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C Schindler

Publications and source records attributed to C Schindler.

At least 127 records · Page 7Linked to original sources
PubMed1994

[Creutzfeldt-Jakob disease. Report of a case with an unusually long course and immunohistochemical localization of the prion protein and overview of current information].

The human spongiform encephalopathies are a group of neurodegenerative disorders of unknown origin. They comprise a group of horizontally transmissible and genetically determined diseases. We present here a case of Creutzfeldt-Jakob disease with an unusually long clinical course, in which the prion protein was localized immunohistochemically. The generally accepted hypothesis on the pathogenesis of these diseases is the so-called 'prion-hypothesis'. The implications of this hypothesis are discussed and a short review of the literature is given.

Atrophy↗
PubMed1993

Characterization of a pathway for ciliary neurotrophic factor signaling to the nucleus.

Components of a signaling pathway that couples the ciliary neurotrophic factor (CNTF) receptor to induction of transcription were identified. CNTF stimulated the tyrosine phosphorylation of p91, a protein implicated in interferon signaling pathways, and of two proteins that are distinct but related to p91. Tyrosine-phosphorylated p91 translocated to the nucleus, where p91 and p91-related proteins bound to a DNA sequence found in promoters of genes responsive to CNTF. This DNA sequence, when inserted upstream of a reporter gene, conferred a transcriptional response to CNTF. A pathway that transduces interferon signals may therefore have a more general function in the propagation of responses to certain neurotrophic factors.

Base Sequence↗
PubMed1993

The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction.

We have produced a cell line which lacks the protein tyrosine kinase JAK1 and is completely defective in interferon response. Complementation of this mutant with JAK1 restored the response, establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways. The reciprocal interdependence between JAK1 and Tyk2 activities in the interferon-alpha pathway, and between JAK1 and JAK2 in the interferon-gamma pathway, may reflect a requirement for these kinases in the correct assembly of interferon receptor complexes.

Animals↗
PubMed1993

Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway.

Interferons (IFNs) alpha/beta (type I) and gamma (type II) bind to distinct cell surface receptors, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention. Previous studies using cell lines selected for their inability to respond to IFN-alpha (ref. 4) have shown that the protein kinase Tyk2 plays a central role in the IFN alpha/beta response. Here we report the isolation of the cell line gamma 1A, selected for its inability to express IFN-gamma-inducible cell-surface markers, that is deficient in all aspects of the IFN-gamma response tested, but responds normally to IFNs alpha and beta. The mutant cells can be complemented by the expression of another member of the JAK family of protein tyrosine kinases, JAK2 (refs 6-9). Unlike IFNs alpha and beta, IFN-gamma induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine kinase activity. These responses are absent in gamma 1A cells. JAK2 is therefore required for the response to IFN-gamma but not to IFNs alpha and beta.

Animals↗
PubMed1993

Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation.

Interferons induce transcriptional activation through tyrosine phosphorylation of the latent, cytoplasmic transcription factor interferon-stimulated gene factor-3 (ISGF-3). Growth factors and cytokines were found to use a similar pathway: The 91-kilodalton subunit of ISGF-3 was activated and tyrosine phosphorylated in response to epidermal growth factor (EGF), platelet-derived growth factor, and colony stimulating factor-1. The tyrosine phosphorylated factor acquired DNA binding activity and accumulated in nuclei. Activation required the major sites for autophosphorylation on the EGF receptor that bind Src homology region 2 domain-containing proteins implicated in Ras activation. However, activation of this factor was independent of the normal functioning of Ras.

3T3 Cells↗
PubMed1993

The gene encoding IFP 53/tryptophanyl-tRNA synthetase is regulated by the gamma-interferon activation factor.

We have obtained genomic DNA encoding the interferon-gamma (IFN-gamma)-inducible IFP 53/tryptophanyl-tRNA synthetase. Comparison with several different IFP 53 cDNA clones revealed a complex pattern of alternatively spliced 5'-untranslated regions. The interferon-responsive region within the IFP 53 promoter was found to contain a gamma-interferon activation site (GAS) but not the interferon-stimulated response element and to bind the gamma-interferon activation factor (GAF). GAF.GAS complexes contained the IFN-regulated 91-kDa protein. Competition experiments defined the GAS boundaries and showed that GAF binding to the IFP 53 GAS could be prevented by an excess of the IFN-gamma response regions of several other IFN-gamma-inducible genes. We thus provide evidence for a central role of GAS.GAF in gene transcription mediated by IFN-gamma and suggest a consensus sequence defining more precisely the requirements for GAF binding to DNA.

Base Sequence↗
PubMed1993

[Acute pancreatitis and stomach wall necrosis caused by cholesterol embolisms].

A 60-year-old man was hospitalized because of a sudden onset of severe pain in the epigastrium and haematemesis. Acute pancreatitis was diagnosed on the basis of an increased serum amylase concentration (642 U/l). Abdominal ultrasound and computed tomography demonstrated a necrotic zone with central liquefaction in the tail of the pancreas adjoining the stomach wall. Gastroscopy revealed as source of the bleeding an extensive mucosal necrosis at the greater curvature of the stomach. At laparotomy, partial resection of the pancreas, gastrectomy and splenectomy were performed. Histological examination of the resected specimens showed multiple cholesterol emboli in the small arteries of the pancreas and the gastric submucosa.

Acute Disease↗
PubMed1993

Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways.

Mutants in complementation group U3, completely defective in the response of all genes tested to interferons (IFNs) alpha and gamma, do not express the 91 and 84 kDa polypeptide components of interferon-stimulated gene factor 3 (ISGF3), a transcription factor known to play a primary role in the IFN-alpha response pathway. The 91 and 84 kDa polypeptides are products of a single gene. They result from differential splicing and differ only in a 38 amino acid extension at the C-terminus of the 91 kDa polypeptide. Complementation of U3 mutants with cDNA constructs expressing the 91 kDa product at levels comparable to those observed in induced wild-type cells completely restored the response to both IFN-alpha and -gamma and the ability to form ISGF3. Complementation with the 84 kDa component similarly restored the ability to form ISGF3 and, albeit to a lower level, the IFN-alpha response of all genes tested so far. It failed, however, to restore the IFN-gamma response of any gene analysed. The precise nature of the DNA motifs and combination of factors required for the transcriptional response of all genes inducible by IFN-alpha and -gamma remains to be established. The results presented here, however, emphasize the apparent general requirement of the 91 kDa polypeptide in the primary transcriptional response to both types of IFN.

Base Sequence↗
PubMed1993

Early events in signalling by interferons.

The heterogeneity of the biological responses to alpha/beta and gamma interferons, the degree of overlap, synergy and antagonism appear to reflect functional interactions between these two signalling pathways. Recent biochemical and genetic experimental approaches have identified some of the effector proteins involved in interferon signalling, and have advanced our understanding of the crosstalk between these signalling networks.

Animals↗
PubMed1993

Effects of infused sodium acetate, sodium lactate, and sodium beta-hydroxybutyrate on energy expenditure and substrate oxidation rates in lean humans.

Infusion of sodium acetate in lean humans results in a decrease in respiratory exchange ratio, which may be advantageous in patients with respiratory failure. However, this potential decrease in respiratory work was observed to be offset by significant thermogenesis. The metabolic effects of sodium acetate, sodium lactate, and sodium beta-hydroxybutyrate, infused at a rate of 20 mumol.kg-1.min-1 for 3 h, was monitored in six healthy human volunteers. Respiratory exchange ratio decreased from 0.85 +/- 0.02 at baseline to 0.75 +/- 0.02, 0.75 +/- 0.02, and 0.80 +/- 0.02, after acetate, lactate, or beta-hydroxybutyrate, respectively (P < 0.05 for each). Acetate produced a larger thermic effect (22.7% of energy infused) than did lactate (16.3%) or beta-hydroxybutyrate (13.6%). Thus, sodium salts of organic acids may potentially decrease the respiratory requirements by decreasing the respiratory exchange ratio. However, this effect is partially offset by the thermic effect of these substrates. The maximal doses and safety of these anions during larger infusion periods remain to be determined.

3-Hydroxybutyric Acid↗
PubMed1993

The response of gamma interferon activation factor is under developmental control in cells of the macrophage lineage.

Gamma interferon activation factor (GAF) rapidly induces transcriptional activation of gamma interferon (IFN-gamma)-responsive genes. Conversion of the GAF from a latent cytoplasmic to an activated, DNA-binding form is an immediate step in the cellular response to IFN-gamma. The amount of IFN-gamma-activated GAF, measured by exonuclease III protection or gel shift assays, increased strongly upon monocytic differentiation of U937 cells. Activated GAF contained the IFN-responsive 91-kDa protein as its DNA-binding activity in gel shift or exonuclease III assays could be inhibited through direct addition of specific antiserum, and it was not present in p91-immunodepleted extracts. There was a differentiation-induced increase in the amount of nonphosphorylated (latent) p91. Transcription rate measurement demonstrated a strong induction of the p91 gene during monocytic differentiation of U937 cells. The amount of p91 which was rapidly phosphorylated in response to IFN-gamma was found to be much higher in the differentiated cells and suggested a differentiation-controlled increase in the signaling leading to p91 phosphorylation. Concomitantly with a better GAF response, transcriptional activation of IFN-gamma-induced genes and the expression of GAF-dependent, transfected reporter plasmids increased in differentiated U937 monocytes. The promonocyte-monocyte transition also affected the IFN-alpha-responsive transcription factor ISGF-3. Differentiated U937 cells contained more of both the alpha-component p91 and the gamma-component p48, which constitutes the DNA-binding subunit of the complex. Our study thus provides evidence that the synthesis of specific transcription factors can be a regulated event to control the cytokine responsiveness of cells during development.

Binding Sites↗
PubMed1993

The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds.

ICSBP, a member of the interferon regulatory factor family, is expressed predominantly in lymphoid tissues and is induced by gamma interferon (IFN-gamma). We have studied the genomic organization of the murine ICSBP gene and its 5' upstream region. The murine ICSBP gene (Icsbp) is present as a single copy on chromosome 8 and consists of nine exons. Transcription initiates at two juxtaposed sites downstream from the TATA and CAAT boxes and produces two species of ICSBP mRNA (3.0 and 1.7 kb), presumably by differential usage of poly(A)+ signals. A sequence from -175 to -155 was identified to be an IFN response region that conferred IFN-gamma induction upon a heterologous promoter in lymphoid cell line EL4. This region includes a motif, TTCNNGGAA, designated the palindromic IFN response element (pIRE), to which an IFN-gamma-inducible, cycloheximide-sensitive factor(s) binds. A similar palindromic motif was found in the upstream region of the murine IRF-1 gene, the IFN-gamma activation site of the guanylate-binding protein gene and the IFN-gamma-responsive region of the Fc receptor type I gene, all of which competed with the pIRE for factor binding in gel mobility shift assays. We show that the pIRE binding factor reacts with the antibody against the 91-kDa subunit of ISGF3 alpha recently shown to bind to the IFN-gamma activation site. These results suggest that this factor is related to the IFN-gamma activation factor and contains the 91-kDa subunit of ISGF3 alpha. Taken together, pIRE represents an IRE that is distinct from the classical IFN-stimulated response element and that is capable of conferring IFN-gamma induction through the binding of the 91-kDa ISGF3 alpha subunit (or an antigenically similar molecule).

Animals↗
PubMed1993

Alterations of thymus cortical epithelium and interdigitating dendritic cells but no increase of thymocyte cell death in the early course of simian immunodeficiency virus infection.

The role of the thymus in the pathogenesis of simian acquired immunodeficiency syndrome was investigated in 18 juvenile rhesus monkeys (Macaca mulatta). The thymus was infected from the first week post-SIVmac inoculation, but the amount of virus-positive cells was very low (< 1 in 10(4) T cells) as demonstrated by polymerase chain reaction and in situ hybridization. First morphological alteration was a narrowing of the cortex at 12 and 24 wpi. Morphometry revealed no increase of pyknotic T cells but a decrease of the proliferation rate and flow cytometry showed a reduction of the immature CD4+/CD8+ double-positive T cells. Ultrastructural analysis revealed vacuolization, shrinkage, and finally cytolysis of the cortical epithelial cells and the interdigitating dendritic cells. Immunofluorescence staining exhibited a widespread loss of cortical epithelial cells. This damage to the thymic microenvironment could explain the breakdown of the intrathymic T cell proliferation. It preceded fully developed simian acquired immunodeficiency syndrome and is therefore considered to play a major role in its pathogenesis.

Animals↗
PubMed1992

Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein.

Interferon-gamma (IFN-gamma) induces the transcription of the gene encoding a guanylate binding protein by activating a latent cytoplasmic factor, GAF (gamma-activated factor). GAF is translocated to the nucleus and binds a DNA element, the gamma-activated site. Through cross-linking and the use of specific antibodies GAF was found to be a 91-kilodalton DNA binding protein that was previously identified as one of four proteins in interferon-stimulated gene factor-3 (ISGF-3), a transcription complex activated by IFN-alpha. The IFN-gamma-dependent activation of the 91-kilodalton DNA binding protein required cytoplasmic phosphorylation of the protein on tyrosine. The 113-kilodalton ISGF-3 protein that is phosphorylated in response to IFN-alpha was not phosphorylated nor translocated to the nucleus in response to IFN-gamma. Thus the two different ligands result in tyrosine phosphorylation of different combinations of latent cytoplasmic transcription factors that then act at different DNA binding sites.

Animals↗
PubMed1992

Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha.

ISGF-3 is an interferon-dependent positive-acting transcription factor that is cytoplasmically activated, possibly through direct interaction with the interferon receptor. The factor has been purified, its component proteins have been separated, and its peptide sequences have been obtained. From the sequences, degenerate oligonucleotide probes were constructed to screen for cDNA clones. Sequencing of the selected clones shows that the 91- and 84-kDa components represent two forms of a previously unknown (to our knowledge) protein. Several antibodies raised against these proteins prove that they indeed do encode protein components of ISGF-3. This work provides reagents to explore the modification of this cytoplasmically activated transcription factor.

Amino Acid Sequence↗
PubMed1992

The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction.

ISGF-3 is a multiprotein transcription factor that is very quickly activated in the cell cytoplasm only after attachment of interferon alpha to the cell surface. To understand the specific cytoplasmic activation of proteins that move to the nucleus and direct increased transcription of specific genes, we have purified and now report completion of the cloning of cDNA encoding the four proteins of ISGF-3. With all of the sequences available, it is clear that three of these proteins are encoded by members of a previously unrecognized gene family. We suggest that proteins encoded by this gene family serve the function of interpreting the fact that a cell surface receptor has bound its ligand so that specific signal transduction to the nucleus can occur.

Amino Acid Sequence↗
PubMed1992

Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor.

The interferon-alpha (IFN-alpha)-stimulated gene factor 3 (ISGF3), a transcriptional activator, contains three proteins, termed ISGF3 alpha proteins, that reside in the cell cytoplasm until they are activated in response to IFN-alpha. Treatment of cells with IFN-alpha caused these three proteins to be phosphorylated on tyrosine and to translocate to the cell nucleus where they stimulate transcription through binding to IFN-alpha-stimulated response elements in DNA. IFN-gamma, which activates transcription through a different receptor and different DNA binding sites, also caused tyrosine phosphorylation of one of these proteins. The ISGF3 alpha proteins may be substrates for one or more kinases activated by ligand binding to the cell surface and may link occupation of a specific polypeptide receptor with activation of transcription of a set of specific genes.

Cell Membrane↗