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[Interferon production in suspensions of swine and human leukocytes on media containing aminopeptide, hemohydrolysate and bovine amniotic fluid].

Production of different kinds of interferon in imported media (medium 199, Eagle's medium) greatly impedes the organization of large-scale interferon production in this country. The search for national substitutes of these media is important therefore. This paper deals with a comparative study of the use of national aminopeptide and hemohydrolysate preparations for interferon production. It was shown that substitution of serum with BAF in preparations of human and swine interferon increased their activity 2- and 4-fold, respectively, and the amount of protein was reduced 10-fold. Specimens of interferons produced with the addition of AP were less effective because the amount of protein increased 4-20-fold while the antiviral activity increased insignificantly. The most effective were interferon preparations obtained with hemohydrolysate medium. Their activity being similar, the amount of protein in interferon samples increased 11/2-2-fold only. Thus, aminopeptide and hemohydrolysate can effectively substitute medium 199 for production of leukocyte human and swine interferon.

Amniotic Fluid↗

PubMed1984

Freeze-fracture of 2-cell mouse embryos. A new method for fracture of very small and scarce biological samples.

Membrane morphology and development of intercellular junctions in 2-cell mouse embryos was studied with freeze-fracture electron microscopy. In order to circumvent the dual problem of relative scarcity of samples and their very small size (about 50 micrometers per blastomere), both of which made conventional microtomy-induced freeze-cleavage impractical, a new protocol for handling 2-cell embryos was derived from freeze-fracture procedures established for monolayer cultures. Freshly-collected 2-cell embryos were placed within a 2 mm2 area on plastic Thermonox or Polystyrene coverslips which had been previously coated with 0.002% poly-l-lysine. The embryos were then fixed in 2.5% glutaraldehyde buffered to pH 7.3 with sodium cacodylate and containing 0.01% ruthenium red. The embryos were washed three times in buffer and then glycerinated. The next day, the 2 mm2 area of coverslip containing the embryos (75-100) was cut out with a fine scalpel, inverted and placed on a drop of Elvanol-glycerol mixture and frozen in a slurry of liquid nitrogen-cooled Freon-22. Fracturing was achieved in a Balzers BAF 301 Freeze-Etch Unit by positioning the microtome blade underneath a corner of the inverted coverslip and raising the knife until the coverslip 'popped off'. This procedure left the surface of the Elvanol droplet covered with fractured embryos. The exposed tissue was shadowed with platinum and coated with carbon. This protocol produces large expanses of blastomere plasma membrane as well as cross-fractures of entire blastomeres and 2-cell embryos. The replicas revealed blastomeres endowed with a rich assortment of pleomorphic microvilli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Expression and activation of B-Raf kinase isoforms in human and murine leukemia cell lines.

The B-raf/c-Rmil proto-oncogene belongs to the raf/mil family of serine/threonine protein kinases. It encodes multiple protein isoforms previously shown to be expressed predominantly in neural tissues. We report here that B-Raf proteins of 95 and 72 kDa are also expressed in various human and murine hematopoietic cell lines. Their relative level of expression is variable depending on the cell line examined. The highest level of expression of p95B-raf was found in UT-7 cells, a human pluripotent cell line established from a patient with a megakaryoblastic leukemia. These cells are able to differentiate toward erythroid or myeloid lineage phenotypes in presence of erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) respectively. We show that treatment of UT-7 cells with EPO, GM-CSF or stem cell factor (SCF) rapidly induces phosphorylation of p95B-raf as indicated by a shift of electrophoretic mobility. This increase in phosphorylation is correlated with a three-fold increase of B-Raf kinase activity. B-Raf activation also increases in a dose-dependent manner in response to EPO and GM-CSF. We also show that both p95B-raf and p72B-raf can be activated by IL-3 in murine BAF-3 pro-B cells and by anti-CD3 in human Jurkat cells, respectively. These observations provide the first evidence that the B-Raf kinase is involved in signal transduction pathways regulating proliferation and differentiation of hematopoietic cells of both myeloid and lymphoid lineages.

Animals↗

PubMed1995

Ultraviolet B light induces G1 arrest in human melanocytes by prolonged inhibition of retinoblastoma protein phosphorylation associated with long-term expression of the p21Waf-1/SDI-1/Cip-1 protein.

UVB irradiation inhibits melanocyte proliferation by causing arrest in G1 (D. Barker, K. Dixon, E. E. Medrano, D. Smalara, S. Im, D. Mitchell, G. Babcock, and Z. A. Abdel-Malek. Cancer Res., 55: 4041-4046, 1995). To determine how, after UVB irradiation, signal transduction pathways, DNA damage, and cell cycle arrest interact in the human melanocyte, we analyzed here the possible activation of tyrosine kinases, the serine-threonine kinases Baf-1 and ERK2, the status of the transcription factor c-fos, and the activation of cell cycle checkpoints induced by expression of p53 protein. We found that in contrast to the UVC response, exposure to UVB irradiation did not stimulate the above kinases. UVB light induced a prolonged c-fos expression, suggesting a mechanism of induction different from the transient expression elicited by growth factors. The tumor suppressor p53 and the p53-inducible cyclin-dependent kinase inhibitor protein p21Waf-1/SDI-1/Cip-1 were expressed at high levels for at least 2 days after UV-irradiation. In parallel, phosphorylation of Rb, the retinoblastoma tumor suppressor gene product, was halted in UVB-irradiated cells and correlated with the expression of the protein p21Waf-1/SDI-1/Cip-1. Our data define for the first time how UVB irradiation affects the expression of crucial regulatory events needed for cell cycle progression in the human melanocyte.

Cells, Cultured↗

PubMed1995

[The cholesterol esterase activity of the blood monocytes and alveolar macrophages in patients with chronic bronchitis].

The activity of cholesterol esterase (CE) in blood monocytes and alveolar macrophages (AMF) of bronchoalveolar fluid (BAF) according to Brecher et al., cell composition of endobronchial cytogram were investigated in 32 patients with chronic bronchitis (CB) and control subjects. In CB sufferers CE activity in AMF was inhibited, while in monocytes it was elevated reaching maximal values in purulent bronchopulmonary CB. Determination of CE activity in AMF and peripheral blood monocytes in CB may serve an additional diagnostic indicator of impaired lipid metabolism and suggests new approaches to investigation of CB pathogenesis.

Adult↗

PubMed1996

Extracellular truncations of h beta c, the common signaling subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5, lead to ligand-independent activation.

The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c-derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid-specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling.

Animals↗

PubMed1996

Selective cooperation of HTLV-1-encoded p40tax-1 with cellular oncoproteins in the induction of hematopoietic cell proliferation.

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL). The virus-encoded p40tax-1, a nuclear oncoprotein, is known to promote transcription of its own as well as a variety of cellular genes. However, the mechanism by which p40tax-1 promotes lymphocyte transformation is not fully understood. In the present study, we examined whether p40tax-1 can induce hematopoietic cell proliferation by cooperating with the products of cellular proto-oncogenes; i.e. an activated form of the src-family protein tyrosine kinase p56lck (lck F505), c-Myc or Bcl-2. These oncoproteins are critical mediators of interleukin 2 (IL-2)-induced proliferative signals. We show that p40tax-1 alone cannot render the hematopoietic cell line, BAF-B03, able to proliferate in the absence of cytokines, but it can do so in cooperation with lckF505, or c-Myc but not with Bcl-2.

Animals↗

PubMed1996

The product of the v-src-inducible gene nr-13 is a potent anti-apoptotic factor.

Tumorigenesis can be induced either by activating cell proliferation or by inhibiting metabolic pathways regulating programmed cell death (apoptosis). There is evidence suggesting that p60(v-src) and other tyrosine kinases protect cells against apoptosis. This effect could contribute to cell transformation by the Rous sarcoma virus. Mechanism of cell death inhibition by p60(v-src) remains largely unknown. We have recently reported that in avian cells p60(v-src) activates the expression of nr-13, a bcl-2-related gene. In this paper, we demonstrate, using the bone marrow derived cell line Baf-3 as an experimental model, that the product of this avian gene (nr-13) is a potent anti-apoptotic factor. In addition, we report that, in quail neuroretinal cells, nr-13 expression is activated upon infection by the Rous sarcoma virus (RSV) but not by other oncogenic retroviruses like FSV or MH2, suggesting that nr-13 is a specific target of v-src. Activation of nr-13 expression may be a key step in cellular transformation by v-src.

Animals↗

PubMed1996

Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor beta c chain.

BAG-1 is a Bci-2-binding protein which functions in protection from apoptotic cell death. Here we provide evidence for interleukin-2 (IL-2)-mediated upregulation of BAG-1 expression. In hematopoietic cell line BAF-B03 F7 cells, gene transfer mediated expression of the IL-2R beta c chain is sufficient to confer proliferation and cell survival responses to IL-2. In these IL-2R beta c-expressing cells, BAG-1 mRNA was dramatically induced by IL-2. The IL-2-mediated induction of BAG-1 expression required the activation of tyrosine kinase(s) and was sensitive to rapamycin as the induction of bcl-2 expression was. Analysis of the transfectants which express mutant IL-2R beta c chains or mutant Janus family protein tyrosine kinase Jak3 lacking the kinase domain showed that the IL-2-mediated BAG-1 gene expression required the serinerich region within the IL-2R beta c chain, but Jak3 activation was dispensable. The signaling pathway for BAG-1 gene expression thus highly resembles that for bcl-2 gene expression, strongly suggesting that their induction shares the same signaling pathway. In addition, deletion of the serine-rich region led to loss of IL-2-mediated protection from apoptotic cell death. Taken together, these studies demonstrate that the serine-rich region of the IL-2R beta c chain mediates the coordinated expression of bcl-2 and BAG-1 genes, thereby contributing to suppression of apoptosis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1998

Multiple pathways of neuronal death induced by DNA-damaging agents, NGF deprivation, and oxidative stress.

Here, we compare the pathways by which DNA-damaging agents, NGF deprivation, and superoxide dismutase 1 (SOD1) depletion evoke apoptosis of sympathetic neurons. Previous work raised the hypothesis that cell cycle signaling plays a required role in neuronal apoptosis elicited by NGF deprivation and the DNA-damaging agent camptothecin. To test this hypothesis, we extended our investigation of DNA-damaging agents to cytosine arabinoside (AraC) and UV irradiation. As with NGF deprivation and camptothecin treatment, the cyclin-dependent kinase inhibitors flavopiridol and olomoucine protected neurons from apoptosis induced by AraC and UV treatment. These observations support the model that camptothecin, AraC, and UV treatment cause DNA damage, which leads to apoptosis by a mechanism that, as in the case of NGF deprivation, includes activation of cell cycle components. Flavopiridol and olomoucine, however, had no effect on death induced by SOD1 depletion, suggesting that CDKs do not play a role in this paradigm of neuronal death. To compare further the mechanisms of death evoked by NGF withdrawal, SOD1 depletion, and DNA-damaging agents, we investigated their responses to inhibitors of cysteine aspartases, elements of apoptotic pathways. The V-ICEinh and BAF, two peptide inhibitors of cysteine aspartases, protected neurons in all three death paradigms. In contrast, the cysteine aspartase inhibitory peptide zVAD-fmk conferred protection from NGF withdrawal and SOD1 depletion, but not DNA-damaging agents, whereas acYVAD-cmk protected only from SOD1 depletion. Taken together, these findings indicate that three different apoptotic stimuli activate separate pathways of death in the same neuron type.

Animals↗

PubMed1997

Dissociation of cytokine signals for proliferation and apoptosis.

Cytokines such as IL-2 or IL-3 prevent cell death through apoptosis, either by preventing apoptosis directly or by sensitizing cells to survival factors present in serum. We demonstrate herein that BAF-B03 cells transfected with the wild-type IL-2R beta-chain undergo apoptosis when stimulated with IL-2 or IL-3 in the absence of serum. IL-2 also induced apoptosis in normal IL-2-responsive human T cell blasts in the absence of serum, and furthermore, epidermal growth factor and fibroblast growth factor induced increased rates of apoptosis in fibroblasts in the absence of serum, suggesting that cytokine-induced apoptosis in the absence of serum survival factors might represent an important biologic phenomenon. In the presence or the absence of serum, IL-2 and IL-3 induced expression of both c-Myc and Bax. In contrast, optimal cytokine-induced expression of Bcl-2 requires serum. Constitutive expression of Bcl-2 prevented cytokine-induced apoptosis. Transferrin mimicked serum by inducing an increase in Bcl-2 expression levels and concurrently prevented apoptosis. These results suggest that the balance between cytokine- and serum-induced Bcl-2 expression and cytokine-induced Bax expression may determine whether a cell undergoes cytokine-induced apoptosis. In BAF/BO3 cells expressing a mutant IL-2Rbeta with a deletion of the acidic domain, IL-2 did not induce either Bax expression or apoptosis. This suggests that the acidic domain of the IL-2R beta-chain plays an essential role in regulating IL-2-mediated Bax expression and apoptosis. Cytokine-induced apoptosis and its counterbalance by survival factors present in serum may play an important role in the regulation of cellular homeostasis during pathophysiologic processes.

Animals↗

PubMed1998

Saturation mutagenesis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential beta subunit tyrosine phosphorylation.

The high-affinity receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are heterodimeric complexes consisting of cytokine-specific alpha subunits and a common signal-transducing beta subunit (hbetac). We have previously demonstrated the oncogenic potential of this group of receptors by identifying constitutively activating point mutations in the extracellular and transmembrane domains of hbetac. We report here a comprehensive screen of the entire hbetac molecule that has led to the identification of additional constitutive point mutations by virtue of their ability to confer factor independence on murine FDC-P1 cells. These mutations were clustered exclusively in a central region of hbetac that encompasses the extracellular membrane-proximal domain, transmembrane domain, and membrane-proximal region of the cytoplasmic domain. Interestingly, most hbetac mutants exhibited cell type-specific constitutive activity, with only two transmembrane domain mutants able to confer factor independence on both murine FDC-P1 and BAF-B03 cells. Examination of the biochemical properties of these mutants in FDC-P1 cells indicated that MAP kinase (ERK1/2), STAT, and JAK2 signaling molecules were constitutively activated. In contrast, only some of the mutant beta subunits were constitutively tyrosine phosphorylated. Taken together, these results highlight key regions involved in hbetac activation, dissociate hbetac tyrosine phosphorylation from MAP kinase and STAT activation, and suggest the involvement of distinct mechanisms by which proliferative signals can be generated by hbetac.

Animals↗

PubMed1998

Caspase-2 (Nedd-2) processing and death of trophic factor-deprived PC12 cells and sympathetic neurons occur independently of caspase-3 (CPP32)-like activity.

We have previously shown that caspase-2 (Nedd-2) is required for apoptosis induced by withdrawal of trophic support from PC12 cells and sympathetic neurons. Here, we examine the relationship of caspase-2 processing and cell death to induction of caspase-3 (CPP32)-like activity in PC12 cells. Caspase-2 processing, at a site tentatively identified as D333, led to the formation of an N-terminal 37 kDa product. This processing correlated temporally with induction of caspase-3-like activity. Agents previously shown to inhibit caspase-3-like activation, such as bcl-2 and the Cdk inhibitor flavopiridol, also acted upstream of caspase-2 processing. The general caspase inhibitors BAF and zVAD-FMK inhibited N-terminal caspase-2 processing. In contrast, the more selective caspase inhibitor DEVD-FMK inhibited the induction of caspase-3-like activity but did not affect caspase-2 processing or significantly suppress death in PC12 cells or sympathetic neurons. This indicates that caspase-3-like activity is not required for either caspase-2 processing or apoptosis in this paradigm. An antisense oligonucleotide to caspase-2 inhibited cell death but did not affect caspase-3-like activity, indicating that caspase-2 is not upstream of this activity and that activation of caspase-3-like caspases is not sufficient for death. Thus, in our paradigm, caspase-2 processing and caspase-3-like activity are induced independently of each other. Moreover, although death requires caspase-2, caspase-3-like activity is neither necessary nor sufficient for death.

Amino Acid Chloromethyl Ketones↗

PubMed1998

Functional cooperation of cyclin C and c-Myc in mediating homotypic cell adhesion via very late antigen-4 activation and vascular cell adhesion molecule-1 induction.

Very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1) are a pair of adhesion molecules mediating cell-cell interaction. The binding activity of each depends on its surface expression, yet integrin activity can also be modulated through inside-out signaling. However, the specific intracellular molecules involved in modulating integrin VLA-4 activation via inside-out signaling or in regulating VCAM-1 expression are poorly understood. We show here that constitutive coexpression of cyclin C and c-Myc in hematopoietic BAF-B03 cells induces homotypic cell adhesion, which results from enhanced VLA-4 ligand-binding activity and induced expression of VCAM-1. Furthermore, regulation of cell adhesion appears to be a feature unique to cyclin C, but not other G1 cyclins, E and D3, and its regulatory function is independent of CDK8 kinase activity. Our results provide a novel role for cyclin C and c-Myc in the regulation of cell adhesion through distinct mechanisms.

Animals↗

PubMed1999

Generation of neuronal intranuclear inclusions by polyglutamine-GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length.

Recent evidence suggests that, in huntingtin and many other proteins, polyglutamine repeats are a toxic stimulus in neurodegenerative diseases. To investigate the mechanism by which these repeats may be toxic, we transfected primary rat cerebellar granule neurons with polyglutamine-green fluorescent protein (GFP) fusion constructs containing 19 (Q19-GFP), 35 (Q35-GFP), 56 (Q56-GFP), or 80 (Q80-GFP) glutamine residues. All constructs, except Q19-GFP, aggregated within the nuclei of transfected cells in a length- and time-dependent manner. Although Q35-GFP expression led to the development of several small aggregates per cell, these aggregates were cleared or degraded, and the cells remained viable. In contrast, Q80-GFP expression resulted in one or two large aggregates and induced cell death. Caspase activation was observed after Q80-GFP aggregation, but inhibition of caspases with Boc-aspartyl(OMe)-fluoromethylketone (BAF) only served to delay, not prevent, toxicity. In addition, aggregation and toxicity were not affected by other modulators of neuronal cell death such as genetic deletion of the proapoptotic bcl-2 family member bax or addition of the protein synthesis inhibitor cycloheximide. Lastly, nuclear condensation did not occur as part of the toxicity. These data suggest that polyglutamine-GFP expression is toxic to primary neurons but that the death is distinct from classical apoptosis.

Animals↗

PubMed1994

Alterations in monoamine levels in discrete regions of rat brain after chronic administration of carbamazepine.

Carbamazepine (25 mg/kg body weight) was administered intraperitoneally to adult male Wistar rats for 45 days and norepinephrine (NE), dopamine (DA) and serotonin (5-HT) levels were simultaneously assayed in discrete brain regions by high performance liquid chromatographic (HPLC) method. Experimental rats displayed no behavioral abnormalities. Body and brain weights were not significantly different from control group of rats. After exposure it was observed that norepinephrine levels were elevated in motor cortex (P < 0.01) and cerebellum (P < 0.05), while dopamine levels were decreased in these two regions (P < 0.001, P < 0.05). However, dopamine levels were increased in hippocampus (P < 0.01). Serotonin levels were significantly decreased in motor cortex (P < 0.001) and hypothalamus (P < 0.001) but increased in striatum-accumbens (P < 0.001) and brainstem (P < 0.001). These results suggest that carbamazepine may mediate its anticonvulsant effect by differential alterations of monoamine levels in discrete brain regions particularly in motor cortex and cerebellum.

Animals↗

PubMed1995

The effect of chronic chlorpromazine administration on monoamine levels in various regions of rat brain.

The neuroleptic drug, chlorpromazine (CPZ) has been shown to exert its antipsychotic effect by blocking post synaptic dopamine receptors. However, its effect on steady state levels of monoamines is still in discrepancy. In the present study, CPZ (4 mg/kg body weight) was administered intraperitoneally to adult Wistar rats chronically for 75 days and the levels of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) were assayed in various brain regions by high performance liquid chromatography (HPLC). After the experimental period body and brain weights were not statistically different from controls. NE and 5-HT levels were increased only in hippocampus by 15% (p < 0.01) and 16% (p < 0.01) respectively. DA levels were consistently increased in cortex by 39% (p < 0.001), striatum-accumbens by 18% (p < 0.01), hippocampus by 27% (p < 0.01), hypothalamus by 34% (p < 0.001), cerebellum by 36% (p < 0.001) and brainstem by 40% (p < 0.001) in CPZ treated rats compared to controls. The results suggest that chronic CPZ administration increases DA levels in almost all regions of brain and reflect the ability of CPZ to preferentially interfere with synaptic transmission mediated by DA in brain. It also suggests that this increase in DA might be responsible for certain side effects seen in patients after chronic CPZ treatment.

Animals↗

PubMed1994

Sodium valproate induced alterations in monoamine levels in different regions of the rat brain.

Sodium valproate is a well established anticonvulsant drug but its exact mode of action is not yet clear. With a view to find out whether the mechanism of action of sodium valproate is mediated by alteration in monoamine levels, apart from GABA, in brain, sodium valproate (200 mg/kg body wt) was administered i.p. to male adult Wistar rats for 45 days. The levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed in different brain regions using high performance liquid chromatographic (HPLC) method. It was noted that at the end of the experimental period there was no change in body or brain weight nor were there any neurological deficits as a result of sodium valproate administration. However, after administration of sodium valproate there was a significant increase in norepinephrine levels in hippocampus (P < 0.01) and brainstem (P < 0.01) while a significant decrease was noted in hypothalamus (P < 0.001). Dopamine levels were significantly increased in motor cortex (P < 0.01), hippocampus (P < 0.01) and hypothalamus (P < 0.001). Serotonin levels were significantly increased in striatum-accumbens and brain stem (P < 0.001). However a marginal increase was also observed in motor cortex and hippocampus. 5-HT levels were significantly decreased in hypothalamus (P < 0.001) and cerebellum (P < 0.01). The present findings suggest the possibility that the anticonvulsant effect of sodium valproate could be due to alterations in monoamine levels apart from its action on GABA, which would indicate also the efficacy of this drug in different types of seizures.

Animals↗