Biomedical subjects

J S Verbeek

Publications and source records attributed to J S Verbeek.

27 records · Page 2Linked to original sources

PubMed1994

Heterogeneity of human IgG Fc receptors.

The complex family of human IgG Fc receptors show a wide cellular distribution and a strong functional heterogeneity. To date, eight different genes that are transcribed into at least 12 different mRNAs have been recognized. Although corresponding products have been identified for only some of the transcripts, in vivo at least six different Fc gamma R isoforms are shown to be present on the surface of all kinds of leukocytes. Upon interaction with immunoglobulin, Fc gamma R mediate a variety of biological responses such as phagocytosis, endocytosis, release of inflammatory mediators, and antibody-dependent cellular cytotoxicity. One of the main questions in Fc gamma R research is determining the specific relationship between a particular Fc gamma R isoform and a particular effector mechanism. The availability of the cDNA and genomic clones corresponding to the different isoforms, combined with different gene transfer systems in vitro and in vivo and the recently developed procedure of gene knockout by homologous recombination, allows the generation of stably transfected cell lines and transgenic animals that express one particular Fc gamma R isoform. These model systems enable us to study the function of a particular Fc gamma R isoform in the context of a particular cell type in vitro and in the context of the intact immune system in vivo.

Genes, Immunoglobulin↗

PubMed1994

Human islet amyloid polypeptide accumulates at similar sites in islets of transgenic mice and humans.

The cellular mechanisms responsible for conversion of islet amyloid polypeptide (IAPP) into insoluble amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP and the amino acid sequence of human IAPP (hIAPP) have both been implicated. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These mice had elevated plasma IAPP concentrations, and they were normoglycemic and normoinsulinemic. No amyloid deposits were detected by light microscopy. To examine the ultrastructure of islets, pancreatic tissue was studied from hIAPP and rIAPP transgenic mice and from age-matched control mice by immunoelectron microscopy. IAPP was immunolocalized in beta-cell secretory granules of all mice, and the COOH- and NH2-terminal flanking peptides of hIAPP were localized in beta-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreactive material were found between capillaries and beta-cells in hIAPP transgenic mice but not in rIAPP transgenic or control mice. Similar nonfibrillar masses were identified in islets of an NIDDM patient. Secondary lysosomes in beta-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by beta-cell lysosomes. Accumulations of IAPP in islet perivascular spaces may represent the early stages of islet amyloid formation.

Aged↗

PubMed1993

Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia.

Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloid↗

PubMed1987

Structural analysis of a variant clone of Snyder-Theilen feline sarcoma virus.

A variant clone of Snyder-Theilen feline sarcoma virus (ST-FeSV) encoding a polyprotein with a molecular weight of approximately 104 kDa (P104) was compared to the P85 encoding prototype clone of ST-FeSV. Analysis of chimeric genes constructed with the viral oncogenes of the two clones indicated that the variant clone coded for a larger polyprotein than the prototype clone because of genetic differences in its 3' portion. Comparative DNA sequence analysis revealed that one nucleotide just upstream of the termination condon TGA in the prototype proviral DNA was deleted from the variant clone resulting in a 468-bp larger open reading frame. Furthermore, it appeared that the U3 regions of the long terminal repeats (LTRs) of the variant clone contained an insertion of 71 bp as compared to the LTRs of the prototype clone. In addition, both clones differed also from each other with respect to genetic sequences deleted from their env gene regions.

Base Sequence↗

PubMed1985

The structure of the human c-fes/fps proto-oncogene.

We have determined the complete nucleotide sequence of a human DNA fragment of approximately 13 kbp, which was shown by Southern blot analysis to contain the entire v-fes/fps cellular homolog. The v-fes/fps homologous sequences were dispersed over 11 kbp in 18 interspersed segments which were flanked by splice junctions. Fusion of these segments created a DNA fragment in which coding regions similar to those observed in the viral oncogenes v-fes of the Gardner-Arnstein (GA) and Snyder-Theilen (ST) strains of feline sarcoma virus and v-fps found in Fujinami sarcoma virus could be identified. A potential initiation site in the first exon was found. About 200 nucleotides downstream of a translational stop codon in the v-fes/fps homologous region, a poly(A) addition signal was identified. The deduced amino acid sequence has a molecular weight of 93 390 dalton resembling NCP92, the recently described human c-fes/fps product. The topography of human c-fes/fps appeared to resemble that of chicken c-fps.

Amino Acid Sequence↗

PubMed1985

Molecular cloning and characterization of feline cellular genetic sequences homologous to the oncogene of the McDonough strain of feline sarcoma virus.

The organization within the cat genome of cellular genetic sequences homologous to the viral oncogene v-fms of the McDonough strain of feline sarcoma virus (SM-FeSV) was determined. Four cosmid clones containing overlapping v-fms homologous cellular DNA inserts representing a contiguous region of cellular DNA of approximately 80 kbp in length have been isolated from a feline cosmid gene library. Within this region of the cat genome, the c-fms genetic sequences are dispersed over a region of around 30 kbp and are interspersed with at least three intervening sequences.

Animals↗

PubMed1985

Molecular cloning of the feline c-fes proto-oncogene and construction of a chimeric transforming gene.

The feline c-fes proto-oncogene, different parts of which were captured in feline leukemia virus (FeLV) to generate the transforming genes (v-fes) of the Gardner-Arnstein (GA) strain of feline sarcoma virus (FeSV) and the Snyder-Theilen strain (ST) of FeSV, was cloned and its genetic organization determined. Southern blot analysis revealed that the c-fes genetic sequences were distributed discontinuously and colinearly with the v-fes transforming gene over a DNA region of around 12.0 kb. Using cloned c-fes sequences, complementation of GA-FeSV transforming activity was studied. Upon replacement of the 3' half of v-fesGA with homologous feline c-fes sequences and transfection of the chimeric gene, morphological transformation was observed. Immunoprecipitation analysis of these transformed cells revealed expression of high Mr fusion proteins. Phosphorylation of these proteins was observed in an in vitro protein kinase assay, and tyrosine residues appeared to be involved as acceptor amino acid.

Animals↗

PubMed1985

A hereditary abnormal c-fms proto-oncogene in a patient with acute lymphocytic leukaemia and congenital hypothyroidism.

A patient with congenital hypothyroidism and acute lymphocytic leukaemia was found to be homozygous for a 0.4 kbp deletion in the c-fms proto-oncogene. This was established by studying DNA from the patient's leukaemic cells, from cultured skin fibroblasts of the patient and from normal white blood cells of both parents. The uncertain relevance of this finding to the condition of the patient is discussed.

Adolescent↗

PubMed1985

Human c-fms proto-oncogene: comparative analysis with an abnormal allele.

The organization of the human c-fms proto-oncogene has been determined and compared with an abnormal allele. The human v-fms homologous genetic sequences are dispersed discontinuously and colinearly with the viral oncogene over a DNA region of ca. 32 kilobase pairs. The abnormal c-fms locus contains a small deletion in its 3' portion. DNA sequencing analysis indicated that it was 426 base pairs in size and located in close proximity to a putative c-fms exon.

Alleles↗