Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work has demonstrated that alpha-particle irradiation of primary human bone marrow cells leads to the transmission of chromosomal instability in the descendants of the irradiated cell, although there is some interindividual variation. We have extended these studies to human EBV-transformed lymphoblastoid cell lines in order to establish an in vitro model system. The five cell lines analyzed, including one from a Fanconi anaemia patient, exhibited high levels of persistent chromatid aberrations up to approximately 40 cell generations after alpha-irradiation. The p53 status of the cell lines was defined according to whether cellular p53 levels were induced by irradiation, translocated to the nucleus and were able to bind a p53 DNA consensus recognition sequence in vitro. Together with the primary bone marrow cell studies, we conclude that alpha-particle induced chromosomal instability is independent of the p53 status of the cell as defined in these studies.
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PMID:No association between p53 status and alpha-particle-induced chromosomal instability in human lymphoblastoid cells. 860 52

Although mutations of the p53 tumour-suppressor gene have been observed occasionally in the advanced stages of myelodysplastic syndromes (MDS), they have not been detected in early refractory anaemia (RA) or RA with ring sideroblasts phases. Using single-strand conformation polymorphism analysis and direct sequencing, we searched for p53 mutations in a patient who progressed from RA to overt leukaemia. A p53 mutation at codon 249 (AGG to ATG) was observed in RA, RA with excess of blasts in transformation and overt leukaemia. We describe a case of MDS with p53 mutation at codon 249 detected in the RA phase.
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PMID:A case of refractory anaemia with p53 point mutation at codon 249 (AGG to ATG). 861 74

Fanconi anemia (FA) is an autosomal recessive disease marked by developmental defects, bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA cross-linking and alkylating agents and accumulate in the G2 phase of the cell cycle in response to these agents. FA cells also display genomic instability, suggesting a possible defect in the p53 pathway. To test the effect of heterologous expression of FAC cDNA on drug-induced cytotoxicity, G2 accumulation, and p53 induction in FA cells, we compared two isogenic FA cell lines: HSC536N (mock), a FA type C cell line sensitive to mitomycin C (MMC), and the same cell line transfected (corrected) with wild-type FAC cDNA (HSC536N [+FAC]). HSC536N (+FAC) cells showed a 30-fold increase in resistance to MMC concentration. Similarly, increases in resistance were observed following exposure to cisplatin, carboplatin, and cyclophosphamide. In addition, HSC536N (+FAC) cells showed a twofold lower G2 accumulation following MMC treatment. To analyze the possible interaction of FAC with the p53 pathway, we analyzed p53 induction in mock and corrected cell lines following exposure to MMC. HSC536N (mock) cells induced p53 at lower MMC concentrations than HSC536N (corrected). Caffeine, a known G2 checkpoint inhibitor, not only inhibited G2 accumulation seen in both cell lines but also caused the resistant HSC536N (+FAC) to become as sensitive to MMC as HSC536N (mock) cell line. We conclude that the FAC protein has a specific cytoprotective effect and may function as a cell cycle regulator of the G2 phase of the cell cycle.
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PMID:The effect of the Fanconi anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation. 870 10

The association of Epstein-Barr virus (EBV) with smooth-muscle tumors was recently reported in the setting of acquired immunodeficiency syndrome (AIDS) and post-transplantation. We report a case of an EBV-associated smooth-muscle tumor arising in a post-transplant (PT) patient who previously was treated successfully for two EBV-associated PT large-cell lymphomas. A 4-year-old girl required cardiac transplantation for dilated cardiomyopathy when she was aged 23 months. Her PT regimen included cyclosporine, azothiaprine, and diltiazem. At 16 months PT, she presented with anemia, guaiac-positive stools, and an abdominal mass diagnosed as diffuse large-cell lymphoma of B-cell phenotype. Immunosuppressive therapy was reduced, and interferon and i.v. immunoglobulin were initiated. She rapidly developed signs of rejection, and a cardiac biopsy was performed, revealing grade IIIB rejection. Subsequently, immunosuppressive therapy increased. At 23 months PT, a biopsy was done of a large pelvic mass that was diagnosed as immunoblastic large-cell lymphoma. After treatment with chemotherapy and retinoic acid, the size of the mass markedly decreased. Follow-up computed tomography scan revealed multiple liver nodules. A needle biopsy of the liver showed a smooth-muscle tumor of indeterminate grade. Both the lymphomas and the smooth-muscle tumor contained EBV within > 95% of tumor cells by Epstein-Barr (EBER1) in situ hybridization, were of strain type A by Epstein-Barr nuclear antigen-2 (EBNA-2) polymerase chain reaction (PCR) and contained an identical 30 base-pair deletion (amino acids 346-355) of the latent membrane protein (LMP)-1 oncogene by PCR analysis. Notably, the initial large-cell lymphoma and the subsequent immunoblastic lymphoma each contained a unique p53 mutation, suggesting that they were distinct. These data suggest that the same virus contributed to the pathogenesis of both the malignant lymphomas and the smooth-muscle tumor.
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PMID:Epstein-Barr virus (EBV)-associated smooth-muscle tumor arising in a post-transplant patient treated successfully for two PT-EBV-associated large-cell lymphomas. Case report. 894 45

The tumor suppressor protein p53 (wtp53) can bind to specific target sequences and activate transcription of genes adjacent to these DNA elements. Two p53 binding sites are present in the gene coding for the Fanconi anemia complementation group C (FAC), one in the promoter region (from -1295 to -1266) and one in the coding region of FAC (from +1828 to +1848). Gel shift experiments show that wtp53 binds to the p53 target sequence in the promoter region of the FAC gene. We have investigated whether binding of p53 to these target sites may affect expression of the FAC gene. Transfection experiments show that overexpression of wtp53 in human diploid fibroblasts and lymphoblasts augments transcription of the FAC gene up to three-fold. The transfection efficacy was approximately 15% for both cell types. The FAC expression activity per transformed cell was stimulated to an estimated level of 18- to 21-fold upon overexpression of p53. The tumor-derived p53 mutants, His175 and His273, that fail to bind DNA showed only a reduced stimulatory activity on FAC transcription. Luciferase assays demonstrated that interaction of p53 with its target site in the FAC promoter does not modulate the promoter activity. We suggest that the p53 binding site contributes to, but may not be an absolute prerequisite for p53-directed transcriptional activation. We conclude that the FAC gene can be added to the list of genes that interact with p53.
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PMID:p53 activates Fanconi anemia group C gene expression. 906 48

The chicken anemia virus protein apoptin induces a p53-independent, Bcl-2-insensitive type of apoptosis in various human tumor cells. Here, we show that, in vitro, apoptin fails to induce programmed cell death in normal lymphoid, dermal, epidermal, endothelial, and smooth-muscle cells. However, when normal cells are transformed they become susceptible to apoptosis by apoptin. Long-term expression of apoptin in normal human fibroblasts revealed that apoptin has no toxic or transforming activity in these cells. In normal cells, apoptin was found predominantly in the cytoplasm, whereas in transformed and malignant cells it was located in the nucleus, suggesting that the localization of apoptin is related to its activity. These properties make apoptin a potential agent for the treatment of a large number of tumors, also those lacking p53 and/or overexpressing Bcl-2.
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PMID:Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells. 915 62

Clinical studies have indicated that folate deficiency may enhance the development of various malignancies. In animal studies that examined the effect of folate deficiency on malignancies, conflicting results have been reported. In some studies, folate deficiency increased the development and growth of malignant tumors; in others, it decreased the development and growth of malignancies. We examined the effect of transient folate deficiency on the development of leukemia in mice infected with the anemia-inducing strain of Friend leukemia virus. Friend virus disease can be considered as a model for human acute leukemias that are preceded by a preleukemic period. These include leukemias that develop in patients who received previous chemotherapy and/or radiation therapy, as well as patients with chronic granulocytic leukemia or myelodysplasia. Folate deficiency around the time of Friend virus-infection delayed the onset but increased the incidence of leukemia. The rates of rearrangement of the Spi-1 (PU.1 ) oncogene by provirus integration and alteration of the p53 tumor-suppressor gene were the same in leukemia cell lines derived from folate-deficient mice as they were in cell lines from control mice. These results indicate that folate deficiency did not exert its enhancement of leukemogenesis through changes in either Spi-1 or p53, even though these two genes have been found to be the most frequently altered ones in Friend virus-induced leukemias. Our results suggest that folate deficiency may enhance the development of acute leukemia in patients who are at high risk for this disease.
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PMID:Folate deficiency delays the onset but increases the incidence of leukemia in Friend virus-infected mice. 935 75

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy. The gene for FA complementation group A (FAA) recently has been cloned. The cDNA is predicted to encode a polypeptide of 1,455 amino acids, with no homologies to any known protein that might suggest a function for FAA. We have used single-strand conformational polymorphism analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants are probably benign polymorphisms, of which nine are common and can be used for various applications, including mapping studies for other genes in this region of chromosome 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants are likely to be pathogenic mutations. Seventeen of these are microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the International Fanconi Anemia Registry for two of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. 3788-3790del appears in a variety of ethnic groups and is found on at least two different haplotypes. We suggest that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germ-line and somatic mutations in a variety of cancer-related genes, including p53, APC, RB1, WT1, and BRCA1, may be a major mechanism for FAA mutagenesis.
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PMID:Sequence variation in the Fanconi anemia gene FAA. 937 98

The initiation step of the carcinogenic process consists in an alteration of genes playing a central role in the cellular life. The next steps of promotion and progression result from anomalies in the response to growth factors, to hormones and/or from the action of tumor promotors leading to cellular hyperplasia. This process generally leads to genetic instability of the initiated cell which in turn allows selection of malignant and invasive clones. The production of DNA damage by physical or chemical agents is dose-dependent. The error-free enzymatic repair processes including excision resynthesis of base damage or of altered nucleotides allow the restitution of intact DNA. The error-prone repair systems permit survival in association with transmissible alterations (genes and chromosomal mutations). Absence of repair leads to cytotoxicity, programmed cell death or disruption of cell cycle control leading to a pretumoral state. The major role played by mutations in the initiation of carcinogenesis is evidenced by the existence of genetic syndromes associated to hypersensitivity to genotoxic agents, defects in DNA repair capacity, anomalies in the expression of certain genes (including the tumor suppressor p53 gene, etc.) and an elevated predisposition to cancer. Xeroderma pigmentosum which is defective in excision-repair, ataxia telangiectasia and Fanconi anemia which are associated to anomalies in DNA recombination and the familial type of colon cancer HPNCP due to inefficient mismatch repair constitute paradigm for this fundamental notion. Alterations in the capacity to rejoin radiation induced DNA strand breaks appears to be associated to over-reactions to radiotherapy of cancer patients. Also the predisposition to develop secondary thyroid tumors following treatment of a primary cancer in childhood seems to involve the same defect. The existence in the general population of heterozygotes for such DNA repair genes should be taken into account for risk evaluation to therapeutic and environmental exposures.
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PMID:[Molecular mechanisms of carcinogenesis: the role of systems of DNA repair]. 962 30

The clinicopathologic, immunohistochemical, and ultrastructural features of soft tissue angiosarcomas are not well defined. Eighty cases of angiosarcoma that involved the deep subcutis, skeletal muscle, retroperitoneum, mesentery, and mediastinum are reported. The lesions occurred in 50 male and 30 female patients who were 5-97 years of age; the peak incidence was in the seventh decade of life. A variety of associated conditions were documented in 20 of these cases, including a history of other neoplasms (some irradiated), synthetic vessel grafts, heritable conditions, and prior trauma or surgery. The angiosarcomas occurred in the extremities (n = 43 cases), trunk (n = 28), and the head and neck (n = 9) regions, with the thigh and the retroperitoneum being the most common sites. They often were characterized as enlarging, painful masses of several weeks' duration and were occasionally associated with acute hemorrhage, anemia, or a coagulopathy. The tumors measured 1-15 cm in diameter (median 5 cm) and frequently were hemorrhagic and multinodular. There was a wide morphologic spectrum within and between cases, including areas similar to cavernous and capillary hemangioma, Dabska tumor, spindle cell and epithelioid hemangioendothelioma, various spindle cell sarcomas, or carcinoma. Histologically, epithelioid angiosarcoma was the most frequently observed pattern; 70% of cases had epithelioid cells that were arranged in nests, clusters, papillae, and gaping vascular channels. Hemorrhage tended to obscure the diagnosis in several cases and often was associated with papillary endothelial hyperplasia-like areas. All 42 cases studied immunohistochemically stained at least focally for Factor VIII-related antigen, and nearly all stained strongly for vimentin, which accentuated the endothelial cells and vessel lumen formation. CD34 antigen was detected in 74% of cases, BNH9 in 72%, and cytokeratins in 35%. Epithelial membrane antigen, S-100 protein, and HMB45 were not detected. Fifty-five percent of the tumors had intracytoplasmic aggregates of laminin. Immunostains for alpha-smooth muscle actin demonstrated a prominent pericytic component in several tumors (24%). Ki67 immunostains with MIB1 indicated high proliferative activity (> or =10%) in 72% of cases. p53 immunoreactivity (>20% nuclear staining) was observed in 20% of cases. Ultrastructural studies performed on poorly differentiated areas of 12 cases showed groups of cells, which were frequently epithelioid, surrounded by basal lamina, and closely associated with pericytes, along with intercellular and intracellular lumina with or without red blood cells. Whorls of abundant intermediate filaments, occasional tonofilamentlike structures, and pinocytotic vesicles also were noted. In contrast to the findings of others, Weibel-Palade bodies were not seen. Follow-up in 49 cases (61%) showed that 53% of patients were dead of disease at a median interval of 11 months, whereas 31% had no evidence of disease at a median interval of 46 months. The remaining patients were either alive with disease (14%) or alive but disease status was unknown (2%). There were local recurrences in 20% of cases and distant metastases in 49%, most frequently to the lungs, followed by the lymph nodes, soft tissues, bone, liver, and other sites. These results indicate that angiosarcoma of soft tissue is a high-grade sarcoma. Older patient age, tumor location in the retroperitoneum, and larger tumor size as well as detection of MIB1 in > or =10% of the tumor cell population were all associated with a poorer prognosis.
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PMID:Angiosarcoma of soft tissue: a study of 80 cases. 963 Jan 75


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