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PubMed2001

Pigpen and endothelial cell differentiation.

Endothelial cells can toggle back and forth between differentiated and relatively undifferentiated states with comparative ease. This is an important characteristic, particularly in adult tissues where the constitutive endothelial cell phenotype is quiescent. It enables rapid repair of wounds, renewal of the vascular intima in parts of the circulatory system with high flow and turbulence, and is essential to the cyclic function of reproductive organs. However, the ability to dedifferentiate can be a severe disadvantage when it is subverted to the support of disease processes such as tumor growth and metastasis. The control of endothelial cell differentiation state is, therefore, a matter of significance to investigators of basic developmental mechanism, as well as those studying an array of neovascular disorders. Recently, studies have advanced beyond the identification of extracellular triggers and overt cellular responses to the analysis of signal transduction pathways and nuclear events. This review focuses on the nuclear protein pigpen that is found in the right place at the right time, and with the necessary equipment, to modulate endothelial cell differentiation. We project that when we better understand the relationship of pigpen to its upstream regulators and downstream effectors, we will also have a better understanding of the mechanisms underlying capillary morphogenesis.

Animals↗
PubMed1980

Production and main characteristics of a fetal calf serum-specific cell line that induces T and B cell differentiation.

Spleen cells from B6 mice injected with fetal calf serum (FCS) could be kept proliferating as a continuous cell line in vitro provided they were culture in the presence of irradiated syngeneic spleen cells and FCS. Cells in this cell line showed a strong proliferative response when stimulated with concanavalin A (Con A), and they were able to mediate the following functions: (1)they helped the generation of alloantigen-specific cytotoxic T lymphocytes (CTL) from thymocyte-spleen cell mixed lymphocyte cultures (MLC), (2)they induced the generation of CTL from normal syngeneic spleen cells in the absence of allogeneic stimulator cells, and (3)they induced normal spleen cells to differentiate into anti-sheep erythrocyte (SRBC) plaque-forming cells (PFC), in the absence of SRBC in the cultures. The use of this cell line (called line 12) may thus provide an interesting approach for the study of cellular and molecular requirements for cell-cell interactions and for the differentiation of T and B effector functions.

Animals↗
PubMed1990

Methylation of 21-23 kD membrane proteins by a membrane-associated protein carboxyl methyltransferase in neuroblastoma cells. Increased methylation in differentiated cells.

Membranes of neuroblastoma N1E-115 cells contain a specific protein carboxyl methyltransferase that methylates a 70 kD protein and a group of 21-23 kD proteins which are tightly bound to the membranes. The enzyme catalyzes the transfer of [methyl-3H] groups from [methyl-3H]S-adenosyl-L-methionine (Km = 0.22 microM) to these proteins to form base-labile carboxymethylesters. These protein methylesters are relatively stable compared to other protein methylesters, as shown by the ability of the 21-23 kD methylated proteins to retain their [methyl-3H] groups at pH values of 7 to 8.5 for at least 12 hr at room temperature. The extent of methylation of the 21-23 kD proteins, but not that of the 70 kD protein, was increased in membranes of cells induced to differentiate by 2% dimethyl sulfoxide (from a basal level of 0.1-0.2 to 0.9-1.2 pmol [methyl-3H] groups incorporated per mg membrane protein). This increase appeared after a lag period of 3 days of growth in the presence of the dimethyl sulfoxide and developed in parallel with the appearance of neurite-like processes in the cells. Kinetic experiments suggest that the amounts of 21-23 kD proteins available for methylation in the membranes of the undifferentiated and of the differentiated cells are limited. This and the previously observed low turnover of methylated 21-23 kD proteins in the intact cells suggest that the differentiated cells express and methylate more 21-23 kD proteins than the undifferentiated cells. These methylated proteins may be involved in differentiation or other functions of the differentiated cell membranes.

Animals↗
PubMed1993

Differanisole A, an inducer of the differentiation of Friend leukemic cells, induces stalk cell differentiation in Dictyostelium discoideum.

Differanisole A isolated from the conditioned medium of a soil microorganism, Chaetomium strain RB-001, is an inducer of the differentiation of the Friend leukemic cells (mouse leukemia cells). The chemical structure of this substance is very similar to that of stalk cell differentiation-inducing factor (DIF) isolated from the cellular slime mould, Dictyostelium discoideum. We examined the effects of differanisole A on Dictyostelium HM44 cells, a mutant strain which is defective in DIF production, and found this substance to be an inducer of stalk cell differentiation in D. discoideum.

Animals↗
PubMed2005

Protein kinase clk/STY is differentially regulated during erythroleukemia cell differentiation: a bias toward the skipped splice variant characterizes postcommitment stages.

Clk/STY is a LAMMER protein kinase capable to phosphorylate serine/arginine-rich (SR) proteins that modulate pre-mRNA splicing. Clk/STY alternative splicing generates transcripts encoding a full-length kinase and a truncated catalytically inactive protein. Here we showed that clk/STY, as well as other members of the family (e.g. clk2, clk3 and clk4), are up-regulated during HMBA-induced erythroleukemia cell differentiation. mRNAs coding for the full-length and the truncated forms were responsible for the overall increased expression. In clk/STY, however, a switch was observed for the ratio of the two alternative spliced products. In undifferentiated cells the full-length transcript was more abundant whereas the transcript encoding for the truncated form predominated at latter stages of differentiation. Surprisingly, overexpression of clk/STY did not alter the splicing switch upon differentiation in MEL cells. These results suggest that clk/STY might contribute to control erythroid differentiation by a mechanism that implicates a balance between these two isoforms.

Acetamides↗
PubMed2005

Effect of inhibitors of histone deacetylase on the induction of cell differentiation in murine and human erythroleukemia cell lines.

Histone deacetylase (HDAC) inhibitors are a novel class of promising anti-cancer agents. Little information is available on the capacity of structurally different HDAC inhibitors to induce terminal cell differentiation in different cell types in relation to enzyme inhibition and subtype selectivity. Consequently, the aim of this study was to provide a comprehensive comparison of these effects. New biarylalanine inhibitors of HDAC were synthesized and compared to a series of standard inhibitors from different laboratories. Chromatographically purified rat liver and immunoprecipitated FLAG-tagged recombinant human HDACs were used as sources of HDAC activity. Enzyme inhibition was studied using a fluorescent substrate and its conversion was monitored by high-performance liquid chromatography. The ability to induce cell differentiation was compared in murine (Friend DS-19) and human (K562) erythroleukemic cell lines, and was quantified by benzidine staining. Inhibition of cell proliferation was evaluated by cell counting. All HDAC inhibitors were identified as potent inhibitors of erythroleukemic cell proliferation. However, we observed a complex pattern of differentiation induction: structurally similar inhibitors resulted in disparate activity profiles, whereas similar profiles were detected within distinct structural classes. Among the newly synthesized biarylalanine compounds, a 3'-methoxy derivative was identified as a very effective inducer of terminal cell differentiation. We conclude that investigation of subtype selectivity of selected HDAC inhibitors does not provide a clear link between selectivity and the observed cellular activity profile. The predictive value of in vitro HDAC inhibition assays for identifying anti-proliferative compounds has been emphasized.

Aminobiphenyl Compounds↗
PubMed2002

[Induction of murine bone marrow stromal cell differentiation into nerve cells].

The in vitro induced differentiation of mouse bone marrow stromal cells into nerve cells by retinoic acid and leukemia inhibitory factor has been shown, using morphological, histochemical and immunocytochemical analyses. The developed techniques allow to obtain up to 30% of neural cells in vitro. A suggestion about pluripotency of bone marrow stromal cells and possibility of their application to the cell therapy is discussed.

Animals↗
PubMed2006

Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage.

We have investigated the phenotypic and bioassay characteristics of bone marrow mesenchymal stromal cells (MSCs) differentiated along a Schwann cell lineage using glial growth factor. Expression of the Schwann cell markers S100, P75, and GFAP was determined by immunocytochemical staining and Western blotting. The levels of the stem cell markers Stro-1 and alkaline phosphatase and the neural progenitor marker nestin were also examined throughout the differentiation process. The phenotypic properties of cells differentiated at different passages were also compared. In addition to a phenotypic characterization, the functional ability of differentiated MSCs has been investigated employing a co-culture bioassay with dissociated primary sensory neurons. Following differentiation, MSCs underwent morphological changes similar to those of cultured Schwann cells and stained positively for all three Schwann cell markers. Quantitative Western blot analysis showed that the levels of S100 and P75 protein were significantly elevated upon differentiation. Differentiated MSCs were also found to enhance neurite outgrowth in co-culture with sensory neurons to a level equivalent or superior to that produced by Schwann cells. These findings support the assertion that MSCs can be differentiated into cells that are Schwann cell-like in terms of both phenotype and function.

Alkaline Phosphatase↗
PubMed2000

Signaling through Ras is essential for ret oncogene-induced cell differentiation in PC12 cells.

Specific germline mutations of the receptor tyrosine kinase, Ret, predispose to multiple endocrine neoplasia types 2A and 2B and familial medullary thyroid carcinoma. The mechanisms by which different Ret isoforms (Ret-2A and Ret-2B) cause distinct neoplastic diseases remain largely unknown. On the other hand, forced expression of these mutated versions of Ret induces the rat pheochromocytoma cell line, PC12, to differentiate. Here we used an inducible vector encoding a dominant-negative Ras (Ras p21(N17)) to investigate the contributions of the Ras pathway to the phenotype induced in PC12 cells by the expression of either Ret-2A or Ret-2B mutants. We show that the Ret-induced molecular and morphological changes are both mediated by Ras-dependent pathways. However, even though inhibition of Ras activity was sufficient to revert Ret-induced differentiation, the kinetics of morphological reversion of the Ret-2B- was more rapid than the Ret-2A-transfected cells. Further, we show that in Ret-transfected cells the suc1-associated neurotrophic factor-induced tyrosine phosphorylation target, SNT, is chronically phosphorylated in tyrosine residues, and associates with the Sos substrate. These results indicate the activation of the Ras cascade as an essential pathway triggered by the chronic active Ret mutants in PC12 cells. Moreover, our data indicate SNT as a substrate for both Ret mutants, which might mediate the activation of this cascade.

Adaptor Proteins, Signal Transducing↗
PubMed1975

Induction of T-cells differentiation in vitro by thymus epithelial cells.

Thymus-reticular epithelial cells (TE-cells) were grown in a cell culture devoid of any lymphocytic elements. These cells were able to induce T-cell differentiation in spleen cells from T-dificient mice as expressed by con-A responsiveness and GvH reactivity. It was also shown that xenogeneic rat TE cells were as effective in the induction of T-cell differentiation in vitro as syngeneic TE cells. This system is therefore ideal for the study of T-cell development.

Animals↗
PubMed1987

Anti-HLA-class II monoclonal antibodies inhibit polyclonal B cell differentiation in vitro at the accessory cell level.

We produced and characterized a panel of anti-HLA class II monoclonal antibodies (mAb) to study the inhibition of T cell-dependent B cell differentiation. The newly produced mAb belonged to different isotypes and subclasses, and recognized at least two different nonpolymorphic HLA class II determinants. We found that anti-HLA class II mAb inhibited the pokeweed mitogen (PWM)- and interleukin 2-driven T cell-dependent IgM synthesis, but did not affect the phorbol myristate acetate-, phytohemagglutinin-, anti-T3- or PWM-induced T cell proliferation. Moreover, when the mAb were tested in a monocyte-independent B cell differentiation assay in which T cells are activated by insoluble anti-T3 mAb in the absence of accessory cells, no effect was seen on IgM synthesis. These data indicate that inhibition of T cell-dependent B cell differentiation by anti-HLA class II mAb is caused by interference with an accessory cell function essential for B cell differentiation.

Antibodies, Monoclonal↗