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1.
The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality
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Pang Q Christianson TA Keeble W Diaz J Faulkner GR Reifsteck C Olson S Bagby GC 《Blood》2001,98(5):1392-1401
The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations affect STAT1 activation, the hypothesis was considered that cross-linker resistance function of FANCC depends on structural elements that differ from those required for the cytokine signaling functions of FANCC. Structure-function studies were designed to test this notion. Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251A, failed to correct defective STAT1 activation. FA-C lymphoblasts carrying these 2 mutants demonstrated a defect in recruitment of STAT1 to the interferon gamma (IFN-gamma) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the characteristic hypersensitive apoptotic responses of FA-C cells to tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved region showed normal STAT1 activation but remained hypersensitive to MMC. The conclusion is that a central highly conserved domain of FANCC is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation. 相似文献
2.
Faivre L Guardiola P Lewis C Dokal I Ebell W Zatterale A Altay C Poole J Stones D Kwee ML van Weel-Sipman M Havenga C Morgan N de Winter J Digweed M Savoia A Pronk J de Ravel T Jansen S Joenje H Gluckman E Mathew CG 《Blood》2000,96(13):4064-4070
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070) 相似文献
3.
Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair 总被引:1,自引:0,他引:1
Leung JW Wang Y Fong KW Huen MS Li L Chen J 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(12):4491-4496
The Fanconi anemia (FA) pathway participates in interstrand cross-link (ICL) repair and the maintenance of genomic stability. The FA core complex consists of eight FA proteins and two Fanconi anemia-associated proteins (FAAP24 and FAAP100). The FA core complex has ubiquitin ligase activity responsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade of biochemical events that allow processing and removal of cross-linked DNA and thereby promotes cell survival following DNA damage. Here, we report the identification of a unique component of the FA core complex, namely, FAAP20, which contains a RAD18-like ubiquitin-binding zinc-finger domain. Our data suggest that FAAP20 promotes the functional integrity of the FA core complex via its direct interaction with the FA gene product, FANCA. Indeed, somatic knockout cells devoid of FAAP20 displayed the hallmarks of FA cells, including hypersensitivity to DNA cross-linking agents, chromosome aberrations, and reduced FANCD2 monoubiquitination. Taking these data together, our study indicates that FAAP20 is an important player involved in the FA pathway. 相似文献
4.
Zhang X Shang X Guo F Murphy K Kirby M Kelly P Reeves L Smith FO Williams DA Zheng Y Pang Q 《Blood》2008,112(5):1683-1686
Previous studies showed that Fanconi anemia (FA) murine stem cells have defective reconstitution after bone marrow (BM) transplantation. The mechanism underlying this defect is not known. Here, we report defective homing of FA patient BM progenitors transplanted into mouse models. Using cells from patients carrying mutations in FA complementation group A (FA-A), we show that when transplanted into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) recipient mice, FA-A BM cells exhibited impaired homing activity. FA-A cells also showed defects in both cell-cell and cell-matrix adhesion. Complementation of FA-A deficiency by reexpression of FANCA readily restored adhesion of FA-A cells. A significant decrease in the activity of the Rho GTPase Cdc42 was found associated with these defective functions in patient-derived cells, and expression of a constitutively active Cdc42 mutant was able to rescue the adhesion defect of FA-A cells. These results provide the first evidence that FA proteins influence human BM progenitor homing and adhesion via the small GTPase Cdc42-regulated signaling pathway. 相似文献
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Role of double-stranded RNA-dependent protein kinase in mediating hypersensitivity of Fanconi anemia complementation group C cells to interferon gamma, tumor necrosis factor-alpha, and double-stranded RNA
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Pang Q Keeble W Diaz J Christianson TA Fagerlie S Rathbun K Faulkner GR O'Dwyer M Bagby GC 《Blood》2001,97(6):1644-1652
Hematopoietic cells bearing inactivating mutations of Fanconi anemia group C (FANCC) are excessively apoptotic and demonstrate hypersensitivity not only to cross-linking agents but also to interferon gamma (IFN-gamma) and tumor necrosis factor-alpha. Seeking essential signaling pathways for this phenotype, this study quantified constitutive and induced RNA-dependent protein kinase (PKR) activation in Fanconi anemia cells of the C complementation group (FA-C). PKR was constitutively phosphorylated and exhibited an increased binding affinity for double-stranded RNA (dsRNA) in FANCC(-/-) cells. FANCC(-/-) cells were hypersensitive to both dsRNA and the combination of dsRNA and IFN-gamma in that these agents induced a higher fraction of apoptosis in FANCC(-/-) cells than in normal cells. Overexpression of wild-type PKR-sensitized FANCC(-/-) cells to apoptosis induced by IFN-gamma and dsRNA. Conversely, inhibition of PKR function by enforced expression of a dominant-negative inhibitory mutant of PKR (PKRDelta6) substantially reduced the IFN and dsRNA hypersensitivity of FANCC(-/-) cells. Two PKR target molecules, IkappaB-alpha and IRF-1, were not differentially activated in FANCC(-/-) cells, but enforced expression of a nonphosphorylatable form of eukaryotic translation initiation factor-2alpha reversed the PKR-mediated block of messenger RNA translation and partially abrogated the PKR-mediated apoptosis in FANCC(-/-) cells. Because no evidence was found of a PKR/FANCC complex in normal cells, it was concluded that an essential function of FANCC is to suppress, indirectly, the activity of PKR and that FANCC inactivation results in IFN hypersensitivity, at least in part, because this function of FANCC is abrogated. 相似文献
7.
Platzbecker U Kurre P Guardiola P Ward JL Radich JP Kiem HP Deeg HJ 《Experimental hematology》2004,32(9):815-821
OBJECTIVE: The pathophysiology of bone marrow failure in Fanconi anemia (FA) patients is thought to involve excessive apoptosis involving signaling triggered by fas ligation and tumor necrosis factor (TNF)-alpha, or interferon (IFN)-gamma exposure. We investigated whether a new member of the TNF family, TRAIL (TNF-related apoptosis-inducing ligand), would similarly trigger preferential apoptotic cell death in FA phenotype cells. MATERIAL AND METHODS: Hematopoietic cells from FANCC(-/-) transgenic mice and human FA-C lymphoblasts (HSC536N) as well as their phenotypically corrected counterparts (FANCC(+/+), HSC536/FA-Cneo) were compared for their response to apoptosis induction by TRAIL and fas ligation in the presence or absence of IFN-gamma. Cells were also studied for the protein and gene expression of TRAIL-receptors, caspase-8 and its inhibitory protein, FLIP. RESULTS: TRAIL exposure by itself or in combination with IFN-gamma did not lead to preferential apoptosis induction in human and murine FA-C phenotype hematopoietic cells. This resistance was unrelated to the expression of TRAIL receptors or FLIP isoforms, but correlated with absent cleavage of pro-caspase-8. Results were validated by those from gene expression profiling of relevant genes in the two lymphoblast cell lines. CONCLUSION: TRAIL, in contrast to fas ligation, does not induce preferential apoptosis in FA-C phenotype cells despite shared downstream signaling described in non-FA models. These data provide further insight into the complexity of FA-C-regulated apoptotic signaling. 相似文献
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Rackoff WR; Orazi A; Robinson CA; Cooper RJ; Alter BP; Freedman MH; Harris RE; Williams DA 《Blood》1996,88(5):1588-1593
This report examines the effect of filgrastim (granulocyte colony- stimulating factor, [G-CSF] in 12 patients with neutropenia [absolute neutrophil count [ANC] < 1,000/mm3]) caused by Fanconi anemia (FA). Two of 14 patients who were evaluated for study entry were ineligible because of unsuspected cytogenetic abnormalities in their bone marrow (BM). G-CSF was started at 5 micrograms/kg/d. All patients had an increase in their ANC at week 8 (mean increase = 15,664/mm3). The median ANC during therapy was 5,030/mm3. Eight of 10 patients who completed 40 weeks on study maintained an ANC > 1,500/mm3 on G-CSF given every-otherday. Four patients had an increase in their platelet count by week 8 without transfusion (maximum increase = 23,000 to 45,000/mm3); however, platelet counts fell toward baseline levels as the G-CSF dose was reduced. BM CFU-MK were increased at week 8 in three of four evaluable patients. Four patients who did not receive red blood cell transfusions had an increase in their hemoglobin level of at least 2.0 g/dL. A fifth patient had a red blood cell transfusion in week 2 and then had a similar increase in hemoglobin level without subsequent transfusion. Eight of 10 patients who completed 40 weeks of treatment showed increases in the percentage of BM CD34+ cells measured by flow cytometry. The same proportion showed increases in peripheral blood CD34+ cells. Increased BM cellularity and myeloid hyperplasia were constant findings and were associated with increased expression of the proliferating cell nuclear antigen. Adverse experiences were mild fever (1 patient) and a new BM cytogenetic abnormality at week 40 (1 patient). This study shows that prolonged administration of G-CSF exerts a stimulatory effect on the BM of FA patients and may be used to maintain a clinically adequate ANC in these patients. G-CSF has beneficial effects on multiple hematopoietic lineages in some patients and may be a good candidate for use in combination cytokine protocols for FA patients with progressive aplastic anemia. G-CSF use results in an increase in circulating CD34+ cells, a finding with important implications for future gene transfer protocols. 相似文献
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R Munekata I Miyazawa H Matsuzaki K Yoshino M Hirano H Muk?yama H Nariuchi 《[Rinshō ketsueki] The Japanese journal of clinical hematology》1990,31(12):1960-1964
A 52 year-old male was admitted to our hospital with the complaint of the hypochondrial pain after meal in February 1989. He was diagnosed to be RAEB and to have common bile duct stone. His red blood cells (RBC) could not be agglutinated with anti-A, anti-B, or anti-A, B. The agglutinability of the cells to Ulex europaeus (anti-H) was the same to the normal type B RBC, and his serum contained anti-I, anti-E, and anti-c. In his saliva, both B and H antigens were detected. The glycosyl B transferase in his serum showed similar activity to that of normal individual with type B RBC. When his RBC were treated with normal type B transferase, the cells obtained the reactivity to anti-B but they agglutinated much weaker than the type O cells treated with the enzyme. These results indicated that the low agglutinability of his RBC could not be due to the low transferase activity but the qualitative or quantitative changes of the precursor molecules of the type B substance of the cells. 相似文献
12.
Summary As part of an overall assessment of immunological function, several aspects of cellular immunity and circulating lymphocyte subpopulations were evaluated in a group of 10 patients with idiopathic autoimmunhemolytic anemia (AIHA). The absolute numbers of circulating T and B cells were reduced in the patient group compared to normals. A shift from corticosteroid-sensitive to corticosteroid-resistent and activated cells in the cytogram of clustered Fe-(III)-hydroxide-glucane saccharose labeled T lymphocytes was apparent. In vitro studies of cellular reactivity, as evaluated by PHA, ConA, PWM, antigens and allogeneic cell induced proliferation showed a blend of general or selective depression and sometimes a normal or increased activity with no definite correlation with both the number of circulating T cells and the extent of the hemolytic activity by the disease. The possible significance of the findings is discussed.This work was supported by the Minister für Wissenschaft und Forschung des Landes NRW II B8-FA 6438 相似文献
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Human monoclonal antibody against Rh(D) antigen: partial characterization of the Rh(D) polypeptide from human erythrocytes 总被引:3,自引:0,他引:3
Bloy C; Blanchard D; Lambin P; Goossens D; Rouger P; Salmon C; Cartron JP 《Blood》1987,69(5):1491-1497
A human monoclonal anti-Rh(D) antibody produced by an Epstein-Barr virus (EBV)-transformed B-cell line (IgG1(lambda), clone H2D5D2) has been purified on protein A-Sepharose column and used for binding studies and immune precipitation of the blood group rhesus (Rh) antigens. Scatchard plot analyses show that the 125I-labeled antibody (iodo-gen procedure), binds to 1.09 X 10(5), 0.43 X 10(5), and 0.32 X 10(5) antigen sites on each D--/D--, R2R2 and R1R1 RBC, respectively, with an association constant of approximately 0.6 X 10(8) mol/L-1. Immune precipitation studies indicate also that the Rh(D) antigen of the Rh(D)-positive RBCs is carried by a 29 kd polypeptide as deduced from sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS- PAGE). No material could be precipitated from Rh(D)-negative or Rhnull RBCs. These results indicate that the monoclonal and the polyclonal human anti-Rh(D) behave similarly. A sample (Blo., presumed genotype R2r or R0R2) showing an increased number of antigen sites (0.76 X 10(5)/cell) and a high binding constant (5.7 X 10(8) mol/L-1) was used, as well as D--/D-- RBCs, for further purification of the 29-kd component. Extraction by Triton X-100 (0.1% to 5%) of the immune complexes formed between the membrane-bound Rh(D) antigens and the monoclonal antibody as well as a direct quantitative estimate of the 29- kd component, suggest that the Rh(D) polypeptide is loosely bound to the skeleton, since less than or equal to 80% can be solubilized from the membrane. In similar conditions, glycophorin A showed a slight association with the Triton-insoluble residue, whereas glycophorin B was easily and completely extracted. In contrast, both the minor RBC sialoglycoproteins, glycophorin C and glycoprotein gamma, remained predominantly bound to the membrane skeleton. The purified Rh(D) polypeptide obtained from Blo. and D--/D-- RBCs by immunoprecipitation and preparative gel electrophoresis was homogenous as judged by SDS- PAGE. Amino acid composition indicated that the Rh(D) protein contained sulfhydryl groups which are essential for biological activity. 相似文献
15.
Smokeless tobacco (snus) is associated with an increased risk of type 2 diabetes: results from five pooled cohorts
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S. Carlsson T. Andersson M. Araghi R. Galanti A. Lager M. Lundberg P. Nilsson M. Norberg N. L. Pedersen Y. Trolle‐Lagerros C. Magnusson 《Journal of internal medicine》2017,281(4):398-406
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Plasma Pro‐C3 (N‐terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C
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Mette J. Nielsen Sanne S. Veidal Morten A. Karsdal Diana J. Ørsnes‐Leeming Ben Vainer Stephen D. Gardner Robert Hamatake Zachary D. Goodman Detlef Schuppan Keyur Patel 《Liver international》2015,35(2):429-437
18.
Gehi A Ix J Shlipak M Pipkin SS Whooley MA 《The American journal of cardiology》2005,95(12):1474-1477
We examined the association between anemia (hemoglobin < or =12 g/dl) and 6 indexes of heart rate variability (HRV) as measured by 24-hour ambulatory electrocardiography in a cross-sectional study of 874 outpatients who had stable coronary heart disease. Of 90 participants who had anemia, 29% to 41% had low HRV, defined as the lowest quartile of each HRV index, compared with 23% to 25% of the 784 participants who did not have anemia (comparison p values <0.05 for all HRV indexes except high-frequency power). With the exception of high-frequency power, each 1 g/dl decrease in hemoglobin was associated with increased odds of having low HRV. This association remained strong after adjustment for potential confounding variables, including ischemia, left ventricular mass, left ventricular ejection fraction, and diastolic dysfunction. Thus, anemia is associated with low HRV in ambulatory patients who have stable coronary heart disease. Low HRV could potentially mediate the association of anemia with increased cardiac risk. 相似文献
19.
Chow KB Sun J Chu KM Tai Cheung W Cheng CH Wise H 《Molecular and cellular endocrinology》2012,348(1):247-254
The ghrelin receptor (GHS-R1a) is remarkable amongst G-protein-coupled receptors for its high degree of constitutive activity, and this agonist-independent activity may be important for its physiological function in the control of food intake and body weight. Ghrelin receptors form heterodimers with the truncated ghrelin receptor polypeptide (GHS-R1b), which has a dominant-negative effect on ghrelin receptor function. Here we show that GHS-R1b has an intracellular localization distinct from ghrelin receptors, being primarily localized in the endoplasmic reticulum. Immunocytochemical studies suggest that GHS-R1b decreases the plasma membrane expression of ghrelin receptors, but the overall distribution profile of ghrelin receptors in isolated subcellular fractions is unaffected by GHS-R1b. Using bioluminescence resonance energy transfer methods, we have shown that while ghrelin receptor homodimers are evenly distributed in all subcellular fractions, GHS-R1a/GHS-R1b heterodimers are concentrated within the endoplasmic reticulum and these results suggest that GHS-R1b traps ghrelin receptors within the endoplasmic reticulum by the process of oligomerization. Furthermore, ghrelin receptors constitutively activated extracellular signal-regulated kinases 1/2 in the endoplasmic reticulum, but this small response was not affected by GHS-R1b and its physiological relevance is uncertain. Taken together, these results suggest that ghrelin receptors can be retained in the endoplasmic reticulum by heterodimerization with GHS-R1b, and constitutive activation of phospholipase C is attenuated due to decreased cell surface expression of ghrelin receptors. However, sufficient ghrelin receptor homodimers can still be expressed on the cell surface for maximal responses to agonist stimulation. 相似文献
20.
A case of weak blood group B expression (Bm) associated with abnormal blood group galactosyltransferase 总被引:2,自引:0,他引:2
Family studies on myeloperoxidase (MPO) deficiency have been carried out by quantitating the peroxidase activity of granulocyte preparations with three methods, namely guaiacol peroxidation, alanine decarboxylation, and spectroscopic analysis. The guaiacol assay failed to show a definite pattern of inheritance in two families with MPO- deficient subjects. Surprisingly, the granulocytes of three histochemically MPO-negative subjects had a peroxidase activity either half or even higher than that of control subjects. The peroxidase activity of these granulocyte preparations in these three subjects showed a positive correlation to the number of eosinophils. The possibility then considered was that eosinophils may have obscured the true pattern of inheritance in this assay. Two other methods of MPO assay, which are not influenced by the presence of eosinophil peroxidase (EPO), were therefore devised. One is based on the ability of MPO, but not EPO, to catalyze decarboxylation of L-alanine in the presence of Triton X-100, and the other relies on the different spectral properties of the two peroxidases. The results obtained with these two methods (1) were strictly comparable, (2) allowed detection of both totally and partially MPO-deficient subjects, (3) differed profoundly from those obtained with the guaiacol method when eosinophil- containing granulocyte preparations were used, and (4) revealed a pattern of autosomal recessive inheritance in the two families studied. The results of the three methods were comparable when eosinophil-free granulocyte preparations were assayed. It is concluded that failure to show a pattern of inheritance in some instances of primary MPO deficiency, or deviations from the autosomal recessive mode of transmission of this defect, may be attributed to interference by EPO. It is proposed that peroxidase assay methods not subject to EPO interference, such as the two described in this article, may be used, particularly in the detection of heterozygote subjects for MPO deficiency in the presence of high eosinophil counts. 相似文献