Disease relevance of FCP1

• Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus [1].
• METHODS: Basal and Tat-mediated transactivation of HIV-1 long terminal repeat (LTR)-driven transcription was compared, by transient transfections, in the presence of FCP1 phosphatase [2].
• These data suggest that the high HbF levels in HbE/beta thalassemia, and other beta thalassemia syndromes, result from increased erythropoietin levels leading to bone marrow expansion, and possibly increased F-cell production, combined with ineffective erythropoiesis giving a survival advantage to F cells [3].
• Microscopic method for assaying F cell production: illustrative changes during infancy and in aplastic anemia [4].
• Ultrastructural analysis of pancreatic carcinogenesis. II. Establishment and morphology of a transplantable hamster pancreatic adenocarcinoma, FCP [5].

High impact information on FCP1

• We show that CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery), resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA [6].
• Stimulation of F-cell production in patients with sickle-cell anemia treated with cytarabine or hydroxyurea [7].
• Treatments that increased F-cell production also increased the patient's hematocrit and caused only minor, transient decreases in white cells [7].
• Fcp1 and Scp1 belong to a family of Mg(2+)-dependent phosphoserine (P.Ser)/phosphothreonine (P.Thr)-specific phosphatases [8].
• Fcp1 plays a major role in the regulation of CTD phosphorylation and, hence, critically influences the function of Pol II throughout the transcription cycle [9].

Chemical compound and disease context of FCP1

• (FCP = fasting plasma C-peptide, RBW = relative body weight, FBG = fasting blood glucose) [10].

Biological context of FCP1

• Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation [1].
• The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s) [1].
• Linkage analysis using polymorphic restriction sites along the X chromosome in eight SS and one AA family localized the F-cell production (FCP) locus to Xp22.2, with a maximum lod score (logarithm of odds of linkage v independent assortment) of 4.6 at a recombination fraction of 0.04 [11].
• Accordingly, the specificity of FCP1 is sufficiently broad to dephosphorylate RNAP IIO at any point in the transcription cycle irrespective of the site of serine phosphorylation within the consensus repeat [12].
• Transcription activation by targeted recruitment of the RNA polymerase II CTD phosphatase FCP1 [13].

Anatomical context of FCP1

• F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% +/- 10% v 13% +/- 8%) [11].
• As an alternative method to assess FCP1 specificity, RNAP IIO isozymes were prepared in vitro by the phosphorylation of purified calf thymus RNAP IIA with specific CTD kinases and used as substrates for FCP1 [12].
• We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities [14].
• In cultured cells treated with CTD kinase inhibitors, the dephosphorylation of RNAPII on serine 2 was inhibited by 45% by preincubation with okadaic acid, which inhibits phosphatases of PPP family, including PP1 but not FCP1 [15].
• To identify FCP1-associated proteins, we constructed a human cell line expressing epitope-tagged FCP1 [16].

Associations of FCP1 with chemical compounds

• FCP1 dephosphorylates serine 2 and serine 5 with comparable efficiency [12].
• The CK2 site adjacent to the RAP74-binding site in the central domain of FCP1 is phosphorylated at a single threonine site (T584) [17].
• Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production [18].
• Oral administration of sodium 4-phenylbutyrate rapidly increases F-cell production in sickle cell disease [19].
• LHC proteins from diatoms are named fucoxanthin-chlorophyll a/c-binding proteins (FCP) [20].

Physical interactions of FCP1

• In addition, we demonstrate that the C-terminus region of FCP1 suffices for efficient binding in vivo to the RAP74 subunit of TFIIF and is also required for the exclusive nuclear localization of the protein [13].

Regulatory relationships of FCP1

• The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype [1].
• Although high doses of erythropoietin can induce F cell production in humans, the practical relevance of such observations is unclear[21]

Other interactions of FCP1

• Dephosphorylation of RNA polymerase II by CTD-phosphatase FCP1 is inhibited by phospho-CTD associating proteins [22].
• The gene for heterocellular HPFH is nonallelic to the beta-globin locus and apparently acted as a modifier of the homozygous beta-thalassemia phenotype by facilitating F-cell production and thus diminishing the pathophysiological consequences of the beta-thalassemia defect [23].
• This is the first study characterizing CD34(+) and CD34(+)CD38(-) hematopoietic progenitor cells in sickle bone marrow, comparing them to sickle peripheral blood and normal bone marrow and using them to generate sickle red blood cells that recapitulate F cell production observed in vivo [24].
• Trimidox-mediated morphological changes during erythroid differentiation is associated with the stimulation of hemoglobin and F-cell production in human K562 cells [25].

Analytical, diagnostic and therapeutic context of FCP1

• SETTING: Cases and controls were identified from a population-based sample of men and women combining all of the 5 cross-sectional surveys conducted from 1979 to 1990 of the Stanford Five-City Project (FCP) [26].
• The purpose of the present study was to determine whether positron emission tomography (PET) studies in monkeys with the dopamine (DA) D2 receptor ligand [18F]fluoroclebopride (FCP) would be significantly influenced by anesthetic induction with isoflurane (approximately 5.0%) compared to induction with 10 mg/kg ketamine [27].
• In the control group the formazan cell percentage (FCP) was 73.8 +/- 1.6% (range 63% to 83%) [28].
• The decreased percentage of FCP per year in LADA patients were correlated with GAD-Ab index, body mass index (BMI) and age at onset (r(s)=0.408, -0.301 and -0.523 respectively, P<0.05) [29].
• METHODS: Silastic models of a Taylor patch, a Miller cuff and a femoro-crural patch prosthesis (FCPP) were attached to a circuit driven by a Berlin Heart, providing a pulsatile flow with an amplitude of 450 to 25 ml/min (mean 200 ml/min) [30].

References