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Results for “Cellular differentiation”

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At least 811 records · Page 45Linked to original sources

PubMed2002

Control of cytomegalovirus lytic gene expression by histone acetylation.

Permissiveness for human cytomegalovirus (HCMV) infection is dependent on the state of cellular differentiation and has been linked to repression of the viral major immediate early promoter (MIEP). We have used conditionally permissive cells to analyze differential regulation of the MIEP and possible mechanisms involved in latency. Our data suggest that histone deacetylases (HDACs) are involved in repression of the MIEP in non-permissive cells as inhibition of HDACs induces viral permissiveness and increases MIEP activity. Non-permissive cells contain the class I HDAC, HDAC3; super-expression of HDAC3 in normally permissive cells reduces infection and MIEP activity. We further show that the MIEP associates with acetylated histones in permissive cells, and that in peripheral blood monocytes the MIEP associates with heterochromatin protein 1 (HP1), a chromosomal protein implicated in gene silencing. As monocytes are believed to be a site of viral latency in HCMV carriers and reactivated virus is only observed upon differentiation into macrophages, we propose that chromatin remodeling of the MIEP following cellular differentiation could potentially play a role in reactivation of latent HCMV.

Acetylation↗

PubMed1998

Effect of desferrioxamine and deferiprone (L1) on the proliferation of MG-63 bone cells and on phosphatase alkaline activity.

In the present work, we studied: (i) the effect of different doses of desferrioxamine and deferiprone on the proliferation of osteoblasts and the possible role of iron in this; and (ii) the effect of both chelators on the metabolic activity of these cells, using the quantification of alkaline phosphatase as an enzymatic marker of cellular activity or differentiation. Cellular proliferation was investigated at different concentrations of deferiprone and desferrioxamine, and the effect of the addition of iron citrate on this proliferation was measured. The production of alkaline phosphatase after incubation with deferiprone (150 and 300 microM) and desferrioxamine (20 and 100 microM) was also studied. Cellular proliferation was completely inhibited with 100 microM of desferrioxamine and 300 microM of deferiprone. In both cases, this effect was corrected by means of co-incubation with iron citrate. In the second phase, using the same dose that inhibited the proliferation, it was observed that after 24 h, both chelators slightly decreased alkaline phosphatase activity, while at 48 and 96 h they increased alkaline phosphatase activity. These results demonstrate that both desferrioxamine and deferiprone inhibit the proliferation of the osteoblast-like cell line MG-63; the effect seems to be related to the chelation of some fraction of available iron. In spite of the effect on bone cell proliferation, the chelators do not impair cellular activity.

Alkaline Phosphatase↗

PubMed2006

Tumors face NO problems?

The effect of nitric oxide (NO) synthase (NOS) II expression on cancer biology is unclear and difficult to define, with multiple reports of pro- and anti-cancer actions. Here we address the major factors that seem likely to account for these paradoxical behaviors, which include variability in NO production, heterogeneity in NO chemistry (and thus its cellular actions), and differential cellular responses. In addition, we suggest that a major determinant of the outcome of NO actions in the tumor environment is cellular adaptation/selection to the cytotoxic actions of NO.

Animals↗

PubMed1991

Retinoid modulation of insulin-like growth factor-binding proteins and inhibition of breast carcinoma proliferation.

Retinoids induce cellular differentiation and inhibit cellular proliferation. Proliferation of human breast carcinoma cells in vitro is markedly inhibited by these compounds. On the other hand, insulin-like growth factors (IGFs) and their receptors seem to be involved in the growth of certain breast carcinoma cells by autocrine or paracrine effects. Since the effects of both IGF-I and IGF-II may be modulated by specific binding proteins (IGF-BPs) we examined the possibility that one mechanism by which retinoic acid may inhibit cancer growth is by an alteration in these BPs, thereby blocking IGF's growth effect. Retinoic acid (RA; 1 microM) completely blocked the effect of IGF-I (50 ng/ml) on enhancing proliferation of MCF-7 cells in culture. This effect of RA was not associated with any significant change in specific IGF-I-binding sites on these cells. RA induced a 3-fold increase in IGF-binding activity in conditioned medium, measured using a polyethylene glycol-immunoglobulin precipitation assay and a charcoal absorption assay. This increase was associated with the appearance of 42- and 46-kDa IGF-BPs on ligand blotting. The effect of RA on these IGF-BPs was time and concentration dependent. In contrast, during some experiments the 27- and 36-kDa BPs actually decreased. These findings support the hypothesis that RA may inhibit the growth of certain breast carcinoma cells by increasing the secretion of certain IGF-BPs, which could directly modulate the growth effect of IGFs.

Breast Neoplasms↗

PubMed2003

NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling?

NF-kappaB is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival, cell growth, cell division, innate immunity, cellular differentiation, and the cellular responses to stress, hypoxia, stretch and ischemia. In the heart, NF-kappaB has been shown to be activated in atherosclerosis, myocarditis, in association with angina, during transplant rejection, after ischemia/reperfusion, in congestive heart failure, dilated cardiomyopathy, after ischemic and pharmacological preconditioning, heat shock, burn trauma, and in hypertrophy of isolated cardiomyocytes. Regulation of NF-kappaB is complicated; in addition to being activated by canonical cytokine-mediated pathways, NF-kappaB is activated by many of the signal transduction cascades associated with the development of cardiac hypertrophy and response to oxidative stress. Many of these signaling cascades activate NF-kappaB by activating the IkappaB kinase (IKK) complex a major component of the canonical pathway. These signaling interactions occur largely via signaling crosstalk involving the mitogen-activated protein kinase/extracellular signalregulated kinase kinases (MEKKs) that are components of mitogen activated protein kinase (MAPK) signaling pathways. Additionally, there are other signaling factors that act more directly to activate NF-kappaB via IkappaB or by direct phosphorylation of NF-kappaB subunits. Finally, there are combinatorial interactions at the level of the promoter between NF-kappaB, its coactivators, and other transcription factors, several of which are activated by MAPK and cytokine signaling pathways. Thus, in addition to being a major mediator of cytokine effects in the heart, NF-kappaB is positioned as a signaling integrator. As such, NF-kappaB functions as a key regulator of cardiac gene expression programs downstream of multiple signal transduction cascades in a variety of physiological and pathophysiological states. We show that genetic blockade of NF-kappaB reduces infarct size in the murine heart after ischemia/reperfusion (I/R), implicating NF-kappaB as a major determinant of cell death after I/R. These results support the concept that NF-kappaB may be an important therapeutic target for specific cardiovascular diseases.

Animals↗

PubMed1988

Tumor necrosis factor-induced changes of gene expression in U937 cells. Differentiation-dependent plasticity of the responsive state.

TNF-alpha alone or in combination with IFN-gamma differentially affects the proliferation and differentiation of the human leukemic cell line U937 and two derivatives C27 and G3. All three cell lines express similar numbers of functional, high affinity receptors for both TNF-alpha and IFN-gamma. In C27 and G3 cells, TNF-alpha as well as IFN-gamma induced changes in steady state levels of specific mRNA, which appear to be associated with TNF-alpha and IFN-gamma diverse effects on cell growth and differentiation. Constitutive differences in membrane phosphorylation patterns suggest that altered transduction of TNF-alpha signals may account for the differential response of these three cell lines. Several lines of evidence indicate that C27 and G3 cells, when compared with parental U937 cells represent discretely higher stages of monocytic differentiation, suggesting that cellular differentiation may contribute to the development of resistance to the action of TNF-alpha.

Antigens, Surface↗

PubMed1997

The microtubule motor cytoplasmic dynein is required for spindle orientation during germline cell divisions and oocyte differentiation in Drosophila.

During animal development cellular differentiation is often preceded by an asymmetric cell division whose polarity is determined by the orientation of the mitotic spindle. In the fruit fly, Drosophila melanogaster, the oocyte differentiates in a 16-cell syncytium that arises from a cystoblast which undergoes 4 synchronous divisions with incomplete cytokinesis. During these divisions, spindle orientation is highly ordered and is thought to impart a polarity to the cyst that is necessary for the subsequent differentiation of the oocyte. Using mutations in the Drosophila cytoplasmic dynein heavy chain gene, Dhc64C, we show that cytoplasmic dynein is required at two stages of oogenesis. Early in oogenesis, dynein mutations disrupt spindle orientation in dividing cysts and block oocyte determination. The localization of dynein in mitotic cysts suggests spindle orientation is mediated by the microtubule motor cytoplasmic dynein. Later in oogenesis, dynein function is necessary for proper differentiation, but does not appear to participate in morphogen localization within the oocyte. These results provide evidence for a novel developmental role for the cytoplasmic dynein motor in cellular determination and differentiation.

Animals↗

PubMed2001

Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C.

The effect of silibinin, an active component of Silybum marianum, on cellular differentiation was investigated in the human promyelocytic leukemia HL-60 cell culture system. Treatment of HL-60 cells with silibinin inhibited cellular proliferation and induced cellular differentiation in a dose-dependent manner. Cytofluorometric analysis and morphologic studies indicated that silibinin induced differentiation of HL-60 cells predominantly into monocytes. Importantly, strongly synergistic induction of differentiation into monocytes was observed when silibinin was combined with 5 nM 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], a well-known differentiation inducer of HL-60 cells into the monocytic lineage. Silibinin enhanced protein kinase C (PKC) activity and increased protein levels of both PKCalpha and PKCbeta in 1,25-(OH)(2)D(3)-treated HL-60 cells. PKC and extracellular signal-regulated kinase (ERK) inhibitors significantly inhibited HL-60 cell differentiation induced by silibinin alone or in combination with 1,25-(OH)(2)D(3), indicating that PKC and ERK may be involved in silibinin-induced HL-60 cell differentiation.

Antioxidants↗

PubMed1993

Correlation between the DNA-binding affinity of topoisomerase inhibiting drugs and their capacity to induce hematopoetic cell differentiation.

There is accumulating evidence that both type I and type II DNA-topoisomerases play a key role in cellular differentiation. Human HL-60 leukemia cells can be induced to monocytic or granulocytic differentiation with various compounds; amongst them camptothecin, a topoisomerase I inhibitor and VP-16, VM-26 and mitoxantrone, all potent topoisomerase II inhibitors. During HL-60 cell differentiation topoisomerase I activity increases and topoisomerase II activity decreases. The two isoenzymes topoisomerase II alpha and topoisomerase II beta seem to have different physiological functions in highly proliferating cells, G0 cells and differentiated cells as their expression is regulated differently. In concentrations sublethal to undifferentiated cells, m-AMSA, also a potent topoisomerase II inhibitor, is able to prevent DMSO-induced granulocytic HL-60 cell differentiation. In drug-sensitive cells derived from several sources (mouse erythroleukemia, human gastric carcinoma, human leukemia), we found a functional heterogeneity of topoisomerase activity which is altered specifically during cellular differentiation. The isoactivities can be separated by their different pH and salt requirements and they exhibit different sensitivity to topoisomerase II inhibiting drugs. Functional heterogeneity of topoisomerases seems to be a prerequisite to high drug sensitivity of the cells, since drug-resistant sublines in our experiments do not exhibit this heterogeneity. We propose that the topoisomerase II inhibiting drugs which are able to induce differentiation, namely the epipodophyllotoxines VP-16 and VM-26, inhibit subfractions of the topoisomerase II pool which are necessary to maintain the undifferentiated status of the cells. These drugs induce differentiation in concentrations 10-100-fold below the lethal dose, the concentration must be sufficient to inhibit topoisomerase II but well below the concentration to induce the cleavable complex. This might be the reason that anthracyclines with a high DNA binding affinity have low differentiation-inducing capacity.

Amsacrine↗

PubMed1986

Differentiation and the multiple drug resistance phenotype in human leukemic cells.

A common feature of mammalian cell lines selected for multiple drug resistance is the overexpression of a high-molecular-weight surface membrane glycoprotein(s). While its amount has been shown to be related to the degree of resistance of such cells, its function in this phenomenon remains obscure. Because there are some biochemical and functional similarities between drug-resistant cells and differentiated cells, we asked if resistance-associated glycoproteins were also associated with cellular differentiation. Using three monoclonal antibodies against antigens known to be associated with differentiation and three monoclonal antibodies that distinguish our multiple drug-resistant human leukemic CEM/VLB100 cells from their drug-sensitive counterparts, we found that the resistant cells were neither altered in their apparent state of differentiation nor were they altered in their ability to respond to a differentiation stimulus with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. We did find, however, that one antibody that recognizes the resistance-associated glycoprotein, Mr 180,000 glycoprotein (gp180), was only minimally altered in amount bound after treatment with the phorbol ester, but two other resistance-associated glycoproteins, Mr 155,000 glycoprotein (gp155) and, to a lesser extent, Mr 130,000 glycoprotein (gp130), were reduced in expression after this treatment. We suggest that the function of the previously described "marker" glycoprotein associated with multiple drug resistance remains unknown, but that the expression of two other resistance-associated glycoproteins also appears to be related to cellular differentiation or maturation in these cells.

Antibodies, Monoclonal↗

PubMed1992

Alteration of neuroblastoma ganglioside metabolism by retinoic acid.

Cellular differentiation is often associated with striking changes in ganglioside metabolism. Because retinoic acid causes cellular differentiation in vitro, we have characterized its effect on ganglioside synthesis and shedding by LAN-5 human neuroblastoma cells. Three major observations were made: (a) 20 microM retinoic acid caused a marked (twofold) increase in cellular ganglioside content, with a slight relative enhancement in GD1a and GT1b synthesis, (b) ganglioside shedding increased in parallel with increased cellular ganglioside content, and also, unexpectedly, (c) retinoic acid caused a quantitatively similar increase in content of cell membrane phospholipids, which are also shed. We conclude that enhanced ganglioside synthesis and shedding by retinoic acid are part of a previously undescribed generalized stimulatory effect on membrane lipid metabolism.

Chromatography, Thin Layer↗

PubMed2003

Disruption of differentiation in human cancer: AML shows the way.

Although much is understood about the ways in which transcription factors regulate various differentiation systems, and one of the hallmarks of many human cancers is a lack of cellular differentiation, relatively few reports have linked these two processes. Recent studies of acute myeloid leukaemia (AML), however, have indicated how disruption of transcription-factor function can disrupt normal cellular differentiation and lead to cancer. This model involves lineage-specific transcription factors, which are involved in normal haematopoietic differentiation. These factors are often targeted in AML--either by direct mutation or by interference from translocation proteins. Uncovering these underlying pathways will improve the diagnosis and treatment of AML, and provide a working model for other types of human cancer, including solid tumours.

Cell Differentiation↗

PubMed2004

Acetylation regulates the differentiation-specific functions of the retinoblastoma protein.

The retinoblastoma tumor-suppressor protein (pRb) is known to induce growth arrest and cellular differentiation. The molecular determinants of pRb function include protein-protein interactions and post-translational modifications such as phosphorylation. Recently, the co-activator p300 was found to acetylate pRb. The biological significance of pRb acetylation, however, remains unclear. In the present study, we provide evidence that pRb undergoes acetylation upon cellular differentiation, including skeletal myogenesis. In addition to p300, the p300-Associated Factor (P/CAF) can mediate pRb acetylation as pRb interacts directly with the acetyltransferase domain of P/CAF in vitro and can associate with P/CAF in differentiated cells. Significantly, by using a C terminal acetylation-impaired mutant of pRb, we reveal that acetylation does not affect pRb-dependent growth arrest or the repression of E2F transcriptional activity. Instead, acetylation is required for pRb-mediated terminal cell cycle exit and the induction of late myogenic gene expression. Based on these results, we propose that acetylation regulates the differentiation-specific function(s) of pRb.

Acetylation↗

PubMed2002

Differential effects of short-chain fatty acids on head and neck squamous carcinoma cells.

OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma (HNSCC) is a major cause of mortality. Despite advances in therapeutic modalities, recurrences and second primaries are commonly observed. Biological agents that can suppress growth of tumors that are otherwise difficult to treat are greatly needed. The present study examined the effects of short-chain fatty acids on HNSCC cell lines. STUDY DESIGN: The effects of short-chain fatty acids on HNSCC cells was examined using tissue culture and immunoblotting techniques. METHODS: The effects of four short-chain fatty acids, arginine butyrate, alpha-methyl hydrocinnamic acid, 2,2-dimethylbutyrate, and alpha-lipoic acid, were evaluated on four HNSCC cell lines (FaDu, SCC9, SCC25, and Detroit-562). Proliferation assays were performed by means of spectrophotometric techniques. Histone deacetylase activity was assessed by identifying the amount of acetylated histone H4. Involucrin expression was determined to assess cellular differentiation. RESULTS: Inhibition of cellular proliferation was determined after 5 days of incubation with increasing doses with short-chain fatty acids. Arginine butyrate and alpha-lipoic acid were most effective in suppressing growth. Arginine butyrate demonstrated strong histone deacetylase inhibition in FaDu cells, while not inducing cellular differentiation. The short-chain fatty acid alpha-lipoic acid demonstrated weak histone deacetylase inhibition but was the only short-chain fatty acid that induced involucrin expression in at least two of the cell lines. Histone deacetylase inhibitory activity or induction of involucrin expression correlated with suppression of cell growth. CONCLUSIONS: Short-chain fatty acids have variable effects on HNSCC cells. Arginine butyrate and alpha-lipoic acid are the most effective in suppressing growth and appear to do so through different biochemical mechanisms. These compounds warrant further research as chemotherapeutic or chemopreventive agents in HNSCC.

Blotting, Western↗

PubMed1985

Defective control of terminal differentiation and its role in carcinogenesis in the 3T3 T proadipocyte stem cell line.

The expression of defects in the control of terminal cellular differentiation has been implicated to be of etiological significance in the pathogenesis of cancer. However, it has not been established whether or not additional defects in the control of cellular differentiation and proliferation are required for the expression of the completely transformed phenotype. We therefore developed four clones of proadipocyte stem cells that express a single specific defect that limits their capacity to undergo the terminal phase in differentiation. The value of these clones is emphasized by the fact that they show no defects in their ability to regulate nonterminal differentiation or proliferation relative to native nontransformed proadipocyte stem cells. Terminal differentiation-defective clones were therefore assayed to determine if they express the completely transformed phenotype. The results show that differentiation-defective stem cells are not tumorigenic in vivo and do not grow in soft agar, which is an in vitro assay for expression of the transformed phenotype by murine mesenchymal cells. These data are interpreted to support the conclusion that the expression of defects in the control of the terminal phase of differentiation per se is not adequate to induce complete neoplastic transformation.

Adipose Tissue↗

PubMed1996

Telomere reduction and telomerase inactivation during neuronal cell differentiation.

Telomerase adds (TTAGGG)n hexanucleotide repeats to the ends of mammalian telomeres. This compensates for telomeric loss with successive rounds of cellular replication. Telomerase activity is detected in many neoplastic cells, but not in most normal somatic cells. To determine whether telomeric length and telomerase activity are associated with cellular differentiation, we measured telomeric lengths and telomerase activity in embryonic NT2 precursor cells prior to and following differentiation into post mitotic hNT neurons. This system allows for studies in a direct neuronal cell lineage and, thus, provides a unique model for studying the role of neuronal telomerase activity. Our results show that telomerase activity was present in precursor cells, but not in neuronal cells. Telomeres were consistently longer in NT2 cells than in hNT cells. These results suggest that changes in telomeric length and loss of telomerase activity play a role in neuronal cellular differentiation.

Base Sequence↗

PubMed1998

Ion channels and early development of neural cells.

In this review we underscore the merits of using voltage-dependent ion channels as markers for neuronal differentiation from the early stages of uncommitted embryonic blastomeres. Furthermore, a fairly large part of the review is devoted to the descriptions of the establishment of a simple model system for neural induction derived from the cleavage-arrested eight-cell ascidian embryo by pairing a single ectodermal with a single vegetal blastomere as a competent and an inducer cell, respectively. The descriptions are focused particularly on the early developmental processes of various ion channels in neuronal and other excitable membranes observed in this extraordinarily simple system, and we compare these results with those in other significant and definable systems for neural differentiation. It is stressed that this simple system, for which most of the electronic and optical methods and various injection experiments are applicable, may be useful for future molecular physiological studies on the intracellular process of differentiation of the early embryonic cells. We have also highlighted the importance of suppressive mechanisms for cellular differentiation from the experimental results, such as epidermal commitment of the cleavage-arrested one-cell Halocynthia embryos or suppression of epidermal-specific transcription of inward rectifier channels by neural induction signals. It was suggested that reciprocal suppressive mechanisms at the transcriptional level may be one of the key processes for cellular differentiation, by which exclusivity of cell types is maintained.

Animals↗

PubMed1982

Timing mechanisms in early embryonic development.

Embryological development takes place in four dimensions and requires the existence of time measuring processes within the embryo. Evidence is accumulating that suggests that the emergence of many events during early embryonic development is controlled by timing mechanisms or developmental clocks. The purpose of this work is to review recent studies on developmental timing with speculations about underlying possible mechanisms. It is an attractive idea that the development of an embryo is timed by a single clock set in motion at fertilization, but this seems not feasible. The clock mechanism which determines the time of initiation of cellular differentiation may be independent of that for the timing of morphogenesis. The clock mechanism for cellular differentiation may be closely associated with the cycles of DNA replication, while the clock which counts the time to onset of early morphogenetic events is found in the cytoplasm. These ideas can provide a framework which may help to organize existing observations and to stimulate new experimental approaches to the problem.

Acetylcholinesterase↗