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)

The human p14(ARF) protein is encoded by an alternative transcript from the INK4a/ARF locus on chromosome 9p21, a locus frequently afflicted in human tumors. By use of two novel specific antisera against p14(ARF) we show that the protein is localized mainly in nucleoli but also in the nucleoplasm. Transfection of full-length and deletion mutant GFP-p14(ARF) fusion proteins confirmed this subcellular localization and assigned the nucleolar localization signal to the exon 2-encoded C-terminal region. In order to determine p14(ARF) expression in human tumor cells, we examined p14(ARF) in 32 tumor cell lines by immunofluorescence staining. Nucleolar p14(ARF) was detected in 10 lines, all of which lacked functional p53. Double immunostaining with p14(ARF) and B23/nucleophosmin or fibrillarin antibodies using 3D microscopy revealed that p14(ARF) is located mainly in the granular component of the nucleolus. p14(ARF) was also found in distinct granular aggregates scattered throughout the nucleoplasm. RNase digestion or selective inhibition of rRNA transcription by low doses of actinomycin D caused nucleoplasmic translocation of p14(ARF). This indicates that the nucleolar localization of p14(ARF) is dependent on ongoing transcriptional activity in intact functional nucleoli.
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PMID:Immunolocalization of human p14(ARF) to the granular component of the interphase nucleolus. 1077 13

Nucleophosmin/B23 was rapidly up-regulated after UV irradiation as p53, PCNA and c-Jun. UV induction of nucleophosmin/B23 was evidently increased at 3 h post-irradiation, and reached a maximum at 12 h, and remained high for at least 24 h. Over-expression of nucleophosmin/B23 made cells more resistant to UV-induced cell growth inhibition and death as compared with control vector-transfected cells through three main observations: cell growth/death percentage determination; clonogenic survival assay; and flow cytometric analysis. Moreover, nucleophosmin/B23 over-expressed cells had a greater capacity to repair UV-damaged reporter plasmid, indicating a higher nucleotide excision repair (NER) activity. Furthermore, PCNA, an essential component for DNA repair machinery, was correlated with nucleophosmin/B23 expression. Both protein level and promoter activity of PCNA were higher in nucleophosmin/B23 over-expressed cells than in control vector-transfected cells. On the other hand, treatment of cells with nucleophosmin/B23 antisense oligonucleotides decreased nucleophosmin/B23 and PCNA proteins, and potentiated the UV-induced cell killing. The effect of PCNA up-regulation may be one of the reasons that nucleophosmin/B23 over-expression made cells resistant to UV-induced growth inhibition and cell-killing.
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PMID:Resistance to UV-induced cell-killing in nucleophosmin/B23 over-expressed NIH 3T3 fibroblasts: enhancement of DNA repair and up-regulation of PCNA in association with nucleophosmin/B23 over-expression. 1175 29

Centrosome hyperamplification occurs frequently in human cancers, and is the major contributing factor for chromosomal instability and aneuploidy. We examined centrosome hyperamplification in bladder cancer cell lines. Samples were incubated with antibodies to the centrosome protein gamma-tubulin. The cell line (RT-4), which has a wild-type p53 status, showed a well-regulated centrosome replication cycle. On the other hand, centrosome hyperamplification was observed in HT-1197 and HT-13r cancer cells by discontinuous sucrose gradient fractionation. We used sucrose gradient fractions enriched for centrosomes by the immunoblot analysis for the presence of gamma-tubulin, a major component of centrosomes. The fractions were then immunoblotted with anti-nucleophosmin/B23 (NPM) antibody. NPM is a primary target of CDK2-cyclin E in the initiation of centrosome duplication. The profile of NPM closely paralleled that of gamma-tubulin, suggesting the association of NPM with the centrosome. Identification of the mechanism underlying the replication of the centrosome should lead to the understanding of the mechanism of chromosomal instability in bladder cancer, and enable us to develop cancer therapeutics targeted to centrosome replication.
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PMID:[Centrosome isolation from cultured bladder cancer cells--p53 mutation and centrosome hyperamplification]. 1269 85

The Arf tumor suppressor inhibits cell cycle progression through both p53-dependent and p53-independent mechanisms, including interference with rRNA processing. Using tandem-affinity-tagged p19(Arf), we purified Arf-associated proteins from mouse NIH 3T3 fibroblasts undergoing cell cycle arrest. Tagged p19(Arf) associated with nucleolar and ribosomal proteins, including nucleophosmin/B23 (NPM), a protein thought to foster the maturation of preribosomal particles. NPM is an abundant protein, only a minor fraction of which binds to p19(Arf); however, a significant proportion of p19(Arf) associates with NPM. The interaction between p19(Arf) and NPM requires amino acid sequences at the Arf amino terminus, which are also required for Mdm2 binding, as well as the central acidic domain of NPM and an adjacent segment that regulates NPM oligomerization. The interaction between p19(Arf) and NPM occurs in primary mouse embryonic fibroblasts, including those lacking both Mdm2 and p53. In an NIH 3T3 derivative cell line (MT-Arf) engineered to conditionally express an Arf transgene, induced p19(Arf) associates with NPM and colocalizes with it in high-molecular-weight complexes (2 to 5 MDa). An NPM mutant lacking its carboxyl-terminal nucleic acid-binding domain oligomerizes with endogenous NPM, inhibits p19(Arf) from entering into 2- to 5-MDa particles, and overrides the ability of p19(Arf) to retard rRNA processing.
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PMID:Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. 1472 47

Because activation of p53 can trigger cell cycle arrest and apoptosis, it is necessary for a cell to suppress this activation until it is absolutely required for survival. The mechanisms underlying this important regulatory event are poorly understood. Here we show that nucleophosmin (NPM) acts as a natural repressor of p53 by setting a threshold for p53 activation in response to UV radiation. NPM binds to the p53 N terminus and inhibits p53 transcriptional activity by more than 70%. Our data indicate that the levels of NPM in a cell determine the UV dose at which the tumor suppressor p53 can be phosphorylated on Ser15. Moreover, we show that NPM is a substrate for the UV-activated protein kinase ATR and inhibits the UV-induced p53 phosphorylation at Ser15. In addition, NPM forms a complex with p53 and ATR in vivo. These data suggest that NPM is an early responder to DNA damage that prevents premature activation of p53. In normal cells, NPM could contribute to suppressing p53 activation until its functions are absolutely required while in cancer cells overexpression of NPM could contribute to p53 inactivation and tumor progression.
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PMID:Nucleophosmin sets a threshold for p53 response to UV radiation. 1508 66

T-cell non-Hodgkin's lymphoma (NHL) represents approximately 10% to 15% of all lymphomas in Western countries. Patients with T-cell NHL are often treated similarly to patients with intermediate grade B-cell NHL, although many reports have demonstrated lower overall survival rates in patients with T-cell NHL compared to patients with B-cell NHL. Updated classifications have recognized specific clinical and pathologic T-cell entities, such as peripheral T-cell lymphoma, not otherwise characterized, angioimmunoblastic lymphoma, systemic anaplastic T-cell lymphoma, adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, and enteropathy-type intestinal T-cell lymphoma. Furthermore, these distinct T-cell NHL subtypes often warrant individualized diagnostic and therapeutic strategies, such as the associated cytophagic histiocytic panniculitis and hemophagocytic syndrome with subcutaneous panniculitis-like T-cell lymphoma, the chromosomal translocation t(2;5), leading to the nucleophosmin anaplastic lymphoma kinase fusion protein, viral pathogenesis of Epstein-Barr virus, human T-cell lymphotropic virus type-1 associated with extranodal NK/T-cell lymphoma nasal type and adult T-cell leukemia/lymphoma, respectively, and the role of radiation therapy in extranodal NK/T-cell lymphoma nasal type. Other active therapeutic agents in T-cell NHL include purine and pyrimidine antimetabolite agents (eg, nucleoside analogues and gemcitabine, respectively), denileukin diftitox, and antinucleoside or retinoic acid with interferon-alpha combination treatment. The exact role of transplantation in patients with T-cell NHL is unknown, but several case series have documented the feasibility of autologous and allogeneic transplant with reported long-term survival rates similar to transplanted B-cell NHL. Identification of relevant proto-oncogenes and tumor suppressor genes involved in the pathogenesis of T-cell NHL, such as the nucleophosmin anaplastic lymphoma kinase fusion protein, p53 and retinoblastoma gene, cyclin-dependent kinase inhibitors, histone deacetylation inhibitors, and infectious etiologies (eg, Epstein-Barr virus and Helicobacter pylori), in addition to their interplay with the various regulatory pathways of cell-cycle progression and apoptosis, represent potential candidates for molecular-based therapy. Prospective multi-institution clinical trials are critically important to determine the most effective treatment regimens that will continue to improve cure rates in these aggressive, yet treatable and often curable, diseases.
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PMID:Treatment of T-cell non-Hodgkin's lymphoma. 1523 6

We have generated two lentiviral vectors for conditional, Cre-lox-regulated, RNA interference. One vector allows for conditional activation, whereas the other permits conditional inactivation of short hairpin RNA (shRNA) expression. The former is based on a strategy in which the mouse U6 promoter has been modified by including a hybrid between a LoxP site and a TATA box. The ability to efficiently control shRNA expression by using these vectors was shown in cell-based experiments by knocking down p53, nucleophosmin and DNA methyltransferase 1. We also demonstrate the usefulness of this approach to achieve conditional, tissue-specific RNA interference in Cre-expressing transgenic mice. Combined with the growing array of Cre expression strategies, these vectors allow spatial and temporal control of shRNA expression in vivo and should facilitate functional genetic analysis in mammals.
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PMID:Cre-lox-regulated conditional RNA interference from transgenes. 1524 Aug 89

p53 tumor suppressor protein acts as a critical monitor preventing survival of cells with irreparable genetic damage. Its levels are tightly controlled by its negative regulator HDM2, and are allowed to rise only during cellular stress. In our recent paper (Kurki, et al. Cancer Cell 2004; 5:465-75) we identify a novel mechanism leading to p53 stabilization following UV damage of the cells. This involves UV damage provoked nucleoplasmic relocalization of a nucleolar protein, nucleophosmin (NPM, B23) and its rapid and transient interactions with both p53 and HDM2. We discuss here implications of recent findings that several p53 pathway proteins interact with NPM and find that its participation in cellular damage responses is limited to transcriptional stress but absent in direct ds DNA breaks. These findings suggest divergence in the routes provoking p53 stability and implicate the nucleolus as a central site participating in transcriptional stress responses.
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PMID:Nucleophosmin, HDM2 and p53: players in UV damage incited nucleolar stress response. 1525 98

Unknown mechanisms govern degradation of the p19Arf tumor suppressor, an activator of p53 and inhibitor of ribosomal RNA processing. Kinetic metabolic labeling of cells with [3H]-leucine indicated that p19Arf is a relatively stable protein (half-life approximately 6 h) whose degradation depends upon the ubiquitin-proteasome pathway. Although p19Arf binds to the Mdm2 E3 ubiquitin protein ligase to activate p53, neither of these molecules regulates p19Arf turnover. In contrast, the nucleolar protein nucleophosmin/B23, which binds to p19Arf with high stoichiometry, retards its turnover, and Arf mutants that do not efficiently associate with nucleophosmin/B23 are unstable and functionally impaired. Mouse p19Arf, although highly basic (22% arginine content), contains only a single lysine residue absent from human p14ARF, and substitution of arginine for lysine in mouse p19Arf had no effect on its rate of degradation. Mouse p19Arf (either wild-type or lacking lysine) and human p14ARF undergo N-terminal polyubiquitination, a process that has not as yet been documented in naturally occurring lysine-less proteins. Re-engineering of the p19Arf N terminus to provide consensus sequences for N-acetylation limited Arf ubiquitination and decelerated its turnover.
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PMID:N-terminal polyubiquitination and degradation of the Arf tumor suppressor. 1528 58

The ARF tumor suppressor is widely regarded as an upstream activator of p53-dependent growth arrest and apoptosis. However, recent findings indicate that ARF can also regulate the cell cycle in the absence of p53. In search of p53-independent ARF targets, we isolated nucleophosmin (NPM/B23), a protein we show is required for proliferation, as a novel ARF binding protein. In response to hyperproliferative signals, ARF is upregulated, resulting in the nucleolar retention of NPM and concomitant cell cycle arrest. The Mdm2 oncogene outcompetes NPM/B23 for ARF binding, and introduction of Mdm2 reverses ARF's p53-independent properties: in vitro, NPM is released from ARF-containing protein complexes, and in vivo S phase progression ensues. ARF induction by oncogenes or replicative senescence does not alter NPM/B23 protein levels but rather prevents its nucleocytoplasmic shuttling without inhibiting rRNA processing. By actively sequestering NPM in the nucleolus, ARF utilizes an additional mechanism of tumor suppression, one that is readily antagonized by Mdm2.
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PMID:ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway. 1548 2


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