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)

There is very limited knowledge about the antibody response against tumor-expressed antigens in lung cancer. To arrive at a more complete picture of lung cancer antigens, we generated 2 cDNA libraries from squamous cell lung carcinoma and isolated 15 immunogenic antigens using autologous sera. Among the antigens most frequently identified were the lymphoid blast crisis oncogene (LBC), an unknown hypothetical protein and the p53-binding protein (TP53 BP), which have already been associated with tumor development. Of the immunogenic antigens, 6 map to chromosomes that are frequently altered in squamous cell lung carcinoma. SEREX database analysis showed that 7 of the identified immunogenic antigens have been associated with the humoral immune response in other human tumors. Screening with heterologous sera of patients with lung carcinoma identified 4 antigens, including human protein kinase C and TP53 BP, which have also been found by autologous screening. Only 1 of the 15 identified antigens reacted with any of the 36 control sera, which were taken from individuals without known disease. Sera from adenocarcinoma and large cell carcinoma of the lung were not reactive for the antigens. In summary, using 2 newly established cDNA libraries, we isolated 15 novel antigens, which were subsequently evaluated for the frequency of their corresponding antibodies in autologous, normal and heterologous sera; their chromosomal localization; and their correlation with survival after surgery.
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PMID:Toward a more complete recognition of immunoreactive antigens in squamous cell lung carcinoma. 1240 7

The tumor suppressor p53 is regulated in part by binding to cellular proteins. We used p53 as bait in the yeast two-hybrid system and isolated homeodomain-interacting protein kinase 1 (HIPK1) as a p53-binding protein. Deletion analysis showed that amino acids 100-370 of p53 and amino acids 885-1093 of HIPK1 were sufficient for HIPK1-p53 interaction. HIPK1 was capable of autophosphorylation and specific serine phosphorylation of p53. The HIPK1 gene was highly expressed in human breast cancer cell lines and oncogenically transformed mouse embryonic fibroblasts. HIPK1 was localized to human chromosome band 1p13, a site frequently altered in cancers. Gene-targeted HIPK1-/- mice were grossly normal but oncogenically transformed HIPK1 -/- mouse embryonic fibroblasts exhibited reduced transcription of Mdm2 and were more susceptible than transformed HIPK1+/+ cells to apoptosis induced by DNA damage. Carcinogen-treated HIPK1 -/- mice developed fewer and smaller skin tumors than HIPK1+/+ mice. HIPK1 may thus play a role in tumorigenesis, perhaps by means of the regulation of p53 and/or Mdm2.
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PMID:Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1). 1270 66

Mdm4 (MdmX) is a p53-binding protein that shares structural similarities with Mdm2 and has been proposed to be a negative regulator of p53 function. Like Mdm2, the absence of Mdm4 has recently been found to induce embryonic lethality in mice that is rescued by p53 deletion. Mdm4-null embryos are reduced in size and die at mid-gestation, and Mdm4-deficient embryos and embryonic fibroblasts displayed reduced rates of cell proliferation. The p53-induced, cyclin-dependent kinase inhibitor p21 is strongly upregulated in Mdm4-null embryos and cells. Here, we report that deletion of p21 delays the mid-gestation lethality observed in Mdm4-null mice, suggesting that Mdm4 downregulates p53-mediated suppression of cell growth. Surprisingly, the absence of p21 also uncovers an antiproliferative effect of Mdm4 on cell growth in vitro and in Mdm4-heterozygous mice. These results indicate that p21 is a downstream modifier of Mdm4, and provides genetic evidence that Mdm4 can function to regulate cell growth both positively and negatively.
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PMID:Absence of p21 partially rescues Mdm4 loss and uncovers an antiproliferative effect of Mdm4 on cell growth. 1471 35

The core protein of Hepatitis C virus affects several biological functions of the host cells such as cellular growth and apoptosis. The core was shown to interact with 53BP2/Bbp/ASPP2, a p53-binding protein, in a yeast two-hybrid assay. The core competed with p53 in binding to ASPP2 in vitro. In an apoptosis assay using human osteosarcoma Saos-2 cells or hepatocellular carcinoma HepG2 cells, ectopic expression of p53 induced apoptosis and ASPP2 enhanced this p53-induced apoptosis. However, coexpression of the core with p53 and ASPP2 increased the number of surviving cells. In a reporter assay, neither ASPP2 nor the core with ASPP2 affected the transcriptional activity of p53 on the promoters of Bax and p21, major p53 target genes. These findings suggest that the core inhibits p53-mediated apoptosis by blocking the interaction between p53 and ASPP2, without modulating the transcriptional activity of p53, which plays a role in oncogenesis of hepatocellular carcinoma.
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PMID:Hepatitis C virus core protein interacts with p53-binding protein, 53BP2/Bbp/ASPP2, and inhibits p53-mediated apoptosis. 1498 81

The human topoisomerase I- and p53-binding protein topors contains a highly conserved, N-terminal C3HC4-type RING domain that is homologous to the RING domains of known E3 ubiquitin ligases. We demonstrate that topors functions in vitro as a RING-dependent E3 ubiquitin ligase with the E2 enzymes UbcH5a, UbcH5c, and UbcH6 but not with UbcH7, CDC34, or UbcH2b. Additional studies indicate that a conserved tryptophan within the topors RING domain is required for ubiquitination activity. Furthermore, both in vitro and cellular studies implicate p53 as a ubiquitination substrate for topors. Similar to MDM2, overexpression of topors results in a proteasome-dependent decrease in p53 protein expression in a human osteosarcoma cell line. These results are similar to the recent finding that a Drosophila topors orthologue ubiquitinates the Hairy transcriptional repressor and suggest that topors functions as a ubiquitin ligase for multiple transcription factors.
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PMID:Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. 1524 80

We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRbeta fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRbeta. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRbeta, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.
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PMID:p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. 1549 36

The adenoviral protein E1A associates with multiple anticancer activities, including stabilization of p53 tumor suppressor, and has been tested through gene therapy approaches in clinical trials. To identify potential E1A-binding proteins involved in E1A's anticancer activities, we screened a yeast two-hybrid library and identified Mdm4, an Mdm2-related p53-binding protein, as a novel E1A-binding protein. The NH(2)-terminal region of Mdm4 and the CR1 domain of E1A were required for the interaction between E1A and Mdm4. E1A preferentially bound to Mdm4 rather than Mdm2 and formed a complex with p53 in the presence of Mdm4, resulting in the stabilization of p53 in a p14(ARF)-independent manner. E1A failed to stabilize p53 in the absence of Mdm4, showing that Mdm4 was required for p53 stabilization by E1A. Moreover, E1A-mediated stabilization of p53 occurred in nucleus. Although it had no effect on the p53-Mdm2 interaction, E1A facilitated Mdm4 binding to p53 and inhibited Mdm2 binding to Mdm4, resulting in decreased nuclear exportation of p53. Thus, our findings highlighted a novel mechanism, whereby E1A stabilized the p53 tumor suppressor through Mdm4.
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PMID:Adenoviral E1A targets Mdm4 to stabilize tumor suppressor p53. 1560 76

The p53-binding protein 53BP1 has been implicated in the DNA damage response and genomic instability. Previous reports have highlighted these roles in vivo in haematopoietic lineages. To investigate the importance of 53BP1 to the DNA damage response in epithelial cells in vivo, we have investigated the role of 53BP1 in mediating apoptosis and proliferation within the murine small intestine following gamma-irradiation. 53BP1 deficiency does not affect the immediate response to gamma-irradiation with normal levels of apoptosis, proliferation and p53 and p21 accumulation. However, 48 h post-gamma-irradiation there was a significant accumulation of cells with much larger nuclei marked by p53 and p21 accumulation. These data reflect increases in polyploidy observed 53BP1-/- deficient fibroblasts following gamma-irradiation. At 72 h post-irradiation both the 4N and 8N populations were significantly increased in 53BP1-/- MEFS. Taken together, these results show that following in vivo exposure to gamma-irradiation, 53BP1 is dispensable for signalling apoptosis and cell-cycle arrest in the intestinal epithelium. However, it is important for prevention of genomic instability within this epithelial cell population.
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PMID:53BP1 deficiency in intestinal enterocytes does not alter the immediate response to ionizing radiation, but leads to increased nuclear area consistent with polyploidy. 1745 83

Genotoxic stress triggers a rapid translocation of p53 to the mitochondria, contributing to apoptosis in a transcription-independent manner. Using immunopurification protocols and mass spectrometry, we previously identified the proapoptotic protein BAK as a mitochondrial p53-binding protein and showed that recombinant p53 directly binds to BAK and can induce its oligomerization, leading to cytochrome c release. In this work we describe a combination of molecular modeling, electrostatic analysis, and site-directed mutagenesis to define contact residues between BAK and p53. Our data indicate that three regions within the core DNA binding domain of p53 make contact with BAK; these are the conserved H2 alpha-helix and the L1 and L3 loop. Notably, point mutations in these regions markedly impair the ability of p53 to oligomerize BAK and to induce transcription-independent cell death. We present a model whereby positively charged residues within the H2 helix and L1 loop of p53 interact with an electronegative domain on the N-terminal alpha-helix of BAK; the latter is known to undergo conformational changes upon BAK activation. We show that mutation of acidic residues in the N-terminal helix impair the ability of BAK to bind to p53. Interestingly, many of the p53 contact residues predicted by our model are also direct DNA contact residues, suggesting that p53 interacts with BAK in a manner analogous to DNA. The combined data point to the H2 helix and L1 and L3 loops of p53 as novel functional domains contributing to transcription-independent apoptosis by this tumor suppressor protein.
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PMID:Oligomerization of BAK by p53 utilizes conserved residues of the p53 DNA binding domain. 1852 70

Polo-like kinase 1 (Plk1) overexpression is associated with tumorigenesis by an unknown mechanism. Likewise, Plk1 was suggested to act as a negative regulator of tumor suppressor p53, but the mechanism remains to be determined. Herein, we have identified topoisomerase I-binding protein (Topors), a p53-binding protein, as a Plk1 target. We show that Plk1 phosphorylates Topors on Ser(718) in vivo. Significantly, expression of a Plk1-unphosphorylatable Topors mutant (S718A) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (SUMO E3) ligase. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1.
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PMID:Plk1-mediated phosphorylation of Topors regulates p53 stability. 1947 92


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