Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiation factor-15 (GDF-15), a distant member of the TGF-beta protein family, has recently been associated with many human cancers, including prostate. We show that both pure GDF-15 and the GDF-15-containing growth medium of 1,25(OH)(2)-vitamin D(3)-treated prostate adenocarcinoma LNCaP cells suppress formation of mature osteoclasts differentiated from RAW264.7 macrophages and bone-marrow precursors by M-CSF/RANKL in a dose-dependent manner. GDF-15 inhibits expression of c-Fos and activity of NFkappaB by delayed degradation of IkappaB. Moreover, GDF-15 inhibits expression of carbonic anhydrase II and cathepsin K, key osteoclast enzymes, and induces changes in SMAD and p38 signaling. The lack of functional osteoclasts can contribute to accumulation of bone matrix by reduction of bone resorption. These results unveil new role of GDF-15 in modulation of osteoclast differentiation and possibly in therapy of bone metastases.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné linie MeSH
• časové faktory MeSH
• faktor stimulující kolonie makrofágů farmakologie   MeSH
• femur cytologie   MeSH
• inbrední kmeny myší MeSH
• izoenzymy metabolismus   MeSH
• kalcitriol farmakologie   MeSH
• karboanhydrasa II antagonisté a inhibitory   MeSH
• kathepsin K antagonisté a inhibitory   genetika   MeSH
• kultivační média speciální farmakologie   MeSH
• kyselá fosfatasa rezistentní k tartarátu MeSH
• kyselá fosfatasa metabolismus   MeSH
• lidé MeSH
• ligand RANK farmakologie   MeSH
• makrofágy cytologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty metabolismus   MeSH
• NF-kappa B antagonisté a inhibitory   MeSH
• osteoklasty účinky léků   metabolismus   MeSH
• protoonkogenní proteiny c-fos antagonisté a inhibitory   MeSH
• růstový diferenciační faktor 15 farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• faktor stimulující kolonie makrofágů MeSH
• izoenzymy MeSH
• kalcitriol MeSH
• karboanhydrasa II MeSH
• kathepsin K MeSH
• kultivační média speciální MeSH
• kyselá fosfatasa rezistentní k tartarátu MeSH
• kyselá fosfatasa MeSH
• ligand RANK MeSH
• NF-kappa B MeSH
• protoonkogenní proteiny c-fos MeSH
• růstový diferenciační faktor 15 MeSH

Autophagy is essential for successful white adipocyte differentiation but the data regarding the timing and relevance of autophagy action during different phases of adipogenesis are limited. We subjected 3T3-L1 preadipocytes to a standard differentiation protocol and inhibited the autophagy within time-limited periods (days 0-2; 2-4; 4-6; 6-8) by asparagine or 3-methyladenine. In the normal course of events, both autophagy flux and the mRNA expression of autophagy related genes (Atg5, Atg12, Atg16, beclin 1) is most intensive at the beginning of differentiation (days 0-4) and then declines. The initiation of differentiation is associated with a 50% reduction of the mitochondrial copy number on day 2 followed by rapid mitochondrial biogenesis. Preadipocytes and differentiated adipocytes differ in the mRNA expression of genes involved in electron transport (Nufsd1, Sdhb, Uqcrc1); ATP synthesis (ATP5b); fatty acid metabolism (CPT1b, Acadl); mitochondrial transporters (Hspa9, Slc25A1) and the TCA cycle (Pcx, Mdh2) as well as citrate synthase activity. Autophagy inhibition during the first two days of differentiation blocked both phenotype changes (lipid accumulation) and the gene expression pattern, while having no or only a marginal effect over any other time period. Similarly, autophagy inhibition between days 0-2 inhibited mitotic clonal expansion as well as mitochondrial network remodeling. In conclusion, we found that autophagy is essential and most active during an initial stage of adipocyte differentiation but it is dispensable during its later stages. We propose that the degradation of preadipocyte cytoplasmic structures, predominantly mitochondria, is an important function of autophagy during this phase and its absence prevents remodeling of the mitochondrial gene expression pattern and mitochondrial network organization.

• Klíčová slova
• 3T3-L1 cells, Adipocytes, Autophagy, Differentiation, Mitochondria, Preadipocytes,
• MeSH
• adipogeneze účinky léků   genetika   MeSH
• asparagin farmakologie   MeSH
• autofagie účinky léků   genetika   MeSH
• buněčná diferenciace účinky léků   genetika   MeSH
• buňky 3T3-L1 MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• myši MeSH
• tukové buňky cytologie   účinky léků   MeSH
• vývojová regulace genové exprese účinky léků   genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• asparagin MeSH

CREB-binding protein (CBP) regulates gene expression by binding to certain components of basal transcription machinery and by histone acetylation. In addition, it integrates various cellular signaling pathways through binding to multiple transcription factors, including the Myb proteins. We report in this study that CBP can partially suppress function of the v-Myb oncoprotein in leukemic cells. Although originally described as an activator of v-Myb function, we show that CBP can also act as a v-Myb suppressor. Ectopic expression of murine CBP in v-Myb-transformed chicken monoblasts reduced transcriptional activation abilities of the v-Myb protein and increased sensitivity to differentiation inducers such as phorbol ester or trichostatin A. In addition, exogenous CBP affected morphology of differentiated cells derived from BM2 monoblasts. These results indicate that cellular context is an important factor determining whether CBP will activate or suppress the protein it targets.

• MeSH
• buněčná diferenciace účinky léků   fyziologie   MeSH
• fagocytóza fyziologie   MeSH
• forbolové estery farmakologie   MeSH
• jaderné proteiny genetika   fyziologie   MeSH
• kur domácí MeSH
• kyseliny hydroxamové farmakologie   MeSH
• monocyty cytologie   účinky léků   fyziologie   MeSH
• myši MeSH
• onkogenní proteiny v-myb fyziologie   MeSH
• protein vázající CREB MeSH
• trans-aktivátory genetika   fyziologie   MeSH
• transformované buněčné linie MeSH
• virová transformace buněk fyziologie   MeSH
• virus ptačí myeloblastózy fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Crebbp protein, mouse MeSH Prohlížeč
• forbolové estery MeSH
• jaderné proteiny MeSH
• kyseliny hydroxamové MeSH
• onkogenní proteiny v-myb MeSH
• protein vázající CREB MeSH
• trans-aktivátory MeSH
• trichostatin A MeSH Prohlížeč

Differentiation during hematopoiesis leads to the generation of many cell types with specific functions. At various stages of maturation, the cells may change pathologically, leading to diseases including acute leukemias (ALs). Expression levels of regulatory molecules (such as the IKZF, GATA, HOX, FOX, NOTCH and CEBP families, as well as SPI-1/PU1 and PAX5) and lineage-specific molecules (including CD2, CD14, CD79A, and BLNK) may be compared between pathological and physiological cells. Although the key steps of differentiation are known, the available databases focus mainly on fully differentiated cells as a reference. Precursor cells may be a more appropriate reference point for diseases that evolve at immature stages. Therefore, we developed a quantitative real-time polymerase chain reaction (qPCR) array to investigate 90 genes that are characteristic of the lymphoid or myeloid lineages and/or are thought to be involved in their regulation. Using this array, sorted cells of granulocytic, monocytic, T and B lineages were analyzed. For each of these lineages, 3-5 differentiation stages were selected (17 stages total), and cells were sorted from 3 different donors per stage. The qPCR results were compared to similarly processed AL cells of lymphoblastic (n=18) or myeloid (n=6) origins and biphenotypic AL cells of B cell origin with myeloid involvement (n=5). Molecules characteristic of each lineage were found. In addition, cells of a newly discovered switching lymphoblastic AL (swALL) were sorted at various phases during the supposed transdifferentiation from an immature B cell to a monocytic phenotype. As demonstrated previously, gene expression changed along with the immunophenotype. The qPCR data are publicly available in the LeukoStage Database in which gene expression in malignant and non-malignant cells of different lineages can be explored graphically and differentially expressed genes can be identified. In addition, the LeukoStage Database can aid the functional analyses of next-generation sequencing data.

• Klíčová slova
• Acute leukemia, B and T lymphocytes, Differentiation plasticity, Gene expression, Hematopoiesis, Lineage promiscuity,
• MeSH
• akutní bifenotypická leukemie genetika   imunologie   patologie   MeSH
• B-lymfocyty imunologie   patologie   MeSH
• buněčná diferenciace genetika   MeSH
• buněčný rodokmen genetika   MeSH
• čipová analýza tkání MeSH
• hematopoéza genetika   MeSH
• imunofenotypizace MeSH
• lidé MeSH
• nádorové proteiny biosyntéza   MeSH
• regulace genové exprese u leukemie MeSH
• T-lymfocyty imunologie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové proteiny MeSH

Maturation of blood cells depends on dramatic changes of expression profiles of specific genes. Although these changes have been extensively studied, their functional outcomes often remain unclear. In this study, we explored the identity and function of an unknown protein that was greatly overexpressed in v-myb-transformed BM2 monoblasts undergoing differentiation to macrophage-like cells. We identified this protein as vimentin, the intermediate filament protein. We show that an increased level of vimentin protein results from activation of the vimentin gene promoter occurring in monoblastic cells induced to differentiate by multiple agents. Furthermore, our studies reveal that the vimentin gene promoter is stimulated by Myb and Jun proteins, the key transcriptional regulators of myeloid maturation. Silencing of vimentin gene expression using siRNA markedly suppressed the ability of BM2 cells to form macrophage polykaryons active in phagocytosis and producing reactive oxygen species. Taken together, these findings document that up-regulation of vimentin gene expression is important for formation of fully active macrophage-like cells and macrophage polykaryons.

• MeSH
• 2D gelová elektroforéza MeSH
• buněčná diferenciace * MeSH
• fibroblasty MeSH
• geny jun genetika   MeSH
• hematopoéza genetika   MeSH
• hmotnostní spektrometrie MeSH
• křepelky a křepelovití MeSH
• kur domácí MeSH
• makrofágy cytologie   fyziologie   MeSH
• monocyty cytologie   fyziologie   MeSH
• onkogenní proteiny v-myb genetika   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protoonkogenní proteiny c-jun fyziologie   MeSH
• regulace genové exprese MeSH
• tetradekanoylforbolacetát MeSH
• transformované buněčné linie MeSH
• transkripční faktory genetika   MeSH
• upregulace MeSH
• vimentin genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• onkogenní proteiny v-myb MeSH
• protoonkogenní proteiny c-jun MeSH
• tetradekanoylforbolacetát MeSH
• transkripční faktory MeSH
• vimentin MeSH

Retinoids represent a popular group of differentiation inducers that are successfully used in oncology for treatment of acute promyelocytic leukemia in adults and of neuroblastoma in children. The therapeutic potential of retinoids is based on their key role in the regulation of cell differentiation, growth, and apoptosis, which provides a basis for their use both in cancer therapy and chemoprevention. Nevertheless, patients treated with retinoids often exhibit or develop resistance to this therapy. Although resistance to retinoids is commonly categorized as either acquired or intrinsic, resistance as a single phenotypic feature is usually based on the same mechanisms that are closely related or combined in both of these types. In this review, we summarize the most common changes in retinoid metabolism and action that may affect the sensitivity of a tumor cell to treatment with retinoids. The availability of retinoids can be regulated by alterations in retinol metabolism or in retinoid intracellular transport, by degradation of retinoids or by their efflux from the cell. Retinoid effects on gene expression can be regulated via retinoid receptors or via other molecules in the transcriptional complex. Finally, the role of small-molecular-weight inhibitors of altered cell signaling pathways in overcoming the resistance to retinoids is also suggested.

• Klíčová slova
• cell differentiation, differentiation therapy, mechanisms of resistance, retinoids,
• MeSH
• biologický transport účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• chemorezistence účinky léků   MeSH
• genetická transkripce účinky léků   MeSH
• lidé MeSH
• receptory kyseliny retinové metabolismus   MeSH
• retinoidy metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• receptory kyseliny retinové MeSH
• retinoidy MeSH

The p53 protein can control cell cycle progression, programmed cell death, and differentiation of many cell types. Ectopic expression of p53 can resume capability of cell cycle arrest, differentiation, and apoptosis in various leukemic cell lines. In this work, we expressed human p53 protein in v-Myb-transformed chicken monoblasts. We found that even this protein possessing only 53% amino acid homology to its avian counterpart can significantly alter morphology and physiology of these cells causing the G2-phase cell cycle arrest and early monocytic differentiation. Our results document that the species-specific differences of the p53 molecules, promoters/enhancers, and co-factors in avian and human cells do not interfere with differentiation- and cell cycle arrest promoting capabilites of the p53 tumor suppressor even in the presence of functional v-Myb oncoprotein. The p53-induced differentiation and cell cycle arrest of v-Myb-transformed monoblasts are not associated with apoptosis suggesting that the p53-driven pathways controlling apoptosis and differentiation/proliferation are independent.

• MeSH
• apoptóza genetika   MeSH
• buněčná diferenciace genetika   fyziologie   MeSH
• buněčný cyklus genetika   MeSH
• G2 fáze genetika   MeSH
• inhibitory růstu genetika   fyziologie   MeSH
• kur domácí MeSH
• lidé MeSH
• monocyty cytologie   MeSH
• nádorový supresorový protein p53 genetika   fyziologie   MeSH
• onkogenní proteiny v-myb genetika   MeSH
• proliferace buněk * MeSH
• signální transdukce genetika   MeSH
• transfekce MeSH
• transformované buněčné linie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• inhibitory růstu MeSH
• nádorový supresorový protein p53 MeSH
• onkogenní proteiny v-myb MeSH

Adenosine deaminase acting on RNA 1 (ADAR1) is the principal enzyme for the adenosine-to-inosine RNA editing that prevents the aberrant activation of cytosolic nucleic acid sensors by endogenous double stranded RNAs and the activation of interferon-stimulated genes. In mice, the conditional neural crest deletion of Adar1 reduces the survival of melanocytes and alters the differentiation of Schwann cells that fail to myelinate nerve fibers in the peripheral nervous system. These myelination defects are partially rescued upon the concomitant removal of the Mda5 antiviral dsRNA sensor in vitro, suggesting implication of the Mda5/Mavs pathway and downstream effectors in the genesis of Adar1 mutant phenotypes. By analyzing RNA-Seq data from the sciatic nerves of mouse pups after conditional neural crest deletion of Adar1 (Adar1cKO), we here identified the transcription factors deregulated in Adar1cKO mutants compared to the controls. Through Adar1;Mavs and Adar1cKO;Egr1 double-mutant mouse rescue analyses, we then highlighted that the aberrant activation of the Mavs adapter protein and overexpression of the early growth response 1 (EGR1) transcription factor contribute to the Adar1 deletion associated defects in Schwann cell development in vivo. In silico and in vitro gene regulation studies additionally suggested that EGR1 might mediate this inhibitory effect through the aberrant regulation of EGR2-regulated myelin genes. We thus demonstrate the role of the Mda5/Mavs pathway, but also that of the Schwann cell transcription factors in Adar1-associated peripheral myelination defects.

• Klíčová slova
• ADAR1, EGR1, MAVS, Schwann cells, differentiation, neural crest,
• MeSH
• adenosindeaminasa * genetika   metabolismus   MeSH
• buněčná diferenciace * genetika   MeSH
• crista neuralis * metabolismus   MeSH
• IFIH1 genetika   metabolismus   MeSH
• myelinová pochva metabolismus   MeSH
• myši knockoutované * MeSH
• myši MeSH
• Schwannovy buňky * metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ADAR1 protein, mouse MeSH Prohlížeč
• adenosindeaminasa * MeSH
• Ifih1 protein, mouse MeSH Prohlížeč
• IFIH1 MeSH

DISP3 (PTCHD2), a sterol-sensing domain-containing protein, is highly expressed in neural tissue but its role in neural differentiation is unknown. In the present study we used a multipotent cerebellar progenitor cell line, C17.2, to investigate the impact of DISP3 on the proliferation and differentiation of neural precursors. We found that ectopically expressed DISP3 promotes cell proliferation and alters expression of genes that are involved in tumorigenesis. Finally, the differentiation profile of DISP3-expressing cells was altered, as evidenced by delayed expression of neural specific markers and a reduced capacity to undergo neural differentiation.

• Klíčová slova
• Cancer, Differentiation, Lipids, Neural cells, Proliferation,
• MeSH
• buněčná diferenciace * MeSH
• buněčné linie MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• metabolismus lipidů MeSH
• mozek cytologie   MeSH
• nervové kmenové buňky cytologie   metabolismus   MeSH
• proliferace buněk MeSH
• regulace genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DISP3 protein, human MeSH Prohlížeč
• membránové proteiny MeSH

• Klíčová slova
• inflammatory disease, metabolic and rare bone disease, molecular mechanism, osteoblast differentiation, osteoclast differentiation,
• MeSH
• buněčná diferenciace MeSH
• kosti a kostní tkáň * MeSH
• osteoklasty * MeSH
• Publikační typ
• úvodníky MeSH