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  • 1
    Keywords: EXPRESSION ; GROWTH ; CELL ; Germany ; IN-VIVO ; ENZYMES ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; RNA ; DOMAIN ; BINDING ; SEQUENCE ; SEQUENCES ; RECOGNITION ; ENCODES ; gene expression ; ASSAY ; REGION ; REGIONS ; NUCLEUS ; DEGRADATION ; DOUBLE-STRANDED-RNA ; OVEREXPRESSION ; AU-RICH ELEMENTS ; SINGLE ; MOTIF ; INTERFERENCE ; regulation ; TRANSLATION ; LEVEL ; ENZYME ; ASSAYS ; ROLES ; CELL-DIVISION ; 3'-UNTRANSLATED REGION ; USA ; DEPLETION ; microbiology ; NOV ; DIVISION ; CYCLIN ; BRUCEI ; STEADY-STATE ; CYTOPLASM ; TURNOVER ; AFRICAN TRYPANOSOME ; MAJOR FRIEDLIN CHROMOSOME-1 ; PROCYCLIC FORM
    Abstract: In the African trypanosome Trypanosoma brucei nearly all control of gene expression is posttranscriptional; sequences in the 3'-untranslated regions of mRNAs determine the steady-state mRNA levels by regulation of RNA turnover. Here we investigate the roles of two related proteins, TbUBP1 and TbUBP2, containing a single RNA recognition motif, in trypanosome gene expression. TbUBP1 and TbUBP2 are in the cytoplasm and nucleus, comprise ca. 0.1% of the total protein, and are not associated with polysomes or RNA degradation enzymes. Overexpression of TbUBP2 upregulated the levels of several mRNAs potentially involved in cell division, including the CFB1 mRNA, which encodes a protein with a cyclin F-box domain. CFB1 regulation was mediated by the 3'-untranslated region and involved stabilization of the mRNA. Depletion of ThUBP2 and TbUBP1 inhibited growth and downregulated expression of the cyclin F box protein gene CFB2; trans splicing was unaffected. The results of pull-down assays indicated that all tested mRNAs were bound to TbUBP2 or TbUBP1, with some preference for CFBI. We suggest that TbUBP1 and TbUBP2 may be relatively nonspecific RNA-binding proteins and that specific effects of overexpression or depletion could depend on competition between various different proteins for RNA binding
    Type of Publication: Journal article published
    PubMed ID: 17873084
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  • 2
    Keywords: CELLS ; EXPRESSION ; CELL ; GENE ; GENE-EXPRESSION ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; MECHANISM ; REDUCTION ; mechanisms ; BIOLOGY ; PHOSPHORYLATION ; SIGNAL ; ALPHA ; gene expression ; heat shock ; NUMBER ; STRESS ; MAMMALIAN-CELLS ; INCREASE ; mRNA ; LEVEL ; ENGLAND ; PROCESSING BODIES ; TRANSLATION INITIATION ; STRESS GRANULES ; P-BODIES ; TURNOVER ; AFRICAN TRYPANOSOME ; UNTRANSLATED REGION ; CYTOPLASMIC FOCI ; CELL BIOLOGY ; POSITION ; trypanosome ; Trypanosoma brucei ; BLOOD-STREAM ; eIF2 alpha ; LEISHMANIA-MAJOR ; MESSENGER-RNA DEGRADATION ; SPLICED-LEADER RNA ; stress granule
    Abstract: In trypanosomes there is an almost total reliance on post-transcriptional mechanisms to alter gene expression; here, heat shock was used to investigate the response to an environmental signal. Heat shock rapidly and reversibly induced a decrease in polysome abundance, and the consequent changes in mRNA metabolism were studied. Both heat shock and polysome dissociation were necessary for (1) a reduction in mRNA levels that was more rapid than normal turnover, (2) an increased number of P-body-like granules that contained DHH1, SCD6 and XRNA, (3) the formation of stress granules that remained largely separate from the P-body-like granules and localise to the periphery of the cell and, (4) an increase in the size of a novel focus located at the posterior pole of the cell that contain XRNA, but neither DHH1 nor SCD6. The response differed from mammalian cells in that neither the decrease in polysomes nor stress-granule formation required phosphorylation of eIF2 alpha at the position homologous to that of serine 51 in mammalian eIF2 alpha and in the occurrence of a novel XRNA-focus
    Type of Publication: Journal article published
    PubMed ID: 18713834
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  • 3
    Keywords: GENE ; GENES ; PATIENT ; COMPLEX ; COMPLEXES ; kidney ; RAT-KIDNEY ; SEQUENCES ; TRANSPORT ; MUTATION ; genetics ; MUTATIONS ; methods ; AMINO-ACID-TRANSPORT ; CANADA ; cystinuria ; SLC3A1 ; SLC7A9 ; amino acid ; EXPRESSION CLONING ; inherited disorder ; KIDNEY CDNA ; microcrystals ; stone
    Abstract: Background. Cystinuria is an inherited disorder of cystine and dibasic amino acid transport in kidney. Subtypes are defined by the urinary cystine excretion patterns of the obligate heterozygous parents: Type I/N (fully recessive or silent); Type II/N (high excretor); Type III/N (moderate excretor). The first gene implicated in cystinuria (SLC3A1 ) is associated with the Type I urinary phenotype. A second cystinuria gene (SLC7A9 ) was recently isolated, and mutations of this gene were associated with dominant (non-Type I) cystinuria alleles. Here we report genotype-phenotype studies of SLC7A9 mutations in a cohort of well-characterized cystinuria probands and their family members. Methods. Individual exons of the SLC7A9 gene were screened by single strand conformation polymorphism (SSCP) analysis and sequencing of abnormally migrating fragments. Results. Seven mutations were identified. A single bp insertion (799insA) was present in four patients: on Type III alleles in two patients and on Type II alleles in two patients. These results suggest that Type II and Type III may be caused by the same mutation and, therefore, other factors must influence urinary cystine excretion. A 4bp deletion in intron 12 (IVS12+4delAGTA) and a missense mutation (1245G--〉A, A354T) were identified on Type III alleles. A nonsense codon (1491G--〉T, E436X) and a possible splicing mutation (IVS9-17G--〉A) were seen in a Type I/III patient, but the mutations could not be assigned to particular alleles. Of additional interest were two missense mutations (316T--〉C, I44T and 967C--〉T, P261L) linked to Type I alleles. Conclusion. Our results provide evidence that some SLC7A9 mutations may be associated with fully recessive (Type I) forms of cystinuria. We also demonstrate SLC7A9 mutations in dominant Types II and III cystinuria. The finding of SLC7A9 mutations in all three subtypes underscores the complex interactions between specific cystinuria genes and other factors influencing cystine excretion. A simpler phenotypic classification scheme (recessive and dominant) for cystinuria is warranted
    Type of Publication: Journal article published
    PubMed ID: 12371955
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  • 4
    Keywords: RECEPTOR ; CANCER ; DISEASE ; RISK ; GENE ; ALLELES ; 8Q24 ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONSORTIUM ; TUMOR SUBTYPES ; URIC-ACID NEPHROLITHIASIS
    Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 x 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 x 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 x 10(-3)). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 22351618
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  • 5
    Keywords: CANCER ; GROWTH ; GROWTH-FACTOR ; SUPPORT ; COHORT ; cohort study ; POPULATION ; RISK ; GENE ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; MUTATION ; cancer risk ; GENOTYPES ; BETA ; TGF-BETA-1 ; BRCA2 ; VARIANT ; secretion ; TGF-BETA ; risk modifiers ; GENOTYPE ; USA ; CANCER-RISK ; GENERAL-POPULATION ; CONSORTIUM ; Hereditary cancer ; TRANSFORMING-GROWTH-FACTOR-BETA-1 GENE
    Abstract: Background The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. Methods To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. Results We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers. Conclusions These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers
    Type of Publication: Journal article published
    PubMed ID: 18523885
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  • 6
    Keywords: PEPTIDE ; RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; tumor ; human ; RISK ; GENE ; SAMPLES ; TUMORS ; PATIENT ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; PROGRESSION ; AGE ; MUTATION ; TUMOR PROGRESSION ; SIGNALING PATHWAY ; MUTATIONS ; BLOOD-PRESSURE ; EPITHELIAL- CELLS ; FACTOR BETA-1 GENE ; GROWTH-FACTOR-BETA ; GROWTH-FACTOR-BETA-1 GENE ; HeLa cells ; MYOCARDIAL-INFARCTION ; T29-〉C POLYMORPHISM
    Abstract: There is evidence that transforming growth factor (TGF)beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGFbeta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGFbeta-SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age similar to50 years, and range 22-92 years. The promoter SNP, C-509T, and the T +29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGFbeta1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGFbeta1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGFbeta1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGFbeta1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity
    Type of Publication: Journal article published
    PubMed ID: 12750287
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  • 7
    Keywords: APOPTOSIS ; SYSTEM ; DEATH ; DISEASE ; GENE ; GENES ; MICE ; ACID ; NERVOUS-SYSTEM ; MUTATION ; REGION ; MUTATIONS ; LIGANDS ; sialic acid ; SIALIC-ACID ; CENTRAL-NERVOUS-SYSTEM ; SYNTHASE ; interaction ; glycosphingolipid ; MYELIN-ASSOCIATED GLYCOPROTEIN ; LUNG-CARCINOMA CELLS ; GM3 ; BRAIN GANGLIOSIDES ; COMPLEX GANGLIOSIDES ; glycosyltransferase ; LACTOSYLCERAMIDE ; neurodegeneration
    Abstract: Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia
    Type of Publication: Journal article published
    PubMed ID: 15710896
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  • 8
    Keywords: EXPRESSION ; GENE ; RNA ; CARCINOGENESIS ; POLYMORPHISMS ; SUSCEPTIBILITY ; METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR ; COMMON MUTATION ; FOLATE STATUS ; CHROMOSOME-17 ; BRCA1/2 mutation carriers ; breast/ovarian cancer risk ; MTHFR 677 C 〉 T polymorphism ; PHB 1630 C 〉 T polymorphism ; PROHIBITIN 3'-UNTRANSLATED REGION
    Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C〉T (rs6917) polymorphism and the MTHFR 677 C〉T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C〉T and MTHFR 677 C〉T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C〉T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 22669161
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