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)

The TP53 gene is considered to be a negative regulator of cell growth whose inactivation is an important step in the development or progression of malignancies. Recently, germ line TP53 mutations have been detected in a familial cancer syndrome, the dominantly inherited Li-Fraumeni syndrome. Using single strand conformation polymorphism analysis of PCR products, we looked for TP53 mutations in DNA of patients with Fanconi anemia, an autosomal recessive disease characterized by increased predisposition to neoplasia. We did not find any TP53 mutation in 13 patients, suggesting that this tumor suppressor gene is not directly involved in the cancer susceptibility observed in Fanconi's anemia.
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PMID:Lack of mutations in the TP53 tumor suppressor gene exons 5 to 8 in Fanconi's anemia. 180 24

Supplementation with 1 g of vitamin C (ascorbic acid) per day decreased the amount of chromosome damage induced in lymphocytes by an exposure to bleomycin during the last 5 h of cell culture. We did not see such changes in lymphocytes from control individuals samples at the same time but not taking vitamin C supplements. This bleomycin assay has been proposed as a test for cancer susceptibility. A similar assay for genetic instability may be useful in detecting heterozygotes for chromosome-breakage syndromes (for example, Fanconi anemia or ataxia telangiectasia). Even though our sample size is small and our results should be interpreted cautiously, statistically significant effects were found with vitamin C supplementation. It would, therefore, be prudent to consider dietary and perhaps other lifestyle factors when interpreting of results from this bleomycin assay and related assays for genetic instability.
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PMID:Vitamin C intake influences the bleomycin-induced chromosome damage assay: implications for detection of cancer susceptibility and chromosome breakage syndromes. 247 99

Fanconi anemia (FA) is a well-known genetic syndrome manifested by bone marrow failure, variable physical anomalies, and cancer susceptibility. This disorder is marked by genotypic and phenotypic heterogeneity and consists of four distinct complementation groups A, B, C, and D. The defective gene responsible for the C group of FA, FACC, was identified by cDNA complementation cloning, and we have recently proposed a trial of gene therapy for group C FA. No animal model yet exists for FA. Consequently, we have studied the effects of constitutive expression of human FACC in two murine transplantation models. In the first model, we demonstrated transduction of FACC to reconstituting stem cells of mutant W/WV mice. In the second model, we demonstrated transduction of FACC to hematopoietic cells transplanted to the bone marrows and spleens of non-myeloablated BALB/c mice. Our data suggest that retroviral-mediated transfer of the normal human FACC cDNA to hematopoietic progenitor and stem cells of mice is feasible and not associated with direct harmful effects to the hematopoietic organ.
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PMID:Retroviral-mediated transduction of the fanconi anemia C complementing (FACC) gene in two murine transplantation models. 754 77

Mutations in the gene defective in Fanconi anemia complementation group C, FAC, are responsible for a subset of Fanconi anemia, a group of autosomal recessive disorders characterized by chromosomal instability, hypersensitivity to cross-linking agents, and cancer susceptibility. Although abnormalities in DNA repair have been suspected, localization of the FAC gene product to the cytoplasm has cast doubt on such a mechanism. Monitoring of interstrand DNA cross-linking shows that the predominant defect in group C cells is in the initial induction of cross-links, not in repair synthesis. Both the cross-linking defect and the enhanced cytotoxicity of cross-linkers on Fanconi anemia group C cells are corrected completely by cytoplasmic isoforms of the FAC protein, but not by an isoform targeted to the nucleus. The ability of FAC to correct these phenotypic abnormalities reaches a maximum threshold despite overexpression leading to higher levels of cytosolic protein. These results demonstrate that cytoplasmic localization is essential for the intracellular activity of the FAC protein. It is proposed that this activity is coupled to a cytoplasmic defense mechanism against a specific class of genotoxic agents.
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PMID:Cytoplasmic localization of FAC is essential for the correction of a prerepair defect in Fanconi anemia group C cells. 862 88

Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, aplastic anemia, and cancer susceptibility. Mutations within the FA complementation group C (FAC) gene account for approximately 14% of diagnosed FA cases. Two mutations, one in exon 1 (delG322) and one in exon 4 (IVS4 + 4 A to T), account for 90% of known FAC mutations. The delG322 mutation results in a mild FA phenotype, while the IVS4 + 4 A to T mutation results in severe FA phenotype. To determine the molecular basis for this clinical variability, we analyzed patient-derived cell lines for the expression of characteristic mutant FAC polypeptides. All cell lines with the delG322 mutation expressed a 50-kD FAC polypeptides, FRP-50 (FAC-related protein), shown to be an amino terminal truncated isoform of FAC reinitiated at methionine 55. All cell lines with the IVS4 + 4 A to T mutation lacked FRP-50. Overexpression of a cDNA encoding FRP-50 in an FA(C) cell line resulted in partial correction of mitomycin C sensitivity. In conclusion, expression of an amino terminal truncated FAC protein accounts, at least in part, for the clinical heterogeneity among FA(C) patients.
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PMID:Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity. 863 4

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

Fanconi anemia (FA) is an autosomal recessive disorder characterized by developmental defects, bone marrow failure, and cancer susceptibility. Cells derived from FA patients are sensitive to crosslinking agents and have a prolonged G2 phase, suggesting a cell cycle abnormality. Although transfection of type-C FA cells with the FAC cDNA corrects these cellular abnormalities, the molecular function of the FAC polypeptide remains unknown. In the current study we show that expression of the FAC polypeptide is regulated during cell cycle progression. In synchronized HeLa cells, FAC protein expression increased during S phase, was maximal at the G2/M transition, and declined during M phase. In addition, the FAC protein coimmunoprecipitated with the cyclin-dependent kinase, cdc2. We next tested various mutant forms of the FAC polypeptide for binding to cdc2. A patient-derived mutant FAC polypeptide, containing a point mutation at L554P, failed to bind to cdc2. The FAC/cdc2 binding interaction therefore correlated with the functional activity of the FAC protein. Moreover, binding of FAC to cdc2 was mediated by the carboxyl-terminal 50 amino acids of FAC in a region of the protein required for FAC function. Taken together, our results suggest that the binding of FAC and cdc2 is required for normal G2/M progression in mammalian cells. Absence of a functional interaction between FAC and cdc2 in FA cells may underlie the cell cycle abnormality and clinical abnormalities of FA.
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PMID:The Fanconi anemia polypeptide, FAC, binds to the cyclin-dependent kinase, cdc2. 924 35

Fanconi anaemia (FA) is an autosomal-recessive disorder characterized by genomic instability, developmental defects, DNA crosslinking agent hypersensitivity and cancer susceptibility. Somatic-cell hybrid studies have revealed five FA complementation groups (A-E; refs 4-6) displaying similar phenotypes, suggesting that FA genes are functionally related. The two cloned FA genes, FAA and FAC, encode proteins that are unrelated to each other or to other proteins in GenBank. In the current study, we demonstrate the FAA and FAC bind each other and form a complex. Protein binding correlates with the functional activity of FAA and FAC, as patient-derived mutant FAC (L554P) fails to bind FAA. Although unbound FAA and FAC localize predominantly to the cytoplasm, the FAA-FAC complex is found in similar abundance in both cytoplasm and nucleus. Our results confirm the interrelatedness of the FA genes in a pathway, suggesting the cooperation of FAA and FAC in a nuclear function.
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PMID:The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. 939 57

Fanconi anemia (FA) is a rare, autosomal recessive disease characterized by multiple congenital abnormalities, bone marrow failure, and cancer susceptibility. Although traditionally described as a classic clinical syndrome, as more is discovered regarding its basic molecular and cell biology, FA is emerging as a true premalignant syndrome. Two of the genes of the five known complementation groups have been cloned, and work to understand their function is underway. Further understanding of these gene products has lent new ideas concerning modes of novel therapy, including gene therapy. The impact of molecular biology on our understanding of basic biology and the clinical care of FA patients is discussed.
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PMID:Molecular biology of Fanconi anemia. 944 45

Fanconi anemia (FA) is an autosomal recessive disorder characterized by bone marrow failure, cancer susceptibility, and a variety of developmental defects. The disease is clinically heterogeneous; eight different complementation groups (FA A-H) and, thus, genetic loci have been discovered. Two genes, FAA and FAC, have been cloned. Disease-associated mutations have been detected and rapid mutation screening makes possible the assignment of patients without resorting to time-consuming cell fusion and complementation analysis. Amplification of specific cDNAs from RNA followed by direct or indirect sequence analysis is a standard method for mutation detection. During the course of such examinations of the FAC gene, we have noted that frequently only one of the expressed alleles is successfully amplified. This can lead to false assignment of patients to a complementation group. As we report here, such cases can be rapidly clarified by retroviral gene transfer and complementation analysis.
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PMID:Retroviral gene transfer for the assignment of Fanconi anemia (FA) patients to a FA complementation group. 952 84


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