Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary pathogenic event of sickle cell anemia is the polymerization of the mutant hemoglobin (Hb) S within the red blood cells, occurring when HbS is in deoxy state in the venous circulation. Polymerization is known to start with nucleation of individual polymer fibers, followed by growth and branching via secondary nucleation, yet the mechanisms of nucleation of the primary fibers have never been subjected to dedicated tests. We implement a technique for direct determination of rates and induction times of primary nucleation of HbS fibers, based on detection of emerging HbS polymers using optical differential interference contrast microscopy after laser photolysis of CO-HbS. We show that: (i). nucleation throughout these determinations occurs homogeneously and not on foreign substrates; (ii). individual nucleation events are independent of each other; (iii). the nucleation rates are of the order of 10(6)-10(8)cm(-3)s(-1); (iv). nucleation induction times agree with an a priori prediction based on Zeldovich's theory; (v). in the probed parameter space, the nucleus contains 11 or 12 molecules. The nucleation rate values are comparable to those leading to erythrocyte sickling in vivo and suggest that the mechanisms deduced from in vitro experiments might provide physiologically relevant insights. While the statistics and dynamics of nucleation suggest mechanisms akin to those for small-molecule and protein crystals, the nucleation rate values are nine to ten orders of magnitude higher than those known for protein crystals. These high values cannot be rationalized within the current understanding of the nucleation processes.
J Mol Biol 2004 Feb 06
PMID:Mechanisms of homogeneous nucleation of polymers of sickle cell anemia hemoglobin in deoxy state. 1474 Dec 2

Hydroxyurea is considered an antineoplastic drug, which also plays an important role in the treatment of sickle cell anemia patients. We evaluated and compared the clastogenic and cytotoxic effects of hydroxyurea, using chromosomal aberrations and mitotic index, respectively, as endpoints. In vitro short-term cultures of lymphocytes were exposed to several concentrations of this drug, at various cell cycle phases. There was a significant increase in the cytotoxicity of hydroxyurea at G1 and G1/S as well in the G2 phase of the cell cycle. Hydroxyurea did not significantly increase chromosome aberrations. There was an S-dependent cytotoxic effect of hydroxyurea, which is expected based on the known activity of hydroxyurea as an inhibitor of ribonucleotide reductase.
Genet Mol Res 2003 Sep 30
PMID:Evaluation of the mutagenic activity of hydroxyurea on the G1-S-G2 phases of the cell cycle: an in vitro study. 1496 81

In patients with sickle cell anemia, fetal hemoglobin (HbF) concentrations vary by 2 orders of magnitude. This variance may be a result of heterogeneity in gene regulatory elements; accordingly, we searched for single nucleotide polymorphisms (SNPs) that might identify this variation. More than 180 SNPs were studied in 38 genes in 280 sickle cell anemia patients. The strongest association with HbF was found with SNPs near a QTL previously localized on chromosome 6q22.3-q23.2. Initially, two SNPs were identified in intergenic portions of this QTL and were associated with about a 20% difference in percent HbF. Subsequently, we genotyped 44 additional SNPs in the genomic region between 136.1 Mb and 137.5 Mb on chromosome 6q. Twelve SNPs, associated with a 20%-30% difference in HbF concentrations, were located in the introns of four genes, PDE7B, MAP7, MAP3K5 and PEX7. In K562 cells, the p38-MAPK pathway has been associated with the activation of gamma-globin gene expression by histone deacetylase inhibitors. Haplotypes C-T-T-T in MAP7 and T-C-C in PEX7 were significantly associated with increases in concentration of HbF, both showing strong dominance. Genetic elements abutting the 6q22.3-q23.2 QTL, may harbor trans-acting elements that help modulate baseline HbF level in sickle cell anemia.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:Polymorphisms near a chromosome 6q QTL area are associated with modulation of fetal hemoglobin levels in sickle cell anemia. 1504 Apr 24

Polymorphisms of multiple cis-acting elements in the beta-globin locus are associated with variable fetal haemoglobin (HbF) level in sickle cell disease. We developed a multiplex assay permitting simultaneous analysis of three polymorphic cis elements spanning 53 kb of the beta-globin locus. We identified concordance between polymorphic alleles in gamma- and beta-globin promoters however a significant number of betaS-chromosomes were identified with polymorphisms in hypersensitive site 2 (HS2) of the beta-globin locus control region juxtaposed to atypical cis alleles in the gamma-promoter. Analysis of an unusually large number of such hybrid haplotype chromosomes provided unique insight into HbF level associated with specific cis alleles. Associations between cis alleles and HbF level in patients were verified by in vitro functional analysis. Our findings indicate that compared to HS2, polymorphism in the gamma-promoter exerts a dominant influence on HbF level in sickle cell disease.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:Dominant influence of gamma-globin promoter polymorphisms on fetal haemoglobin expression in sickle cell disease. 1504 Apr 25

Inhibition of beta-globin gene expression by antisense nucleic acids is a potentially powerful therapeutic strategy for sickle cell disease. To develop clinically relevant beta-globin antisense agents we created nine stable mouse erythroleukemia cell lines expressing unique anti-beta-globin RNA transcripts with different potentials for cross-hybridization with gamma-globin mRNA. We observed variable inhibition of beta-globin expression independent of the hybridization potential of the respective antisense beta-globin RNA transcript. Similarly, inhibition of gamma-globin expression by anti-beta transcripts varied widely in the nine stable cell lines. Three neighboring regions in the beta-globin gene with low RNA folding potentials conferred significantly stronger antisense effect toward beta-globin while sparing the homologous targets in gamma-globin. We have identified for the first time targets in the beta-globin gene for which the homologous regions in gamma-globin are relatively inaccessible to antisense attack. Our findings offer the prospect of using this approach to reduce the proportion of intracellular hemoglobin S. Gene therapy strategies which combine gamma-globin induction along with beta-globin inhibition using antisense vectors may yield more favorable anti-sickling effects longterm.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:Selective inhibition of beta-globin RNA transcripts by antisense RNA molecules. 1504 Apr 26

It has been demonstrated by our laboratory that the irreversibly sickled cell (ISC) spectrin-4.1-actin complex dissociates slowly as compared to ternary complexes formed out of control (AA) and reversibly sickle cell (RSCs) core skeletons. These studies indicated that the molecular basis for the inability of irreversibly sickled cells (ISCs) to change shape is a skeleton that disassembles, and therefore reassembles, very slowly. The present study is based on the following observations: a) alpha-spectrin repeats 20 and 21 contain ubiquitination sites, and b) The spectrin repeats beta-1 and beta-2 are in direct contact with spectrin repeats alpha-20 and alpha-21 during spectrin heterodimer formation, and contain the protein 4.1 binding domain. We demonstrate here that alpha-spectrin ubiquitination at repeats 20 and 21 increases the dissociation of the spectrin-protein-4.1-actin ternary complex thereby regulating protein 4.1's ability to stimulate the spectrin-actin interaction. Performing in vitro ternary complex dissociation assays with AA control and sickle cell SS spectrin (isolated from high-density sickle cells), we further demonstrate that reduced ubiquitination of alpha-spectrin is, in part, responsible for the locked membrane skeleton in sickle cell disease.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:Ubiquitination of spectrin regulates the erythrocyte spectrin-protein-4.1-actin ternary complex dissociation: implications for the sickle cell membrane skeleton. 1504 Apr 29

Physiological removal of old erythrocytes from the circulation by macrophages is initiated by binding of autologous IgG to senescent cell antigen (SCA). SCA is generated from the anion exchanger band 3. This process is accompanied by a number of alterations in the function and structure of band 3. We measured these aging-related parameters in erythrocytes from individuals with sickle cell anemia. Most sickle erythrocytes have characteristics that are also found in senescent normal erythrocytes, such as an increased density and considerable concentrations of cell-bound IgG. Together with the concomitant changes in structure and function of band 3, these data suggest that most sickle erythrocytes have undergone a process of accelerated aging. Preliminary results indicate that this process is reversed upon vitamin E supplementation. These data show that the erythrocyte aging paradigm may provide a useful conceptual framework for the study of the pathophysiology and the evalution of therapeutic intervention in sickle cell disease, and support the view that oxidation can generate neoantigens that are recognized by autoantibodies.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:Erythrocyte aging in sickle cell disease. 1504 Apr 31

Acute chest syndrome (ACS) is the leading cause of death in sickle cell disease. Severe ACS often develops in the course of a vasoocclusive crisis (VOC), and frequently involves pulmonary fat embolism. Secretory phospholipase A2 (sPLA2), a potent inflammatory mediator, is elevated in ACS, and sPLA2 levels in serum or plasma predict impending ACS. In addition sPLA2 may play a major role in the actual damage to the lung resulting in a new pulmonary infiltrate on chest radiography, respiratory symptoms, and ultimately alveolar collapse and the impairment of gas exchange. The data indicate that measurement of sPLA2 can be useful in alerting the clinician to patients with impending ACS, and suggest that instituting early therapies based on sPLA2 levels, including inhibition of sPLA2 activity, may be useful to prevent or reduce the clinical morbidity of ACS in sickle cell disease.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:The role of secretory phospholipase A2 in acute chest syndrome. 1504 Apr 32

In addition to its mediation of vascular relaxation and neurotransmission, nitric oxide (*NO) potently modulates oxygen radical reactions and inflammatory signaling. This participation of *NO in free radical and oxidative reactions will yield secondary oxides of nitrogen that display frequently-undefined reactivities and unique signaling properties. In sickle cell disease (SCD) inflammatory-derived oxidative reactions impair *NO-dependent vascular function. A combination of clinical and knockout-transgenic SCD mouse studies show increased rates of xanthine oxidase-dependent superoxide (O2*-) production and reveal the presence of an oxidative and nitrative inflammatory milieu in the sickle cell vasculature, kidney and liver. Considering the critical role of endothelial *NO production in regulating endothelial adhesion molecule expression, platelet aggregation, and both basal and stress-mediated vasodilation, the O2*- mediated reduction in *NO bioavailability can significantly contribute to the vascular dysfunction and organ injury associated with SCD.
Cell Mol Biol (Noisy-le-grand) 2004 Feb
PMID:Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease--mechanisms and consequences. 1504 Apr 33

Band 3 proteins, members of the anion exchange family of proteins (AE 0-3), are involved in a number of physiological activities such as cell volume and osmotic homeostasis, HCO3-/Cl- exchange, red cell aging, IgG binding and cellular removal, and the maintenance of the structural integrity of cells. They are present in the membranes of all cells and cellular organelles examined including Golgi, mitochondria and nuclei. The first polymorphisms of band 3 discovered were the asymptomatic band 3 Memphis variants carrying the Lys --> Gly substitution at position 56 in the cytoplasmic tail, and band 3 Texas (high transport band 3 Texas) with a mutation in the critical transmembrane, anion transport domain (Pro --> Leu substitution at position 868). The rate at which band 3 mutations were discovered accelerated in the mid 1990s and there are now over 50 known. The most common polymorphisms of band 3 are the Diego blood group antigens which reside on extracellular loops of the protein. Southeast Asia ovalocytosis (SAO; a nine amino acid deletion of residues 400-408) is a band 3 mutation known only in the heterozygous state in which it does not cause disease. It is thought to confer resistance to malaria by altering red cell deformability. Band 3 mutations are responsible for a subset of the heterogeneous group of disorders known as hereditary spherocytosis (HS). HS is a relatively common congenital or inherited group of anemias characterized by chronic hemolysis and abnormal red cell morphology. Red cells in the subset of HS with band 3 mutations behave like they are band 3 deficient either because the mutant protein is not incorporated into the membrane or because it is not functional. HS can be caused by mutations in any of at least 5 proteins involved in membrane stability. Band 3 mutations are associated with diseases in cells besides erythrocytes. For example, 2 types of distal renal tubular acidosis are the result of band 3 mutations either alone or combined with SAO. Band 3 alterations are implicated in neurological diseases such as familial paroxysmal dyskinesia, idiopathic generalized epilepsies, and neuro- or choreoacanthocytosis although they have not been demonstrated to be causative. Mutations in other genes can cause changes in band 3. An example is sickle cell anemia where the increased oxidation causes accelerated aging of band 3 and increased IgG binding and cellular removal.
Cell Mol Biol (Noisy-le-grand) 2004 Mar
PMID:Band 3 and its alterations in health and disease. 1509 83


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