Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic instability may underlie the etiology of multistep gastric carcinogenesis. The altered microsatellites observed in tumors with the ubiquitous somatic mutation (USM) phenotype may represent the expression of such instability. Similarly, p53 mutations may allow the accumulation of genetic alterations caused by multiple mechanisms. In 40 sporadic gastric adenocarcinomas, nine tumors (22.5%) with p53 mutations in exons 5-8, and six tumors (15%) with the USM+ phenotype, were detected. None of the tumors had both alterations. The tumors with p53 mutations were predominantly in the proximal stomach whereas the USM+ tumors were predominantly in the distal stomach. The mutant p53 alleles were homogeneously distributed throughout the primary tumors, but usually absent from adjacent normal or dysplastic epithelium, indicating that p53 mutations are typically acquired before the bulk of clonal expansion. The loss of mutant p53 alleles during progression was also rarely observed in metastatic foci. Altered microsatellites were homogeneously present in the USM+ primary and metastatic tumors and one synchronous tubular adenoma, but were not detected in adjacent normal and metaplastic epithelium. These findings also demonstrate that the USM+ phenotype is expressed before the bulk of clonal expansion. In most (5 of 6) USM+ tumors, the sizes of the altered microsatellites differed between regions, indicating that the instability usually persists during clonal expansion. These findings indicate that both p53 mutations and the USM+ phenotype are present prior to the bulk of tumor growth and therefore may contribute to, rather than be a late consequence of, malignant transformation.
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PMID:p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail. 806 74

The tumor growth suppressor WAF1/CIP1 was recently shown to be induced by p53 and to be a potent inhibitor of cyclin-dependent kinases. In the present studies, we sought to determine the relationship between the expression of WAF1/CIP1 and endogenous regulation of p53 function. WAF1/CIP1 protein was first localized to the nucleus of cells containing wild-type p53 and undergoing G1 arrest. WAF1/CIP1 was induced in wild-type p53-containing cells by exposure to DNA damaging agents, but not in mutant p53-containing cells. The induction of WAF1/CIP1 protein occurred in cells undergoing either p53-associated G1 arrest or apoptosis but not in cells induced to arrest in G1 or to undergo apoptosis through p53-independent mechanisms. DNA damage led to increased levels of WAF1/CIP1 in cyclin E-containing complexes and to an associated decrease in cyclin-dependent kinase activity. These results support the idea that WAF1/CIP1 is a critical downstream effector in the p53-specific pathway of growth control in mammalian cells.
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PMID:WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. 811 1

The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. Introduction of WAF1 cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of WAF1 coding sequences. The WAF1 promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene. These studies define a gene whose expression is directly induced by p53 and that could be an important mediator of p53-dependent tumor growth suppression.
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PMID:WAF1, a potential mediator of p53 tumor suppression. 824 52

The wild-type p53 gene product is a nuclear phosphoprotein that suppresses cell and tumor growth. Mutations of the p53 gene are by now the most frequently recognized genetic alterations in human malignancies and occur in many types of carcinomas as well as in astrocytomas and sarcomas. Wild-type p53 protein has a short half-life, is present in very low quantities in normal cells and cannot be detected immunohistochemically. Mutant p53 proteins have longer half-lives and are usually present in immunohistologically detectable amounts. It is generally agreed that the presence of p53 immunostaining indicates the presence of an abnormal p53 protein and is strongly suggestive of a mutation in the p53 gene. In this study, we stained paraffin sections from eight samples of gliosarcomas from seven patients with an antibody to p53. All tumors contained p53-immunoreactive nuclei in both the glial and the sarcomatous component. In five tumors, a majority of nuclei was positive in the sarcomatous component while only a minority of nuclei was positive in the glial areas. In one tumor, the reverse was seen. In another tumor, approximately half the nuclei were positive in both components and in one tumor, only a minority of nuclei were positive in either component (this lesion was the recurrence of a tumor in which the majority of the sarcoma's nuclei had been positive). These data indicate that p53 mutations may play a role in the pathogenesis of gliosarcomas and suggest an origin of both the glial and sarcomatous components from a common progenitor.
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PMID:Distribution of p53 protein expression in gliosarcomas: an immunohistochemical study. 838 97

Antitumor CTL responses were studied in a model tumor hearing a mutant human p53 gene. We found ineffective induction of antitumor CTL in mice bearing these tumors associated with measurable defects in the function of dendritic cells (DC) from these animals. In this study we investigate the mechanism of this defect in mature DC and find that functional DC can be generated by growth from the bone marrow of tumor-hearing animals. Tumor cell supernatants did not affect the function of mature DC obtained from the spleen of tumor-bearing animals, but significantly suppressed the ability to generate functional DC from the bone marrow of control mice in vitro. This suggests that tumor cells may release factors which block early stages of DC maturation from precursors. DC generated from the bone marrow of tumor-bearing mice showed normal potential to stimulate allogeneic T cells, to stimulate anti-mutant p53 peptide-specific cytotoxic T cells, and to induce anti-p53 CTL responses in vivo in control mice. Repeated immunization with peptide-pulsed DC generated from the bone marrow of control mice (every 4-5 days) blocked progression of established tumors. Immunization of mice with peptide-pulsed DC obtained from the spleen of tumor-bearing mice (4 weeks after tumor injection) did not affect the tumor growth, whereas immunization with peptide-pulsed DC generated from bone marrow of tumor-bearing mice resulted in significantly prolonged survival and delayed tumor growth. Tumor progression was associated with change of the balance Th1/Th2 cells in favor of the Th2-like cytokine profile, while effective immunization was associated with a shift to the Th1 phenotype. Thus, frequent immunization of mice with mutant p53 peptide-pulsed DC generated from stem cells of tumor-bearing hosts can induce effective antitumor CTL responses associated with production of Th1 cells and lead to significant antitumor effects.
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PMID:Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. 866 91

Mutation of the p53 gene is found in about one third of astrocytic brain tumors, and expansion of tumor cell clones containing mutant p53 has been implicated in astrocytic tumor progression. However, admixture of normal cells in astrocytic tumor specimens limits the power of traditional studies of tumor cell clonality. To address this problem we have employed a yeast p53 functional assay that scores the content of mutant p53 alleles in tumors and cell lines quantitatively. We have analyzed 17 cases where matching tumor material and derived cell lines were available. The yeast assay gave > 20% red (i.e., mutant p53-containing) yeast colonies in 7 out of 17 cases. One case had no mutations in the primary tumor but gave 76% red colonies in a recurrence, clearly demonstrating tumor overgrowth by a mutant clone. During early passages of cultured tumor cells, mutant p53 content increased rapidly with passage due to outgrowth of mutant clones from a heterogeneous starting population. In addition, de novo p53 mutations appeared during culture in 2 cases. This indicates that there is stronger selective pressure for mutation during the establishment of cell lines in vitro than during tumor growth in vivo. Our results demonstrate the utility of the p53 functional assay for studies of clonality and support the hypothesis of clonal progression of brain tumors in vivo.
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PMID:Clonality and stability of the p53 gene in human astrocytic tumor cells: quantitative analysis of p53 gene mutations by yeast functional assay. 870 23

Human malignancies are often characterized by mutations of the p53 tumor suppressor gene. In a large proportion of cases, the mutation results in production of an altered protein that can bind and inactivate the wild-type gene product. This "dominant-negative" activity of mutant p53 molecules may limit the utility of p53 gene therapy of cancer. Using replication-deficient recombinant adenoviruses (rAd-p53) as a p53 gene delivery system, we evaluated the effects of p53 reintroduction on a series of 45 human cell lines containing wild-type, mutated, or no p53 protein. Results indicate a p53-specific, dose-dependent, and promoter-specific growth inhibition of a majority of p53-altered cell lines that correlates with the degree of adenovirus transgene expression. Similar effects were not observed on cells containing wild-type p53. rAd-p53 inhibited the growth of cells expressing various mutant p53 proteins including those characterized as "dominant negative mutants", and the antiproliferative effects were not abrogated by high levels of endogenous mutated p53 protein. In vivo, rAd-p53 also suppressed tumor growth and increased survival of nude mice bearing tumors that express mutant p53. These results support a role for p53 gene therapy of cancer, including malignancies harboring mutations in this tumor suppressor gene.
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PMID:Adenovirus-mediated p53 gene transfer inhibits growth of human tumor cells expressing mutant p53 protein. 872 11

Mice bearing palpable tumors expressing a mutant p53 gene were treated with intravenous injection of mutant p53-specific peptide-pulsed dendritic cells (DCs). Control groups were treated with control peptide-pulsed DCs. All mice received three injections of 10(5) DCs on days 0, 5, and 10 after the start of the therapy. Half of the animals in each group were also treated with intraperitoneal injections of interleukin (IL)-12 (300 ng per mouse every other day, from day 0 to day 20). Mice treated with control peptide-pulsed DCs showed fast tumor progression. This growth was not substantially affected by treatment with IL-12 alone. Tumor growth in mice treated with mutant p53 peptide-pulsed DCs was significantly slowed during therapy, but resumed after cessation of therapy. In contrast, tumor growth in mice receiving both specific peptide-pulsed DCs and IL-12 remained very slow even 4 weeks after termination of the immunotherapy. To investigate the immunological basis for these effects, mutant p53 specific cytotoxic T lymphocyte (CTL) response was tested in mice 2 weeks after the last injection of DCs. Significant levels of CTLs were registered only in mice treated with IL-12 in addition to specific immunization. Thus, IL-12 dramatically improved the effect of the mutant p53-specific immunotherapy of palpable, preexisting tumors, supporting the use of IL-12 as an immunoadjuvant in clinical trials of tumor-specific peptide-pulsed DC.
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PMID:IL-12 and mutant P53 peptide-pulsed dendritic cells for the specific immunotherapy of cancer. 904 60

In response to DNA damage, p53 protein accumulates in the cell nucleus causing cells to undergo DNA repair or apoptosis, programmed cell death. Reintroduction of wild-type p53 into tumors with null or mutant p53 offers a novel strategy for controlling tumor growth, by inducing apoptotic death in neoplastic cells. The efficacy of a replication-deficient p53 adenovirus construct was tested against three human breast cancer cell lines expressing mutant p53, MDA-MB-231, -468, and -435. 231 and 468 cells were both highly transduced at a multiplicity of infection of 10. By contrast, 435 cells were rarely transduced. p53 adenovirus-mediated gene therapy was highly effective against 231 and 468 tumor xenografts in nude mice. At a total dose of 2.2 x 10(9) cellular infectious units (CIU), inhibition of 231 tumor growth was 86% (P < or = .01). Thirty-seven percent of that growth inhibition was due to p53, while 49% was adenovirus-specific. Inhibition of 468 tumor growth was 74% (P < or = .001). Forty-five percent of that inhibition was p53-specific, while 28% was adenovirus-specific. The ED50 values for 231 tumors and 468 tumor growth inhibition were 3 x 10(8) CIU and 2 x 10(8) CIU, respectively. Injection of p53 Ad into 231 or 468 tumors induced apoptosis. By contrast, growth inhibition in 435 tumors treated with p53 adenovirus was not significant, probably due to low adenovirus transduction. 231 and 435 cells both expressed high levels of alpha v, beta 1, beta 3, and beta 5 integrin subunits, ruling out lack of the appropriate integrins as the reason for the low infection rate in 435 cells. Our results demonstrate the ability of wild-type p53 to curtail cancerous cell growth in vivo in tumors expressing mutant p53. The ability of beta-gal Ad to infect tumor cells in vitro was generally predictive of in vivo p53 Ad efficacy.
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PMID:Efficacy of p53 adenovirus-mediated gene therapy against human breast cancer xenografts. 908 Jan 22

A disturbance in the balance between cell proliferation and cell loss, or apoptosis, may underlie neoplastic development. Therefore, we determined spontaneous apoptotic and proliferative rates in normal, hyperplastic, adenomatous, and malignant colorectal epithelia. In paired sections, DNA strand breaks were detected using the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, and apoptotic cells were also identified in H&E-stained slides by morphological criteria. Cell proliferation, bcl-2, and p53 expression were analyzed using specific monoclonal antibodies. In normal mucosa, luminal epithelial cells demonstrated higher rates of apoptosis compared to cells in the proliferative zone. Neoplastic transformation was associated with a significant increase in rates of apoptosis and proliferation. However, apoptosis, but not proliferation, decreased at the adenoma-to-carcinoma transition coincident with expression of mutant p53. In carcinomas, both mutant p53 and bcl-2 protein levels were associated with attenuated apoptotic rates. In conclusion, apoptosis is an important regulator of growth in normal and neoplastic colorectal epithelia. Increased apoptosis and proliferation accompany neoplastic transformation, suggesting that an alteration in apoptotic rates is an important event in colorectal carcinogenesis. Furthermore, the imbalance in these processes found in carcinomas may facilitate tumor growth and progression.
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PMID:Increased apoptosis accompanies neoplastic development in the human colorectum. 981 59


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