Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication, and DNA repair. However, the contribution of these complexes to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of the Snf2h gene during the development of the mammalian retina. We show that Snf2h is expressed in both retinal progenitors and post-mitotic retinal cells. Using Snf2h conditional knockout mice (Snf2h cKO), we found that when Snf2h is deleted, the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. The depletion of Snf2h did not influence the ability of retinal progenitors to generate all the differentiated retinal cell types. Instead, the Snf2h function is critical for the proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although all retinal cell types appear to be specified in the absence of the Snf2h function, cell-cycle defects and concomitantly increased apoptosis in Snf2h cKO result in abnormal retina lamination, complete destruction of the photoreceptor layer, and consequently, a physiologically non-functional retina.

• MeSH
• adenosintrifosfatasy * metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• chromatin * metabolismus   MeSH
• chromozomální proteiny, nehistonové * metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• proliferace buněk MeSH
• restrukturace chromatinu * MeSH
• retina MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Tako-tsubo kardiomyopatie je relativně vzácný syndrom, pro který jsou charakteristické reverzibilní lokalizované poruchy kinetiky, zejména apikálních a středních segmentů levé komory. Velmi často imituje akutní koronární syndrom. Přesné patofyziologické mechanismy nejsou zcela známy. Za hlavní příčinu této kardiomyopatie je považována silná stresová zátěž. V ojedinělých případech může být tako-tsubo kardiomyopatie způsobena i jinými faktory. Prezentujeme vzácný případ stresové kardiomyopatie vzniklý v souvislosti s léčbou anagrelidem. Anagrelid je nejčastěji podáván pacientům s esenciální trombocytemií. Patří mezi inhibitory fosfodiesterázy III a prostřednictvím specifických signálních drah působí i na myokard. Naše kasuistické sdělení jako první v České republice popisuje případ tako-tsubo kardiomyopatie vzniklé v souvislosti s podáváním vysokých dávek anagrelidu.

Takotsubo cardiomyopathy is a rare syndrome. Most often imitates acute coronary syndrome. It is characterized by transient wall motion abnormalities, especially in the apical segments of the left ventricle. Less frequently it is possible to find transient akinesis or dyskinesis in the mid-ventricular segments of the left ventricle. Pathophysiological mechanisms are not completely clear. The main cause of stress cardiomyopathy is stress insult. But in rare cases takotsubo cardiomyopathy can be caused by other conditions. We reported a rare case of takotsubo cardiomyopathy caused by high dose anagrelide therapy. Anagrelide is most often used in patients with thrombocythemia. It belongs to phosphodiesterase III inhibitors and through specific pathways has certain effects on myocardium. It is the first case of takotsubo cardiomyopathy resulting from anagrelide therapy in the Czech Republic.

• MeSH
• Aspirin aplikace a dávkování   MeSH
• chinazoliny aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• inhibitory agregace trombocytů farmakologie   škodlivé účinky   terapeutické užití   MeSH
• klopidogrel aplikace a dávkování   MeSH
• koronární angiografie MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada léků MeSH
• takotsubo kardiomyopatie diagnostické zobrazování   chemicky indukované   MeSH
• trombocytopenie * farmakoterapie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

The imitation switch nuclear ATPase Smarca5 (Snf2h) is one of the most conserved chromatin remodeling factors. It exists in a variety of oligosubunit complexes that move DNA with respect to the histone octamer to generate regularly spaced nucleosomal arrays. Smarca5 interacts with different accessory proteins and represents a molecular motor for DNA replication, repair, and transcription. We deleted Smarca5 at the onset of definitive hematopoiesis (Vav1-iCre) and observed that animals die during late fetal development due to anemia. Hematopoietic stem and progenitor cells accumulated but their maturation toward erythroid and myeloid lineages was inhibited. Proerythroblasts were dysplastic while basophilic erythroblasts were blocked in G2/M and depleted. Smarca5 deficiency led to increased p53 levels, its activation at two residues, one associated with DNA damage (S15Ph°s) second with CBP/p300 (K376Ac), and finally activation of the p53 targets. We also deleted Smarca5 in committed erythroid cells (Epor-iCre) and observed that animals were anemic postnatally. Furthermore, 4-hydroxytamoxifen-mediated deletion of Smarca5 in the ex vivo cultures confirmed its requirement for erythroid cell proliferation. Thus, Smarca5 plays indispensable roles during early hematopoiesis and erythropoiesis. Stem Cells 2017;35:1614-1623.

• MeSH
• adenosintrifosfatasy nedostatek   metabolismus   MeSH
• anemie patologie   MeSH
• buněčná diferenciace * MeSH
• buněčný cyklus MeSH
• chromozomální proteiny, nehistonové nedostatek   metabolismus   MeSH
• delece genu MeSH
• erytroidní buňky cytologie   MeSH
• erytropoéza MeSH
• genotyp MeSH
• hematopoetické kmenové buňky cytologie   metabolismus   MeSH
• hematopoéza MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• poškození DNA genetika   MeSH
• proliferace buněk MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The protein Isw1 of Saccharomyces cerevisiae is an imitation-switch chromatin-remodeling factor. We studied the mechanisms of its nuclear import and found that the nuclear localization signal (NLS) mediating the transport of Isw1 into the nucleus is located at the end of the C-terminus of the protein (aa1079-1105). We show that it is an atypical bipartite signal with an unconventional linker of 19 aa (KRIR X(19) KKAK) and the only nuclear targeting signal within the Isw1 molecule. The efficiency of Isw1 nuclear import was found to be modulated by changes to the amino acid composition in the vicinity of the KRIR motif, but not by the linker length. Live-cell imaging of various karyopherin mutants and in vitro binding assays of Isw1NLS to importin-α revealed that the nuclear translocation of Isw1 is mediated by the classical import pathway. Analogous motifs to Isw1NLS are highly conserved in Isw1 homologues of other yeast species, and putative bipartite cNLS were identified in silico at the end of the C-termini of imitation switch (ISWI) proteins from higher eukaryotes. We suggest that the C-termini of the ISWI family proteins play an important role in their nuclear import.

• MeSH
• adenosintrifosfatasy chemie   genetika   metabolismus   MeSH
• aktivní transport - buněčné jádro genetika   MeSH
• aminokyselinové motivy MeSH
• buněčné jádro metabolismus   MeSH
• DNA vazebné proteiny chemie   genetika   metabolismus   MeSH
• jaderné lokalizační signály * genetika   MeSH
• mutace MeSH
• nukleocytoplazmatické transportní proteiny genetika   metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny chemie   genetika   metabolismus   MeSH
• Saccharomyces cerevisiae genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH