2: cracking the "Wip" on p53 stability. 1833 94

The nematode Caenorhabditis elegans contains a single ancestral p53 family member, cep-1, which is required to activate apoptosis of germ cells in response to DNA damage. To understand how the cep-1/p53 pathway is regulated in response to genotoxic stress, we performed an RNA interference screen and identified the neddylation pathway and components of an SCF (Skp1/cullin/F-box) E3 ubiquitin ligase as negative regulators of cep-1-dependent germ cell apoptosis. Here, we show that the cullin gene cul-1, the Skp1-related gene skr-1, and the ring box genes rbx-1 and rpm-1 all negatively regulate cep-1-dependent germ cell apoptosis in response to the DNA-alkylating agent N-ethyl-N-nitrosourea (ENU). We also identified the F-box protein FSN-1, previously shown to form an SCF ligase that regulates synapse development, as a negative regulator of cep-1-dependent germline apoptosis. The hypersensitivity of fsn-1 mutants to ENU-induced germline apoptosis was completely suppressed by a cep-1 loss-of-function allele. We further provide evidence that the transcriptional activity, phosphorylation status, and levels of endogenous CEP-1 are higher in fsn-1 mutants compared with wild-type animals after ENU treatment. Our results uncover a novel role for the SCF(FSN-1) E3 ubiquitin ligase in the regulation of cep-1-dependent germ cell apoptosis.
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PMID:The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans. 1834 Mar 46


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