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

p19(ARF) is a key regulator of the p53-mediated apoptotic and tumor suppressor pathway. The proapoptotic Bax gene is a transcription target of p53, yet genetic studies in some animal models have suggested that Bax and p53 loss may cooperate in tumorigenesis. ARF-deficient mice are tumor prone, and to determine whether Bax loss could cooperate in the development of these tumors, we generated mice null for both ARF and Bax. The tumor latency of Bax+/+ARF-/-, Bax+/-ARF-/- and Bax-/-ARF-/- mice was similar with a mean survival of 48.9, 48.1, and 47.6 weeks, respectively. In Bax+/+ARF-/- mice, the predominant tumor type was B- and T-cell lymphoma followed by sarcomas and a lack of carcinomas. However, the frequency of lymphoma development dramatically decreased, whereas that of sarcomas and carcinomas increased, in a gene dosage-dependent manner in Bax+/-ARF-/- and Bax-/-ARF-/- mice. Furthermore, uncommon tumors of ARF-/- mice (osteosarcoma and hemangiosarcoma) were observed in Bax/ARF-double null mice, and tumor types not described previously in ARF-null mice (mixed germ cell tumor, Triton tumor, and histiocytic sarcoma) also developed in Bax-/-ARF-/- animals. Importantly, multiple primary malignant tumors of different lineage arose in 25% of the Bax-/-ARF-/- mice, whereas only one tumor type per animal was observed in Bax+/+ARF-null littermates. Finally, the wild-type Bax allele was retained in tumors arising in Bax+/-ARF-/- mice. Thus, Bax appears to function as a tumor modifier rather than as a classic tumor suppressor, and the combined loss of Bax and the ARF allows for the emergence of multiple malignant tumor types, an alteration of the tumor spectrum, and tumors not observed previously in ARF-null mice.
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PMID:Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice. 1192 42

We report the case of a 39 years old woman, with bilateral fibrocystic breast disease and several surgeries for this cause, including bilateral mammary implants. Nineteen months after the implants an angiosarcoma of the left breast was diagnosed. In the specimen from radical mastectomy infiltration of the adipose tissue was found but no metastases to the axillary lymph node resected. Prognostic factors were investigated in surgical specimen and immunophenotypic characterization was made, considering Ki-67 and p53 expression. The patient finished chemotherapic treatment and is well, without neoplastic disease relapse, 16 months after diagnosis. We comment the possible relation between silicona's implants and angiosarcoma's genesis, association not reported before in the literature. The adverse effects of silicone implants and angiosarcoma histogenesis were reviewed.
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PMID:[Breast angiosarcoma in a patient with multiple surgical procedures and breast implant. Report of a case]. 1201 51

The INK4a-ARF locus, located on chromosome 9p21, encodes 2 cell cycle-regulatory proteins, p16(INKa) and p14(ARF), acting through the Rb-CDK4 and p53 pathways. This study was done to investigate the contribution of the INK4a-ARF locus in tumorigenesis of angiosarcoma of the liver. Alterations of p14(ARF), p16(INKa), and p53 in primary liver angiosarcoma from 19 patients were analyzed by methylation-specific polymerase chain reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR), microsatellite analysis, and DNA sequencing. As a control group, 12 angiosarcomas from other organs were analyzed. Promoter methylation of p14(ARF) was found in 5 of 19 cases (26%), and p16(INKa) showed aberrant promoter methylation in 12 of 19 cases (63%). One tumor (5%) had homozygous deletion of the INK4a-ARF locus. Methylation and deletion correlated with loss of mRNA transcription. Methylated p14(ARF) appeared in the context of a methylated p16(INKa) promoter in 3 cases of the 5 angiosarcomas methylated at p14(ARF). p14(ARF) aberrant methylation was not related to the presence of p53 mutations, which was detected in 6 of 19 (32%) cases. Alterations of the INK4a-ARF locus or p53 as were not established independent prognostic factors in these tumors. In conclusion, our data indicate that the INK4a-ARF locus is frequently inactivated in angiosarcoma of the liver and occurs independently of p53 mutations.
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PMID:Abnormalities of the ARF-p53 pathway in primary angiosarcomas of the liver. 1237 12

Riddelliineis a naturally occurring pyrrolizidine alkaloid found in certain poisonous rangeland plants of the western United States. In National Toxicology Program 2-year studies, riddelliine induced high incidences of hemangiosarcoma in the liver of F344/N rats (both sexes) and B6C3F1 mice (males). To understand this pathogenesis, we tested short-term effects of riddelliine. Three groups (control; 1.0 mg/kg/day, high dose used in the 2-year study; and 2.5 mg/kg/day) of seven male F344/N rats per group were terminated after 8 consecutive doses and 30 doses (6 weeks, excluding weekends). Serum vascular endothelial growth factor (VEGF), histological, immunohistochemical [factor VIII-related antigen/von Willebrand factor (fVIII-ra/vWf)], VEGF, VEGF receptor-2 (VEGFR2), glutathione S-transferase-pi, S-phase (BrdU), p53, apoptosis, and ultrastructural evaluations were performed on the liver. Following 8 doses of 1.0 and 2.5 mg/kg/day, increased numbers of apoptotic and S-phase nuclei appeared in hepatocytes and endothelial cells. Following 30 doses of 1.0 and 2.5 mg/kg/day, hepatocytes exhibited reduced mitosis, fewer S-phase nuclei, increased hypertrophy, and fatty degeneration, while endothelial cells showed karyomegaly, cytomegaly, decreased apoptosis, more S-phase nuclei, and p53 positivity. Hepatocytes of treated animals expressed higher VEGF immunopositivity. That altered endothelial cells were fVIII-ra/vWf and VEGFR2 positive confirmed their identity. These changes may have promoted hemangiosarcoma development upon long-term exposure through endothelial adduct formation, apoptosis, proliferation of endothelial cells having undamaged and/or damaged DNA, and mutation. Endothelial proliferation may also have been promoted through endothelial arrest at S phase, which was associated with endothelial karyo- and cytomegaly, resulting in hepatocytic hypoxia, triggering VEGF induction.
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PMID:The hepatic endothelial carcinogen riddelliine induces endothelial apoptosis, mitosis, S phase, and p53 and hepatocytic vascular endothelial growth factor expression after short-term exposure. 1246 Jul 43

Tumors of endothelial origin develop rarely. Until now, only two angiosarcoma (AS)-derived endothelial cell lines have been be isolated, ISO-HAS and AS-M. Both AS-derived endothelial cell lines presented the typical endothelial characteristics, such as the expression of CD31 and von Willebrand factor, but differed from normal endothelial cells in a nuclear expression of p53, in a delayed angiogenic reaction, and a reduced expression of caveolin. In addition, differences in the expression of cytokines and cell adhesion molecules responsive to proinflammatory stimuli were observed. While AS-M showed an expression pattern similar to that of human umbilical vein endothelial cells (HUVEC), ISO-HAS clearly differed from primary endothelial cells by a constitutive expression of E-selection, granulocyte macrophage colony-stimulating factor, and vascular endothelial cell adhesion molecule-1. Even though the telomeres of both AS-derived established cell lines were longer than telomeres of freshly isolated HUVEC, neither transcripts encoding telomerase nor telomerase activity were detected, suggesting that the tumor cells of endothelial origin may use a telomerase-independent mechanism for maintaining the telomere length. This observation has implications for development of therapeutic approaches for angiosarcoma.
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PMID:Tumorigenic conversion of endothelial cells. 1451 78

A novel human endothelial cell line, AS-M, has been established from a cutaneous angiosarcoma on the scalp. The cells expressing platelet endothelial cell adhesion molecule-1 (CD31) were isolated using magnetic beads and subsequently cultured for a year. To date, the cells have undergone more than 100 population doublings (PDs). The AS-M cells manifested endothelial characteristics, such as active uptake of acetylated low-density lipoprotein labeled with 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil-Ac-LDL), capacity to bind the Ulex europeaus agglutin-I (UEA-I), and expression of von Willebrand factor (vWF) and CD31. The single cell-derived clone, AS-M.5, showed a constitutive expression of CD31, vWF, angiotensin-converting enzyme (ACE), endoglin (CD105), and the endothelial cell receptor tyrosine kinases KDR and Tie-1. Similarly to freshly isolated endothelial cells, the AS-M.5 responded to induction by bacterial lipopolysaccharide (LPS) by increased transcription of cell adhesion molecules and cytokines. The AS-M.5 cultures required endothelial growth supplements for optimal growth and long-term propagation in vitro. However, in contrast to normal endothelial cells, p53 gene products were detected in nuclei of AS-M.5 cells. Cytogenetic analyses consistently revealed a hypodiploid karyotype with complete loss of one homologue of several chromosomes and a homogeneous pattern of distinct karyotypic changes. Although the AS-M.5 presented characteristics suggestive of tumor cells, they did not develop into tumors when inoculated subcutaneously into nude mice. The cell line AS-M.5 could be a useful model system to study endothelial pathobiology in vitro.
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PMID:Establishment and characterization of an angiosarcoma-derived cell line, AS-M. 1474 47

P53: gene alterations correlate highly with advanced ovarian carcinoma in women. In mice, p53 deficiency predominantly results in the formation of lymphomas and sarcomas. However, ovarian epithelial tumors have not been documented in p53 homozygous mutant (p53-/-) mice, probably because they die before other tumors can form. To determine whether p53-/- ovaries can develop epithelial tumors, they were transplanted into the ovarian bursae of histocompatible wild-type recipient females. The p53-/- ovarian grafts formed tumors approximately 1 year post-transplantation. The tumor type was angiosarcoma, suggesting that vascular tissues are predisposed to tumor formation in p53-/-ovaries. These findings suggest that p53 deficiency alone is not sufficient for ovarian epithelial tumorigenesis in mice. Thus, other genetic lesions are likely required to develop mouse models of human ovarian cancer.
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PMID:Tumor formation in p53 mutant ovaries transplanted into wild-type female hosts. 1533 65

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.
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PMID:Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. 1558 24

Primary sarcomas of the breast are extremely rare with less than 1% of all malignant tumours of the breast reported in literature. At our Institution 1315 malignant tumours of the breast were diagnosed between 1999-2004; nine of them corresponded to primary sarcomas: angiosarcoma (3), leiomyosarcoma (1), low-grade fibromyxoid sarcoma (1), dematofibrosarcoma protuberans (1), liposarcoma (1), osteosarcoma (1), malignant peripheral nerve sheath tumour (1). Histopathological specimens stained with routine techniques and immunoperoxidase were reviewed; proliferation index and p53 over-expression were also determined. Patients' clinical reports were also reviewed to determine prognosis (favorable and unfavorable). The incidence observed (0.7%) is similar to those already published by others authors. Proliferation index was correlated with type of evolution, being an unfavourable prognosis factor when it was equal or major to 30%. Most of the tumours (67%) showed p53 (mayor or equal to 20% of nuclear staining) over-expression but this did not show a direct relationship with the evolution of each neoplasm.
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PMID:[Primary sarcomas of the breast]. 1671 62

The prophylactic use of zidovudine (3'-azido-3'-deoxythymidine, AZT) during pregnancy greatly reduces transmission of HIV-1 from infected mothers to their infants; however, the affinity of host cell DNA polymerases for AZT also allows for its incorporation into host cell DNA, predisposing to cancer development. To expand upon previous transplacental carcinogenesis assays performed in CD-1 mice, the transplacental carcinogenicity of AZT was evaluated in a second mouse strain and a second rodent species. Date-mated female mice and rats were gavaged daily with 0, 80, 240, or 480 mg AZT/kg bw during the last 7 days of gestation. At 2 years postpartum, male and female B6C3F1 mouse and F344 rat offspring (n = 44-46 of each sex and species/treatment group) were necropsied for gross and microscopic tissue examinations. Under the conditions of these two-year studies, there was clear evidence of carcinogenic activity based upon significant dose-related trends and increases in the incidences of hemangiosarcoma in male mice and mononuclear cell leukemia in female rats. There was some evidence of carcinogenic activity in the livers of male mice based upon a positive trend and an increased incidence of hepatic carcinoma in the high-dose AZT group. The incidence of gliomas in female rats exceeded the historical background rates for gliomas in F344 rats. P53 overexpression was detected in some AZT-treated mouse neoplasms. These and other cancer-related findings confirm and extend those of previous transplacental carcinogenicity studies of AZT in mice, support the need for long-term follow-up of nucleoside reverse transcriptase inhibitor (NRTI)-exposed children, and indicate the necessity for effective protective strategies against NRTI-induced side effects.
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PMID:Transplacental carcinogenicity of 3'-azido-3'-deoxythymidine in B6C3F1 mice and F344 rats. 1735 26


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