Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Fanconi anemia (FA) is an autosomal recessive disorder characterized by chromosomal instability and abnormalities in the processing of DNA lesions induced by cross-linking agents. We previously reported that after photoaddition of psoralen derivatives the frequency of HPRT- mutants was significantly lower in FA than in normal human lymphoblasts. The hypomutability in FA cells was shown to be associated with an increased deletion frequency at the HPRT gene level. Further characterization of 70 unrearranged mutants (without detectable changes in restriction enzyme fragment length) according to the HPRT gene expression is reported here. Northern blot hybridization analysis demonstrates considerable differences in mRNA phenotyping between normal and FA cells. In normal cells, the minority of spontaneous (31%) and psoralen-induced mutants (0% and 14% according to treatment) arise from mutations that alter the HPRT gene transcription. In contrast to normal cells, in the majority of mutants isolated from FA cells, HPRT gene expression is found to be affected. Indeed a large proportion of either spontaneous (67%) or psoralen-induced (56% and 46%) mutants did not produce detectable amounts of mRNA. These results suggest that the mutagenic processing of spontaneous and psoralen-photoinduced lesions differs in normal and FA cells.
Somat Cell Mol Genet 1991 Nov
PMID:HPRT gene expression differs in mutants derived from normal and Fanconi anemia cells: analysis of spontaneous and psoralen-photoinduced mutants. 168 31

Immunohistochemically detectable erythropoietin-like substance(Epo) in granular convoluted tubule(GCT) cells of submandibular glands (SMG's) was examined in mice in which hemolytic anemia had been induced by phenylhydrazine (ph), and in mice subjected to hypoxia, nephrectomy, or testosterone (TP) injections. Staining for Epo was negative in GCT cells of SMG's in normal mice, while positive staining occurred in GCT cells of the anemic mice and mice subjected to hypoxia or nephrectomy. A positive Epo reaction was also revealed at the luminal borders of distal tubules, and in cells of proximal and distal tubules in the kidney, and in some hepatic and spleen cells, of mice that had received combination regimens producing anemia and hypoxia, or had been nephrectomized. Increased staining of Epo was found in GCT cells of SMG's, and in proximal and distal kidney tubules of mice given the combination treatment plus TP injections. The detection of Epo in GCT cells suggests these extrarenal cells to be sites of accumulation or biosynthesis of the protein under certain specific conditions such as hemolytic anemia and hypoxia.
Cell Mol Biol 1991
PMID:Erythropoietin expressed in granular convoluted tubule cells of mice submandibular glands under hypoxia, anemia, and nephrectomy. 193 6

We have used a host cell reactivation system to study the effect of 8-methoxypsoralen (8-MOP) reaction on CAT (chloramphenicol acetyltransferase) and NEO (aminoglycoside phosphotransferase) expression in normal human cells, as well as two cell lines with possible DNA repair-processing defects. Plasmid DNA was treated with psoralen plus near-ultraviolet (NUV) irradiation. The reacted plasmids, pSV2cat and pSV2neo, were transfected into Fanconi anemia (FA), xeroderma pigmentosum (XP), and normal human fibroblast cells for transient or stable assay. The cells were assayed for CAT activity at various times after transfection or selected for G418 resistance. The extent of adduct formation required to inhibit expression was much less (difference of D37 greater than 2.5) in FA or XP cells compared to normal. We conclude that in FA and XP cells, the reactivation of CAT was much less than in normal cells. The possibility of differential DNA uptake and/or degradation in transient assay was ruled out by analysis of plasmid DNA recovered from transfected cells. The data of the two independent assays indicate that FA and XP cells are deficient in cross-linked DNA repair.
Somat Cell Mol Genet 1991 May
PMID:Reactivation of psoralen-reacted plasmid DNA in Fanconi anemia, xeroderma pigmentosum, and normal human fibroblast cells. 204 39

We previously demonstrated that 3'-azido-3'-deoxythymidine (AZT) inhibits proliferation of human bone marrow progenitor cells in vitro and that incorporation of AZT into nuclear DNA may be one mechanism responsible for AZT-induced bone marrow toxicity [Antimicrob. Agents Chemother. 31:452-454 (1987); Mol. Pharmacol. 36:9-14 (1989)]. The present study explores possible genetic mechanisms involved in AZT-induced anemia by evaluating the effects of AZT on globin gene expression at both the transcriptional and the translational levels in butyric acid-induced K-562 human erythroleukemia cells. AZT, at concentrations ranging from 10 to 250 microM, was added to cells 25 hr after initiation of induction of hemoglobin (Hb) synthesis with 1.4 mM butyric acid. Hb synthesis, as measured by benzidine staining, was inhibited by AZT in a dose- and time-dependent manner in these cells. AZT inhibition of cell growth was not the major contributing factor in the net inhibition of Hb synthesis in K-562 cells. As assessed by Northern blot analysis, AZT inhibition of Hb synthesis was associated with a decrease in globin mRNA steady state levels without inhibition of total RNA synthesis or actin mRNA steady state levels. In particular, a decrease of globin mRNA levels of 23% by 25 microM AZT was observed, reaching a maximum inhibition of 59% in the presence of 250 microM AZT. In vitro translation experiments demonstrated that essentially all nonglobin translatable mRNAs were not inhibited by AZT concentrations as high as 250 microM, whereas globin mRNAs coding for epsilon, zeta, A gamma, G gamma, and alpha chains were substantially inhibited to similar levels by AZT, in a dose-dependent manner. Transcriptional run-on studies with isolated nuclei from AZT-treated K-562 cells demonstrated a 20 and 50% inhibition of in vitro synthesized globin transcripts from cells exposed to 25 and 100 microM AZT, respectively. 2',3'-Dideoxycytidine also inhibited K-562 cell growth in the same concentration range as AZT but, of importance, had no effects on Hb production. These data suggest that inhibition of globin gene expression may play a role in the cytotoxicity of AZT to the erythroid cell.
Mol Pharmacol 1990 Dec
PMID:3'-Azido-3'-deoxythymidine inhibits globin gene transcription in butyric acid-induced K-562 human leukemia cells. 217 2

It has been shown by genetic complementation analysis that a mitomycin C-sensitive mutant (V-H4) of Chinese hamster V79 cells is the first rodent equivalent of Fanconi anemia (FA) group A. The V-H4 mutant shows many typical characteristics of cells derived from FA patients. V-H4 cells exhibit increased sensitivity towards cross-linking agents as MMC (approximately 30-fold), cis-DDP (approximately 10-fold), DEB (approximately 10-fold), and PUVA (approximately 1.6-fold), but an only slightly increased sensitivity to monofunctional alkylating agents (EMS and MMS) and actinomycin D. V-H4 cells are also moderately sensitive to adriamycin (1.6-fold), and not sensitive to H2O2. The levels of chromosomal aberrations induced by MMC and cis-DDP treatment are higher (4- to 6-fold) in V-H4 cells than in the wild-type V79 cells. Genetic complementation analysis with other Chinese hamster mutants hypersensitive to MMC (irs1, irs1SF, UV20 and UV41) indicates clearly that V-H4 belongs to a different, new complementation group. This unique mutant is very stable and can serve as a vehicle to isolate the complementing FA-A gene from normal human DNA.
Somat Cell Mol Genet 1990 Nov
PMID:The Chinese hamster V79 cell mutant V-H4 is phenotypically like Fanconi anemia cells. 226 31

Erythropoietin (EPO) is the primary humoral regulator of mammalian erythropoiesis. The single-copy EPO gene is normally expressed in liver and kidney, and increased transcription is induced by anemia or cobalt chloride administration. To identify cis-acting DNA sequences responsible for regulated expression, transgenic mice were generated by microinjection of a 4-kilobase-pair (kb) (tgEPO4) or 10-kb (tgEPO10) cloned DNA fragment containing the human EPO gene, 0.7 kb of 3'-flanking sequence, and either 0.4 or 6 kb of 5'-flanking sequence, respectively. tgEPO4 mice expressed the transgene in liver, where expression was inducible by anemia or cobalt chloride, kidney, where expression was not inducible, and other tissues that do not normally express EPO. Human EPO RNA in tgEPO10 mice was detected only in liver of anemic or cobalt-treated mice. Both tgEPO4 and tgEPO10 mice were polycythemic, demonstrating that the human EPO RNA transcribed in liver is functional. These results suggest that (i) a liver inducibility element maps within 4 kb encompassing the gene, 0.4 kb of 5'-flanking sequence, and 0.7 kb of 3'-flanking sequence; (ii) a negative regulatory element is located between 0.4 and 6 kb 5' to the gene; and (iii) sequences required for inducible kidney expression are located greater than 6 kb 5' or 0.7 kb 3' to the gene. RNase protection analysis revealed that human EPO RNA in anemic transgenic mouse liver and hypoxic human hepatoma cells is initiated from several sites, only a subset of which is utilized in nonanemic transgenic liver and human fetal liver.
Mol Cell Biol 1990 Mar
PMID:Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements. 230 68

We characterized an anemia-inducing mutation in the human gene for triosephosphate isomerase (TPI) that resulted in the production of prematurely terminated protein and mRNA with a reduced cytoplasmic half-life. The mutation converted a CGA arginine codon to a TGA nonsense codon and generated a protein of 188 amino acids, instead of the usual 248 amino acids. To determine how mRNA primary structure and translation influence mRNA stability, in vitro-mutagenized TPI alleles were introduced into cultured L cells and analyzed for their effect on TPI RNA metabolism. Results indicated that mRNA stability is decreased by all nonsense and frameshift mutations. To determine the relative contribution of the changes in mRNA structure and translation to the altered half-life, the effects of individual mutations were compared with the effects of second-site reversions that restored translation termination to normal. All mutations that resulted in premature translation termination reduced the mRNA half-life solely or mainly by altering the length of the mRNA that was translated. The only mutation that altered translation termination and that reduced the mRNA half-life mainly by affecting the mRNA structure was an insertion that shifted termination to a position downstream of the normal stop codon.
Mol Cell Biol 1988 Feb
PMID:Premature translation termination mediates triosephosphate isomerase mRNA degradation. 283 37

By comparing fibroblast strains derived from individuals exhibiting chromosome instability and/or mutagen hypersensitivity (Cockayne syndrome, ataxia telangiectasia, and Fanconi anemia) with strains derived from healthy donors, the fibroblast micronucleus assay has been established as a reproducible measure of the genotypic variation in spontaneous or mitomycin C (MMC)-induced chromosomal instability. The patient strains that were moderately or exquisitely sensitive to MMC, whereas the mildly sensitive strain (Cockayne syndrome) overlapped with the control range. The reproducibility of the assay was evaluated within and between experiments. Paired comparison analyses between duplicate cultures and between repeat experiments failed to show any significant differences between micronucleus frequencies within strains, whereas a significant differences in the spontaneous micronucleus frequencies between strains was observed. In addition to its value as a test system for genotoxins, the fibroblast micronucleus assay may be useful for investigating genetically determined hypersensitivity to mutagens, elevated spontaneous chromosomal breakage, and chromosome segregation errors.
Environ Mol Mutagen 1988
PMID:Micronucleus assay in human fibroblasts: a measure of spontaneous chromosomal instability and mutagen hypersensitivity. 313 7

Goats and some sheep synthesize a juvenile hemoglobin, Hb C (alpha 2 beta C2), at birth and produce this hemoglobin exclusively during severe anemia. Sheep that synthesize this juvenile hemoglobin are of the A haplotype. Other sheep, belonging to a separate group, the B haplotype, do not synthesize hemoglobin C and during anemia continue to produce their adult hemoglobin. To understand the basis for this difference we have determined the structural organization of the beta-globin locus of B-type sheep by constructing and isolating overlapping genomic clones. These clones have allowed us to establish the linkage map 5' epsilon I-epsilon II-psi beta I-beta B-epsilon III-epsilon IV-psi beta II-beta F3' in this haplotype. Thus, B sheep lack four genes, including the BC gene, and have only eight genes, compared with the 12 found in the goat globin locus. The goat beta-globin locus is as follows: 5' epsilon I-epsilon II-psi beta X-beta C-epsilon III-epsilon IV-psi beta Z-beta A-epsilon V-epsilon VI-psi beta Y-beta F3'. Southern blot analysis of A-type sheep reveals that these animals have a beta-globin locus similar to that of goat, i.e., 12 globin genes. Thus, the beta-globin locus of B-haplotype sheep resembles that of cows and may have retained the duplicated locus of the ancestor of cows and sheep. Alternatively, the B-sheep locus arrangement may be the result of a deletion of a four-gene set from the triplicated locus.
Mol Biol Evol 1988 Mar
PMID:Structural organization of the beta-globin locus of B-haplotype sheep. 336 82

Considerable variation can be observed in the clinical presentation of Fanconi anemia (FA) patients and in the degree of sensitivity of their cells to DNA damaging agents. We have examined the hypothesis that genetic heterogeneity underlies this variation by testing for complementation in somatic cell hybrids constructed from FA cells. Hybrids were formed by fusing lymphoblastoid cell lines derived from four different FA patients. Complementation of the cellular defects in FA was tested by examining sensitivity to growth inhibition by mitomycin C(MMC), spontaneous chromosome breakage, and MMC-induced chromosome breakage in the hybrid cells. These studies revealed the presence of at least two complementation groups, suggesting that there may be two or more different FA genes.
Somat Cell Mol Genet 1985 Jan
PMID:Identification of two complementation groups in Fanconi anemia. 391 52


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