Practically all mammalian cells including human can switch, according to micro- or macroenvironmental conditions, from states of cellular quiescence to inflammatory activation and vice versa. Along with recent knowledge, cellular quiescence is not a passive, but a highly active state with broad engagement of the cell synthetic and secretory machinery. Inflammatory activation is a beneficial process in cases of infection; however, if its control fails, it may degrade into autoimmune diseases or cancer growth. Control over cellular quiescence is exerted predominantly by a set of zinc-finger transcription proteins, referred to as Krüppel-like factors (KLFs). This review article offers recent information concerning activities of Krüppel-like factor 4 in the vascular wall.

• MeSH
• ateroskleróza patofyziologie   MeSH
• cévní endotel fyziologie   MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• svaly hladké cévní zranění   fyziologie   patofyziologie   MeSH
• transkripční faktory Krüppel-like fyziologie   MeSH
• zánět patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• KLF2 protein, human MeSH Prohlížeč
• KLF4 protein, human MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• transkripční faktory Krüppel-like MeSH

• Klíčová slova
• CBP, KIX, MED15, Sox9, SoxE, Stem cell, iPSCs,
• MeSH
• geny myc MeSH
• Krüppel-like faktor 4 MeSH
• oktamerní transkripční faktor 3 genetika   MeSH
• transkripční faktory SOXB1 MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Krüppel-like faktor 4 MeSH
• oktamerní transkripční faktor 3 MeSH
• transkripční faktory SOXB1 MeSH

The human iPSC cell line, CARS-FiPS4F1 (ESi064-A), derived from dermal fibroblast from the apparently healthy carrier of the mutation of the gene SACSIN, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors. The pluripotency was assessed by immunocytochemistry and RT-PCR. This iPSC line can be used as control for Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease.

• MeSH
• dospělí MeSH
• indukované pluripotentní kmenové buňky metabolismus   MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• mutace MeSH
• proteiny tepelného šoku genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• KLF4 protein, human MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• proteiny tepelného šoku MeSH
• SACS protein, human MeSH Prohlížeč

MicroRNA (miRNAs) are short noncoding RNA molecules involved in many cellular processes and shown to play a key role in somatic cell induced reprogramming. We performed an array based screening to identify candidates that are differentially expressed between dermal skin fibroblasts (DFs) and induced pluripotent stem cells (iPSCs). We focused our investigations on miR-145 and showed that this candidate is highly expressed in DFs relative to iPSCs and significantly downregulated during reprogramming process. Inhibition of miR-145 in DFs led to the induction of "cellular plasticity" demonstrated by: (a) alteration of cell morphology associated with downregulation of mesenchymal and upregulation of epithelial markers; (b) upregulation of pluripotency-associated genes including SOX2, KLF4, C-MYC; (c) downregulation of miRNA let-7b known to inhibit reprogramming; and (iv) increased efficiency of reprogramming to iPSCs in the presence of reprogramming factors. Together, our results indicate a direct functional link between miR-145 and molecular pathways underlying reprogramming of somatic cells to iPSCs.

• Klíčová slova
• Induced pluripotent stem cells, KLF4, Mesenchymal-to-epithelial transition, OCT4, Reprogramming, SOX2, c-MYC, miR-145, microRNA,
• MeSH
• fibroblasty cytologie   metabolismus   MeSH
• indukované pluripotentní kmenové buňky cytologie   MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• mikro RNA genetika   metabolismus   MeSH
• molekulární sekvence - údaje MeSH
• přeprogramování buněk * genetika   MeSH
• regulace genové exprese MeSH
• reprodukovatelnost výsledků MeSH
• sekvence nukleotidů MeSH
• škára cytologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• KLF4 protein, human MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• mikro RNA MeSH
• MIRN145 microRNA, human MeSH Prohlížeč

The human iPSC cell line, GLC-FiPS4F1 (ESi047-A), derived from dermal fibroblast from the patient with congenital glaucoma caused by the mutation of the gene CYP1B1, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors.

• MeSH
• buněčná diferenciace MeSH
• buněčné kultury metody   MeSH
• buněčné linie MeSH
• cytochrom P450 CYP1B1 genetika   MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• glaukom vrozené   genetika   MeSH
• indukované pluripotentní kmenové buňky cytologie   metabolismus   MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• mutace genetika   MeSH
• Mycoplasma izolace a purifikace   MeSH
• přeprogramování buněk MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CYP1B1 protein, human MeSH Prohlížeč
• cytochrom P450 CYP1B1 MeSH
• KLF4 protein, human MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH

The human iPSC cell lines, PLANFiPS1-Sv4F-1 (RCPFi004-A), PLANFiPS2-Sv4F-1 (RCPFi005-A), PLANFiPS3-Sv4F-1 RCPFi006-A), derived from dermal fibroblast from three patients suffering PLAN (PLA2G6-associated neurodegeneration; MIM 256600) caused by mutations in the PLA2G6 gene, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors. The pluripotency was assessed by immunocytochemistry and RT-PCR. Differentiation capacity was verified in vitro. This iPSC line can be further differentiated toward affected cells to better understand molecular mechanisms of disease and pathophysiology.

• MeSH
• buněčná diferenciace MeSH
• buněčné linie MeSH
• fosfolipasy A2, skupina VI MeSH
• indukované pluripotentní kmenové buňky * MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• mutace MeSH
• neuroaxonální dystrofie * MeSH
• přeprogramování buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fosfolipasy A2, skupina VI MeSH
• KLF4 protein, human MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• PLA2G6 protein, human MeSH Prohlížeč

BACKGROUND: Myelodysplastic syndrome with isolated chromosome 5q deletion (5q- syndrome) is a clonal stem cell disorder characterized by ineffective hematopoiesis. MicroRNAs (miRNAs) are important regulators of hematopoiesis and their aberrant expression was detected in some clonal hematopoietic disorders. We thus analyzed miRNA expressions in bone marrow CD34+ cells of 5q- syndrome patients. Further, we studied gene expressions of miR-143, miR-145, miR-378 and miR-146a mapped within the 5q deletion. RESULTS: Using microarrays we identified 21 differently expressed miRNAs in 5q- patients compared to controls. Especially, miR-34a was markedly overexpressed in 5q- patients, suggesting its role in an increased apoptosis of bone marrow progenitors. Out of four miRNAs at del(5q), only miR-378 and miR-146a showed reduced gene expression in the patients. An integrative analysis of mRNA profiles and predicted putative targets defined potential downstream targets of the deregulated miRNAs. The list of targets included several genes that play an important role in the regulation of hematopoiesis (e.g. KLF4, LEF1, SPI1). CONCLUSIONS: The study demonstrates global overexpression of miRNAs is associated with 5q- phenotype. Identification of hematopoiesis-relevant target genes indicates that the deregulated miRNAs may be involved in the pathogenesis of 5q- syndrome by a modulation of these targets. The expression data on miRNAs at del(5q) suggest the presence of mechanisms for compensation of a gene dosage.

• MeSH
• antigeny CD34 biosyntéza   genetika   MeSH
• chromozomální delece MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• lidské chromozomy, pár 5 genetika   metabolismus   MeSH
• makrocytární anemie genetika   metabolismus   MeSH
• mikro RNA biosyntéza   genetika   MeSH
• myelodysplastické syndromy genetika   metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD34 MeSH
• KLF4 protein, human MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• mikro RNA MeSH

Human induced pluripotent stem cell line was generated from commercially available primary human prostate fibroblasts HPrF derived from a fetus, aged 18-24 weeks of gestation. The fibroblast cell line was reprogrammed with Yamanaka factors (OCT4, SOX2, c-MYC, KLF4) using CytoTune™-iPS 2.0 Sendai Reprogramming Kit. Pluripotency of the derived transgene-free iPS cell line was confirmed both in vitro by detecting the expression of factors of pluripotency on a single-cell level, and in vivo using teratoma formation assay. This iPS cell line will be a useful tool for studying both normal prostate development and prostate cancer disease.

• MeSH
• fibroblasty * cytologie   metabolismus   MeSH
• indukované pluripotentní kmenové buňky * cytologie   metabolismus   MeSH
• Krüppel-like faktor 4 MeSH
• lidé MeSH
• plod * cytologie   embryologie   MeSH
• přeprogramování buněk MeSH
• prostata * cytologie   embryologie   MeSH
• techniky buněčného přeprogramování * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

It is estimated that only 0.02% of disseminated tumour cells are able to seed overt metastases1. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unclear. Here, combining transposon technology2 and fluorescence niche labelling3, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. We identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal and pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism through which plexin B2 interacts with class IV semaphorins on tumour cells, leading to KLF4 upregulation and thereby promoting the acquisition of epithelial traits. Our results highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumour cells before the establishment of a growth-promoting niche. Our findings further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the plexin-B2-semaphorin axis abolishes metastatic colonization of the liver and therefore represents a therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumour-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.

• MeSH
• CRISPR-Cas systémy * genetika   MeSH
• fluorescence MeSH
• hepatocyty * metabolismus   cytologie   patologie   MeSH
• játra * cytologie   metabolismus   patologie   MeSH
• kolorektální nádory patologie   metabolismus   MeSH
• Krüppel-like faktor 4 metabolismus   MeSH
• lidé MeSH
• melanom metabolismus   patologie   MeSH
• metastázy nádorů * farmakoterapie   patologie   prevence a kontrola   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater * farmakoterapie   metabolismus   patologie   prevence a kontrola   sekundární   MeSH
• nádory slinivky břišní metabolismus   patologie   MeSH
• proteiny nervové tkáně * antagonisté a inhibitory   metabolismus   MeSH
• semaforiny antagonisté a inhibitory   metabolismus   MeSH
• transpozibilní elementy DNA MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• KLF4 protein, human MeSH Prohlížeč
• Klf4 protein, mouse MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• PLXNB2 protein, human MeSH Prohlížeč
• Plxnb2 protein, mouse MeSH Prohlížeč
• proteiny nervové tkáně * MeSH
• semaforiny MeSH
• transpozibilní elementy DNA MeSH

PURPOSE: Pediatric sarcomas are bone and soft tissue tumors that often exhibit high metastatic potential and refractory stem-like phenotypes, resulting in poor outcomes. Aggressive sarcomas frequently harbor a disrupted p53 pathway. However, whether pediatric sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear. METHODS: We utilized a unique panel of pediatric sarcoma models and tumor tissue cohorts to investigate the correlation between the expression of stemness-related transcription factors, p53 pathway dysregulations, tumorigenicity in vivo, and clinicopathological features. TP53 mutation status was assessed by next-generation sequencing. Major findings were validated via shRNA-mediated silencing and functional assays. The p53 pathway-targeting drugs were used to explore the effects and selectivity of p53 reactivation against sarcoma cells with stem-like traits. RESULTS: We found that highly tumorigenic stem-like sarcoma cells exhibit dysregulated p53, making them vulnerable to drugs that restore wild-type p53 activity. Immunohistochemistry of mouse xenografts and human tumor tissues revealed that p53 dysregulations, together with enhanced expression of the stemness-related transcription factors SOX2 or KLF4, are crucial features in pediatric osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma development. p53 dysregulation appears to be an important step for sarcoma cells to acquire a fully stem-like phenotype, and p53-positive pediatric sarcomas exhibit a high frequency of early metastasis. Importantly, reactivating p53 signaling via MDM2/MDMX inhibition selectively induces apoptosis in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts. CONCLUSIONS: Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.

• Klíčová slova
• Cancer stemness, Pediatric sarcomas, Prognosis, Targeted therapy, p53,
• MeSH
• dítě MeSH
• Krüppel-like faktor 4 * MeSH
• lidé MeSH
• mladiství MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * metabolismus   patologie   MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   MeSH
• předškolní dítě MeSH
• regulace genové exprese u nádorů MeSH
• sarkom * genetika   patologie   metabolismus   MeSH
• signální transdukce MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• KLF4 protein, human MeSH Prohlížeč
• Klf4 protein, mouse MeSH Prohlížeč
• Krüppel-like faktor 4 * MeSH
• nádorový supresorový protein p53 * MeSH