- MeSH
- Diamondova-Blackfanova anemie komplikace genetika MeSH
- Klippelův-Feilův syndrom etiologie genetika MeSH
- lidé MeSH
- mutace MeSH
- registrace MeSH
- ribozomální proteiny genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Myotonic dystrophy kinase-related Cdc42-binding kinase alpha (MRCKalpha, formally known as CDC42BPA) is a serine/threonine kinase that can regulate actin/myosin assembly and activity. Recently, it has been shown that it possesses a functional iron responsive element (IRE) in the 3'-untranslated region (UTR) of its mRNA, suggesting that it may be involved in iron metabolism. Here we report that MRCKalpha protein expression is also regulated by iron levels; MRCKalpha colocalizes with transferrin (Tf)-loaded transferrin receptors (TfR), and attenuation of MRCKalpha expression by a short hairpin RNA silencing construct leads to a significant decrease in Tf-mediated iron uptake. Our results thus indicate that MRCKalpha takes part in Tf-iron uptake, probably via regulation of Tf-TfR endocytosis/endosome trafficking that is dependent on the cellular cytoskeleton. Regulation of the MRCKalpha activity by intracellular iron levels could thus represent another molecular feedback mechanism cells could use to finely tune iron uptake to actual needs.
- MeSH
- endocytóza MeSH
- endozomy enzymologie MeSH
- HeLa buňky MeSH
- lidé MeSH
- malá interferující RNA genetika MeSH
- protein-serin-threoninkinasy genetika metabolismus MeSH
- receptory transferinu metabolismus MeSH
- RNA interference MeSH
- transferin metabolismus MeSH
- železo metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia that is usually diagnosed during early infancy. Apart from defects in red blood cell maturation, the disorder is also associated with various physical anomalies in 40% of patients. Mutations in the ribosomal protein (RP) S19 are found in 25% of patients, while mutations in other proteins of the small ribosomal subunit--RPS17 and RPS24--have been found in a fraction of patients. Recently, mutations in RPL5, RPL11, and RPL35a of the large ribosomal subunit have also been reported in several DBA patients. Here, we present the identification of mutations in the RPL5 and RPL11 genes in patients from the Czech DBA Registry. Mutations in RPL5 were identified in eight patients from 6 out of 28 families (21.4%), and mutations in RPL11 in two patients from 2 out of 28 families (7.1%). Interestingly, all 10 patients with either an RPL5 or RPL11 mutation exhibited one or more physical anomalies; specifically, thumb anomalies (flat thenar) were always present, while no such anomaly was observed in seven patients with an RPS19 mutation. Moreover, 9 out of 10 patients with either an RPL5 or RPL11 mutation were born small for gestational age (SGA) compared to 3 out of 7 patients from the RPS19-mutated group. These observations may suggest that mutations, at least in RPL5, seem to generally have more profound impact on fetal development than mutations in RPS19. Since RPL5 and RPL11, together with RPL23, are also involved in the MDM2-mediated p53 pathway regulation, we also screened the RPL23 gene for mutations; however, no mutations were identified. 2009 Wiley-Liss, Inc.
- MeSH
- Diamondova-Blackfanova anemie genetika patologie MeSH
- dítě MeSH
- dospělí MeSH
- financování organizované MeSH
- frekvence genu MeSH
- kojenec MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- registrace MeSH
- ribozomální proteiny genetika MeSH
- senioři MeSH
- zdraví rodiny MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Geografické názvy
- Česká republika MeSH
Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia characterized as a normochromic macrocytic anemia with a selective deficiency in red blood cell precursors in otherwise normocellular bone marrow. In 40% of DBA patients, various physical anomalies are also present. Currently two genes are associated with the DBA phenotype--the ribosomal protein (RP) S19 mutated in 25% of DBA patients and RPS24 mutated in approximately 1.4% of DBA patients. Here we report the identification of a mutation in yet another ribosomal protein, RPS17. The mutation affects the translation initiation start codon, changing T to G (c.2T>G), thus eliminating the natural start of RPS17 protein biosynthesis. RNA analysis revealed that the mutated allele was expressed, and the next downstream start codon located at position +158 should give rise to a short peptide of only four amino acids (Met-Ser-Arg-Ile). The mutation arose de novo, since all healthy family members carry the wild-type alleles. The identification of a mutation in the third RP of the small ribosomal subunit in DBA patients further supports the theory that impaired translation may be the main cause of DBA pathogenesis. (c) 2007 Wiley-Liss, Inc.
Human untranslated region (UTR) databases were searched to identify novel proteins potentially regulated by an iron responsive element (IRE), and found two candidates-cell cycle phosphatase Cdc14A variant 1 and myotonic dystrophy kinase-related Cdc42-binding kinase alpha (MRCKalpha), both possessing a putative IRE in their 3'UTR. In further experiments, we focused on MRCKalpha. Biochemical analyses of the MRCKalpha IRE revealed that it was functional and mediated the response to iron level in the same way as transferrin receptor 1 IREs (TfR) did. Similarly to TfR mRNA, MRCKalpha mRNA is stabilized, when iron supply is low, while it is destabilized under iron-rich conditions. The expression of MRCKalpha mRNA was found to be ubiquitous; the highest levels were noted in testes, the lowest in skeletal muscle. The level of MRCKalpha mRNA in various tissues strongly positively correlates with the level of TfR mRNA, indicating its possible role in the transferrin iron uptake pathway.
- MeSH
- buňky K562 MeSH
- CD antigeny metabolismus MeSH
- financování organizované MeSH
- lidé MeSH
- nepřekládané oblasti genetika MeSH
- protein-serin-threoninkinasy genetika metabolismus MeSH
- proteiny regulující obsah železa genetika metabolismus MeSH
- receptory transferinu metabolismus MeSH
- železo farmakologie MeSH
- Check Tag
- lidé MeSH
- MeSH
- Fanconiho anemie genetika MeSH
- lidé MeSH
- pseudogeny MeSH
- ribozomální proteiny genetika MeSH
- Check Tag
- lidé MeSH
