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J H van Es

Publications and source records attributed to J H van Es.

10 recordsLinked to original sources
PubMed2001

The many faces of the tumor suppressor gene APC.

Inactivation of the tumor suppressor adenomatous polyposis coli (APC) protein is a critical early step in the development of familial and sporadic colon cancer. Close examination of the function of APC has shown that it is a multifunctional protein involved in a wide variety of processes, including regulation of cell proliferation, cell migration, cell adhesion, cytoskeletal reorganization, and chromosomal stability. Tantalizing clues to the different functions of APC have been provided by the identification of proteins interacting with several discrete motifs within APC. Each of these putative functions could link APC inactivation with tumorigenesis. Here, we will summarize recent findings regarding the diverse role of APC. We will emphasize the interaction of APC with different binding partners, the role of these complex interactions for normal functioning of the cell, and how disruption of these interactions may play a role in tumor development. The rapid progress made recently shows the many faces of APC, leading to a constant reappreciation of this multitasking tumor suppressor protein.

Adenomatous Polyposis Coli↗
PubMed2001

Mutations in the APC tumour suppressor gene cause chromosomal instability.

Two forms of genetic instability have been described in colorectal cancer: microsatellite instability and chromosomal instability. Microsatellite instability results from mutations in mismatch repair genes; chromosomal instability is the hallmark of many colorectal cancers, although it is not completely understood at the molecular level. As truncations of the Adenomatous Polyposis Coli (APC) gene are found in most colorectal tumours, we thought that mutations in APC might be responsible for chromosomal instability. To test this hypothesis, we examined mouse embryonic stem (ES) cells homozygous for Min (multiple intestinal neoplasia) or Apc1638T alleles. Here we show that Apc mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation. Consistent with this, APC accumulates at the kinetochore during mitosis. Apc mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores. This phenotype is recapitulated by the induced expression of a 253-amino-acid carboxy-terminal fragment of APC in microsatellite unstable colorectal cancer cells. We conclude that loss of APC sequences that lie C-terminal to the beta-catenin regulatory domain contributes to chromosomal instability in colorectal cancer.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor.

The adenomatous polyposis coli (APC) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta (GSK-3beta), axin/conductin and betacatenin. Complex formation induces the rapid degradation of betacatenin. In colon carcinoma cells, loss of APC leads to the accumulation of betacatenin in the nucleus, where it binds to and activates the Tcf-4 transcription factor (reviewed in [1] [2]). Here, we report the identification and genomic structure of APC homologues. Mammalian APC2, which closely resembles APC in overall domain structure, was functionally analyzed and shown to contain two SAMP domains, both of which are required for binding to conductin. Like APC, APC2 regulates the formation of active betacatenin-Tcf complexes, as demonstrated using transient transcriptional activation assays in APC -/- colon carcinoma cells. Human APC2 maps to chromosome 19p13.3. APC and APC2 may therefore have comparable functions in development and cancer.

Adenomatous Polyposis Coli↗
PubMed1993

VH4.21-encoded natural autoantibodies with anti-i specificity mirror those associated with cold hemagglutinin disease.

The Ig VH regions of virtually all human pathogenic cold agglutinin (CA) anti-i/l autoantibodies are encoded by a single Ig VH gene segment, VH4.21, in conjunction with a highly variable CDR3 structure. The anti-I specificity is often associated with V kappa III-encoded L chains, whereas anti-i autoantibodies appear to use a broader array of kappa and lambda VL gene segments. B cells expressing VH4.21 are abundantly present in adult lymphoid tissues from healthy individuals but their relationship with B cells secreting pathogenic CA is unknown. Herein we have analyzed the distribution of VH4.21-expressing B cells in fetal, neonatal, and adult B cell populations using the monoclonal anti-VH4.21 antibody 9G4. In addition, we have analyzed the anti-i and anti-I binding capacity and V regions of 19 VH4.21-encoded mAb secreted by cord and adult blood-derived cell lines from healthy individuals. The results show that VH4.21 expressing B cells are overrepresented in all repertoires studied and are evenly distributed over cord blood CD5+ and CD5- B cell populations. VH4.21-encoded H chains strongly predispose for anti-i binding capacity, regardless of the VL regions or H chain CDR3 structure. The avidity of some of these antibodies was similar to those of pathogenic CA. In addition, we found evidence for monospecific anti-I binding in antibodies encoded by other members of the VH4 gene family. We conclude that VH4.21-encoded antibodies with anti-i specificity from the normal B cell repertoire mirror their pathogenic counterparts and that naturally occurring anti-I antibodies may be encoded by a more diverse array of VH4 genes.

Agglutinins↗
PubMed1992

Sequence analysis of members of the human Ig VH4 gene family derived from a single VH locus. Identification of novel germ-line members.

We have generated a mouse x human heterohybridoma that contains a single copy of chromosome 14 and, thus, a haploid set of Ig VH genes. This cell line was used to investigate the germ-line content and nucleotide sequences of members of the VH4 gene family in a polymerase chain reaction-based approach. The analysis of 58 full-length sequences revealed the presence of 12 different germ-line VH4 genes, each of which is potentially functional. These germ-line VH4 genes were compared with the nucleotide sequences of published VH4 genes. Three VH4 genes were 100% identical to previously published sequences and belong to a group of VH4 genes that are strongly conserved and highly prevalent in the human population. Three VH4 genes in our collection displayed greater than 99.3% sequence identity with reported germ-line VH4 sequences and likely represent allelic counterparts of these genes. Six genes displayed less than 97.2% sequence identity with published VH4 genes and were identified as novel members of the human VH4 gene family or more distantly related alleles of known VH4 genes. Collectively, these data suggest that, overall, the human VH4 gene family may be more diverse than hitherto assumed, whereas a number of individual members are nonpolymorphic and extremely well conserved.

Amino Acid Sequence↗
PubMed1992

High frequency of somatically mutated IgM molecules in the human adult blood B cell repertoire.

Nucleotide sequence analysis of cDNA encoded by the single member of the human immunoglobulin VH6 gene family show that blood B cells in adults, but not in neonates, frequently express somatically mutated IgM molecules. The number of mutations in VH6-encoded cDNA from adult blood ranged from 2 to 19 mutations/VH gene (average 10.1/VH gene). The distribution of silent and replacement mutations suggests that at least some of the VH6 genes were derived from B cells that were activated and selected by antigen. We conclude that the blood B cell repertoire in adult humans, in contrast to its much-studied murine splenic counterpart, is a rich source of highly mutated IgM molecules.

Adult↗
PubMed1992

Molecular approaches to the study of human B-cell and (auto)antibody repertoire generation and selection.

We have shown that the restricted repertoire of VH genes expressed in second trimester human fetal liver is not solely determined by JH proximity. Furthermore, by following the fate of two VH gene segments in different B-cell repertoires, we have provided evidence that multiple factors contribute to the frequency with which individual VH genes are utilized. We found that the repertoire of adult blood IgM-bearing B cells contains a high proportion of B lymphocytes that express extensively mutated VH genes. Finally, we show that somatically-mutated variants of particular VH and VL genes that, in germline configuration, are frequently found in the early B-cell repertoire and in natural autoantibodies, encode pathogenic IgG autoantibodies characteristic of human SLE. These VH and VL genes harbor all the characteristics of an antigen-driven B-cell activation and selection process.

Amino Acid Sequence↗
PubMed1991

Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus.

The processes that govern the generation of pathogenic anti-DNA autoantibodies in human systemic lupus erythematosus (SLE) are largely unknown. Autoantibodies may arise as a consequence of polyclonal B cell activation and/or antigen-driven B cell activation and selection. The role of these processes in humoral autoimmunity may be studied by molecular genetic analysis of immunoglobulin (Ig) variable (V) regions of antibodies that are characteristic of SLE. We have analyzed the gene elements that encode a high affinity, IgG anti-double-stranded DNA autoantibody secreted by a monoclonal Epstein-Barr virus (EBV)-transformed cell line derived from a patient with active SLE. In addition, we have identified, cloned, and sequenced the germline counterparts of the VH and VL genes expressed in this autoantibody. The comparison of both sets of gene elements shows that the autoantibody VH and VL regions harbor numerous somatic mutations characteristic of an antigen-driven immune response. The light chain expressed in this autoantibody is a somatically mutated variant of the kv325 germline gene that is frequently associated with paraproteins having autoantibody activity and with Ig molecules produced by malignant B cells that express the CD5 antigen. Furthermore, the utilized DH segment has been repeatedly found in multireactive, low affinity IgM anti-DNA autoantibodies from SLE patients and healthy individuals. These results suggest that pathogenic IgG anti-DNA autoantibodies in human SLE may arise through antigen-driven selection of somatic mutations in the gene elements that frequently encode multireactive IgM autoantibodies.

Amino Acid Sequence↗
PubMed1991

Induction and characterization of monoclonal anti-idiotypic antibodies reactive with idiotopes of canine parvovirus neutralizing monoclonal antibodies.

Monoclonal anti-idiotypic (anti-Id) antibodies (Ab2) were generated against idiotypes (Id) of canine parvovirus (CPV) specific monoclonal antibodies (MoAbs). The binding of most of these anti-Id antibodies to their corresponding Id could be inhibited by antigen, thus classifying these anti-Id antibodies as Ab2 gamma or Ab2 beta. By inhibiting experiments it was shown that these anti-Id antibodies did not recognize interspecies cross-reactive idiotopes, but recognized private idiotopes, uniquely associated with the Id of the anti-CPV MoAb used for immunization. This classifies these anti-Id antibodies as non-internal image Ab2 gamma. The potential use of these non-internal image anti-Id antibodies for the induction of antiviral antibodies in the CPV system is discussed.

Animals↗