Cíl: Cílem je popsat případ, kdy 4G/4G polymorfismus genu pro inhibitor aktivátoru plazminogenu 1 (PAI-1) je nezávislým rizikovým faktorem pro vznik placentární insuficience. Design: Kazuistika. Pracoviště: Ústav veřejného zdravotnictví, State University of Ceará (UECE), Fortaleza-CE, Brazílie. Kazuistika: Dědičná hypofibrinolýza, způsobená 4G/4G homozygotním stavem genu kódujícího inhibitor aktivátoru plazminogenu 1, je nezávislým rizikovým faktorem pro vznik komplikací v průběhu těhotenství. Ke vzniku placentární insuficience dochází pravděpodobně indukcí trombózy. V našem případě se jednalo o těhotnou s nízce rizikovým těhotenstvím bez jakýchkoliv klinických projevů v průběhu gravidity. Na počátku 3. trimestru se u této těhotné zjistila růstová retardace plodu s centralizací oběhu a bylo vysloveno podezření na insuficienci placenty. Ihned po porodu se u pacientky objevila hluboká žilní trombóza dolní končetiny. Při anatomicko-patologickém rozboru placenty byly popsány infarkty různého stáří. Příčinou vzniku těchto komplikací u pacientky byl pravděpodobně zjištěný homozygotní stav genu 4G/4G kódující inhibitor aktivátoru plazminogenu 1 (PAI-1).
Objective: To describe a case report of 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency. Design: Case report. Setting: Department of Public Health, State University of Ceará (UECE), Fortaleza-CE, Brazil. Case report: Hereditary hypofibrinolysis, which is mediated by 4G/4G homozygosity for the PAI-1 gene, is an independent risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency. We report a case of a low risk pregnancy, which separately presented placental insufficiency and fetal centralization at the beginning of the third trimester, without any other clinical manifestations during pregnancy. However, immediately after childbirth, the patient had a deep vein thrombosis of a lower limb. The anatomopathological examination of the placenta showed old and recent placental infarcts. Homozygosity for the 4G allele of PAI-1 gene was subsequently diagnosed as the sole probable causal factor.
- MeSH
- distres plodu * MeSH
- dospělí MeSH
- fibrinolýza fyziologie MeSH
- homozygot MeSH
- inhibitor aktivátoru plazminogenu 1 * genetika MeSH
- lidé MeSH
- placentární insuficience * etiologie MeSH
- polymorfismus genetický genetika MeSH
- poporodní období MeSH
- růstová retardace plodu MeSH
- těhotenství MeSH
- třetí trimestr těhotenství MeSH
- ultrasonografie dopplerovská MeSH
- ultrasonografie prenatální MeSH
- žilní trombóza * etiologie komplikace MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Východisko. Faktor V Leiden (G1691A) či mutace genu pro protrombin FII G20210A jsou nezávislé rizikové faktory žilní trombózy a kombinovaný výskyt genotypu 4G/4G PAI-1 ještě toto riziko zvyšuje. Cíl. Primárním cílem bylo zjistit frekvenci minoritních alel a genotypů FVL, FII G20210A a PAI-1 4G/5G u zdravých osob kavkazské rasy v Praze a v regionu středních Čech. Druhotným cílem bylo zjistit výskyt jejich vzájemných kombinací. Metody. Genotypizace byla provedena u 1450 zdravých osob (dárců krve, 981 mužů a 469 žen) pomocí robotické izolace DNA a následnou amplifikací PCR s analýzou křivky tání (Light Cycler 480 System, Roche). Výsledky. Frekvence minoritních alel mutací FV Leiden a FII G20210A byla 4,5 %, respektive 1,3 %. Frekvence alely 4G PAI-1 byla 55,9 %. Frekvence genotypů byly: GG 91,10 %, GA 8,83 % a AA 0,07 % pro FV Leiden; GG 97,38 %, GA 2,55 % a AA 0,07 % pro FII G20210A a 4G/4G 30,69 %, 4G/5G 50,34 % a 5G/5G 18,97 % pro PAI-1. U obou pohlaví se tyto frekvence nelišily. Kombinace heterozygotní mutace FII s heterozygotní mutací FV Leiden se vyskytovala v 0,14 %. Kombinace genotypu PAI-1 4G/4G s heterozygotní mutací FV Leiden se vyskytovala v 2,83 % a s heterozygotní mutací FII v 0,62 %. Závěry. Zjištěné frekvence genotypů a alel potvrzují relativně vysokou prevalenci hereditárních trombofilií v České republice.
Background. Factor V Leiden (G1691A) and prothrombin gene (FII G20210A) mutations are independent risk factors of venous thrombosis and this risk is further increased by the combined genotype 4G/4G PAI-1. Aim. The primary objective was to identify the frequency of mutations of minor alleles and genotypes of FVL, FII G20210A and PAI-1 4G/5G in healthy Caucasians in the Prague and Central Bohemia regions. The secondary objective was to identify the occurrence of their mutual combinations. Method. Genotyping was performed in 1,450 healthy individuals (blood donors, 981 men and 469 women) using robotic DNA isolation and subsequent PCR and melting curve analysis (Light Cycler 480 System, Roche). Results. The minor allele frequencies in FV Leiden and FII G20210A mutations were 4.5 % and 1.3% respectively. The frequency of the 4G PAI-1 allele was 55.9%. The genotype frequencies were as follows: GG 91.10%, GA 8.83% and AA 0.07% for FV Leiden; GG 97.38%, GA 2.55% and AA 0.07% for FII G20210A and 4G/4G 30.69%, 4G/5G 50.34% and 5G/5G 18.97% for PAI-1. No differences in these frequencies were found between the genders. The occurrence of the combined heterozygous FII and heterozygous FV Leiden mutations was 0.14%. The PAI-1 4G/4G genotype was combined with the heterozygous FV Leiden mutation in 2.83% of cases and with the heterozygous FII mutation in 0.62% of cases. Conclusions. The found frequencies of genotypes and alleles confirm a relatively high prevalence of hereditary thrombophilia in the Czech Republic.
- MeSH
- alely MeSH
- dospělí MeSH
- financování organizované MeSH
- genotyp MeSH
- interpretace statistických dat MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- prevalence MeSH
- rezistence k aktivovanému proteinu C genetika MeSH
- statistika jako téma MeSH
- tromboembolie genetika MeSH
- trombofilie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Geografické názvy
- Česká republika MeSH
Plasminogen activator ihnibitor (PAI 1) belongs to the plasminogen activator system, which is part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumors. Its plasma level is normally low but 4G/4G homozygotes have higher concentrations of PAI 1. This genotype may be associated with worse prognosis and proximal location of colorectal cancer than 5G/5G homozygotes. In our prospective evaluation we examined plasma level PAI 1 (using photometric microplate method ELISA) pre-surgery and, subsequently, 6-8 weeks later, from 80 patients. For the PAI 1 rs1799889 -675 4G/5G polymorphism test the PCR amplification was used.Analysis of collected data was confirmed that significantly higher plasma levels of PAI 1 were found in patients before starting therapy, which decreased (p=0.004) after initiation of treatment. Patients with higher plasma level PAI 1 before (p=0.013) and after therapy (p=0.004) had significantly shorter survival. We found no relationship between polymorphisms of PAI 1 (-675 4G/5G) in relation to stage, survival or tumor location. PAI 1 is useful as a negative marker of prognosis and could be advantageous when planning adjuvant treatment of patients with colorectal carcinoma. Although opinions on the importance of polymorphisms of PAI 1 in relation to the prognosis are not uniform, it does seem that their role in the prognosis of patients with colorectal cancer is not essential.
PROBLEM: This study compares the frequencies of plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and its relationship with eight antiphospholipid antibodies (aPLs) in serum of 157 patients with repeated pregnancy loss (RPL). METHOD OF STUDY: PAI-1 (-675) 4G/5G polymorphism was determined using standard PCR-RFLP method. Enzyme-linked immunosorbent assay was used for the detection of aPLs against ph-serine, ph-ethanolamine, ph-inositol, ph-DL-glycerol, phosphatidic acid, annexin V, cardiolipin, and beta2-GPI. Allelic frequency and distribution of genotypes were calculated. The prevalence of the risk conferring 4G allele and 4G/4G homozygous genotype in patients and controls was compared, and the correlation between aPLs positivity and PAI-1 4G/4G genotype was tested by chi-square test. RESULTS: Statistically highly significant correlation between RPL and PAI-1 (-675) 4G/4G genotype was found. No correlation between PAI-1 (-675) 4G/5G polymorphism and the presence of antiphospholipid antibodies in RPL patients was observed. CONCLUSIONS: PAI-1 (-675) 4G/4G homozygous genotype increases the risk of RPL independently from the aPLs positivity.
- MeSH
- antifosfolipidové protilátky krev MeSH
- běloši genetika MeSH
- dospělí MeSH
- frekvence genu MeSH
- genotyp MeSH
- habituální potrat krev genetika imunologie MeSH
- inhibitor aktivátoru plazminogenu 1 genetika MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Protein synthesis is a highly efficient process and is under exacting control. Yet, the actual abundance of translation factors present in translating complexes and how these abundances change during the transit of a ribosome across an mRNA remains unknown. Using analytical ultracentrifugation with fluorescent detection we have determined the stoichiometry of the closed-loop translation factors for translating ribosomes. A variety of pools of translating polysomes and monosomes were identified, each containing different abundances of the closed-loop factors eIF4E, eIF4G, and PAB1 and that of the translational repressor, SBP1. We establish that closed-loop factors eIF4E/eIF4G dissociated both as ribosomes transited polyadenylated mRNA from initiation to elongation and as translation changed from the polysomal to monosomal state prior to cessation of translation. eIF4G was found to particularly dissociate from polyadenylated mRNA as polysomes moved to the monosomal state, suggesting an active role for translational repressors in this process. Consistent with this suggestion, translating complexes generally did not simultaneously contain eIF4E/eIF4G and SBP1, implying mutual exclusivity in such complexes. For substantially deadenylated mRNA, however, a second type of closed-loop structure was identified that contained just eIF4E and eIF4G. More than one eIF4G molecule per polysome appeared to be present in these complexes, supporting the importance of eIF4G interactions with the mRNA independent of PAB1. These latter closed-loop structures, which were particularly stable in polysomes, may be playing specific roles in both normal and disease states for specific mRNA that are deadenylated and/or lacking PAB1. These analyses establish a dynamic snapshot of molecular abundance changes during ribosomal transit across an mRNA in what are likely to be critical targets of regulation.
- MeSH
- elongace translace peptidového řetězce * MeSH
- eukaryotický iniciační faktor 4E metabolismus MeSH
- eukaryotický iniciační faktor 4G metabolismus MeSH
- iniciace translace peptidového řetězce * MeSH
- messenger RNA genetika metabolismus MeSH
- multiproteinové komplexy metabolismus MeSH
- poly A MeSH
- polyribozomy metabolismus MeSH
- proteiny vázající selen metabolismus MeSH
- proteosyntéza MeSH
- ribozomy metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
MicroRNAs (miRNAs) are crucial components of homeostatic and developmental gene regulation. In turn, dysregulation of miRNA expression is a common feature of different types of cancer, which can be harnessed therapeutically. Here we identify miR-139-5p suppression across several cytogenetically defined acute myeloid leukemia (AML) subgroups. The promoter of mir-139 was transcriptionally silenced and could be reactivated by histone deacetylase inhibitors in a dose-dependent manner. Restoration of mir-139 expression in cell lines representing the major AML subgroups (t[8;21], inv[16], mixed lineage leukemia-rearranged and complex karyotype AML) caused cell cycle arrest and apoptosis in vitro and in xenograft mouse models in vivo. During normal hematopoiesis, mir-139 is exclusively expressed in terminally differentiated neutrophils and macrophages. Ectopic expression of mir-139 repressed proliferation of normal CD34(+)-hematopoietic stem and progenitor cells and perturbed myelomonocytic in vitro differentiation. Mechanistically, mir-139 exerts its effects by repressing the translation initiation factor EIF4G2, thereby reducing overall protein synthesis while specifically inducing the translation of cell cycle inhibitor p27(Kip1). Knockdown of EIF4G2 recapitulated the effects of mir-139, whereas restoring EIF4G2 expression rescued the mir-139 phenotype. Moreover, elevated miR-139-5p expression is associated with a favorable outcome in a cohort of 165 pediatric patients with AML. Thus, mir-139 acts as a global tumor suppressor-miR in AML by controlling protein translation. As AML cells are dependent on high protein synthesis rates controlling the expression of mir-139 constitutes a novel path for the treatment of AML.
- MeSH
- buněčná diferenciace genetika MeSH
- eukaryotický iniciační faktor 4G biosyntéza genetika MeSH
- genový knockdown MeSH
- lidé MeSH
- mikro RNA biosyntéza genetika MeSH
- myeloidní leukemie genetika patologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk genetika MeSH
- proteosyntéza * MeSH
- regulace genové exprese u leukemie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Translation reinitiation is a gene-specific translational control mechanism. It is characterized by the ability of short upstream ORFs to prevent full ribosomal recycling and allow the post-termination 40S subunit to resume traversing downstream for the next initiation event. It is well known that variable transcript-specific features of various uORFs and their prospective interactions with initiation factors lend them an unequivocal regulatory potential. Here, we investigated the proposed role of the major initiation scaffold protein eIF4G in reinitiation and its prospective interactions with uORF's cis-acting features in yeast. In analogy to the eIF3 complex, we found that eIF4G and eIF4A but not eIF4E (all constituting the eIF4F complex) are preferentially retained on ribosomes elongating and terminating on reinitiation-permissive uORFs. The loss of the eIF4G contact with eIF4A specifically increased this retention and, as a result, increased the efficiency of reinitiation on downstream initiation codons. Combining the eIF4A-binding mutation with that affecting the integrity of the eIF4G1-RNA2-binding domain eliminated this specificity and produced epistatic interaction with a mutation in one specific cis-acting feature. We conclude that similar to humans, eIF4G is retained on ribosomes elongating uORFs to control reinitiation also in yeast.
- MeSH
- DEAD-box RNA-helikasy genetika MeSH
- eukaryotický iniciační faktor 3 genetika MeSH
- eukaryotický iniciační faktor 4E genetika MeSH
- eukaryotický iniciační faktor 4G genetika MeSH
- iniciace translace peptidového řetězce genetika MeSH
- kodon iniciační genetika MeSH
- lidé MeSH
- otevřené čtecí rámce genetika MeSH
- proteosyntéza genetika MeSH
- ribozomy genetika MeSH
- Saccharomyces cerevisiae - proteiny genetika MeSH
- Saccharomyces cerevisiae genetika MeSH
- transkripční faktory bZIP genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- bronchiální astma genetika imunologie komplikace MeSH
- časná přecitlivělost genetika imunologie MeSH
- inhibitor aktivátoru plazminogenu 1 genetika imunologie MeSH
- lidé MeSH
- polymorfismus genetický genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
