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A M Cleton-Jansen

Publications and source records attributed to A M Cleton-Jansen.

51 records · Page 3Linked to original sources
PubMed1995

E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers.

Compelling experimental evidence exists for a potent invasion suppressor role of the cell-cell adhesion molecule E-cadherin. In addition, a tumour suppressor effect has been suggested for E-cadherin. In human cancers, partial or complete loss of E-cadherin expression correlates with malignancy. To investigate the molecular basis for this altered expression we developed a comprehensive PCR/SSCP mutation screen for the human E-cadherin gene. For 49 breast cancer patients the occurrence of tumour-specific mutations in the E-cadherin gene was examined. No relevant DNA changes were encountered in any of 42 infiltrative ductal or medullary breast carcinoma samples. In contrast, four out of seven infiltrative lobular breast carcinomas harboured protein truncation mutations (three nonsense and one frameshift) in the extracellular part of the E-cadherin protein. Each of the four lobular carcinomas with E-cadherin mutations showed tumour-specific loss of heterozygosity of chromosomal region 16q22.1 containing the E-cadherin locus. In compliance with this, no E-cadherin expression was detectable by immunohistochemistry in these four tumours. These findings offer a molecular explanation for the typical scattered tumour cell growth in infiltrative lobular breast cancer.

Base Sequence↗
PubMed1995

Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13.

Loss of heterozygosity (LOH) on chromosome 13 occurs on 25-30% of breast tumours. This may reflect the inactivation of the retinoblastoma susceptibility gene RB1. However, recently another candidate tumour-suppressor gene has been identified on chromosome 13 by linkage analysis, the breast cancer susceptibility gene BRCA2. To investigate the involvement of BRCA2 in sporadic breast cancer 200 breast tumours were tested for LOH on chromosome band 13q12-q14, using 11 highly polymorphic microsatellite markers. LOH was found in 65 tumours, which all showed simultaneously loss of BRCA2 and RB1. Of 12 breast tumour cell lines tested with polymorphic microsatellite markers, seven showed a contiguous region of homozygosity on 13q12-q14, suggesting LOH in the tumour from which the cell line had been derived. One cell line showed homozygosity in the BRCA2 region and heterozygosity at RB1. This is the only indication that BRCA2 is a distinct target for LOH on chromosome 13 in addition to RB1.

Alleles↗
PubMed1995

Mapping of the breast basic conserved gene (D16S444E) to human chromosome band 16q24.3.

The breast basic conserved gene (D16S444E) is a candidate tumor suppressor gene previously mapped to human chromosome 16. We determined the map position of D16S444E more precisely using a somatic mouse x human hybrid panel and fluorescence in situ hybridization on metaphase spreads and interphase nuclei. We show that the D16S444E gene is localized on band 16q24.3 and is located between APRT and D16S44.

Animals↗
PubMed1994

Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations.

In breast cancer, loss of heterozygosity (LOH) on 17p is a frequent event and a likely target is the p53 gene on 17p13.1. However, several LOH mapping studies have indicated that, in some breast tumors, LOH affects only the most distal 17p markers, suggestive of a second tumor suppressor locus in 17p13.3. In order to distinguish which gene has most probably served as the target for LOH on 17p, we have screened 141 breast tumors for somatic mutations in the p53 gene in conjunction with detailed LOH mapping on the short arm of chromosome 17. A total of 32 mutations were detected in 31 tumors, 15 of which have never been reported in breast cancer before. The majority are point mutations leading to an amino acid change in the protein. In addition, we have stained a subset of 87 tumors for the p53 protein by immunohistochemistry. In 21 of these tumors (24%), nuclear staining was detected in over 25% of the tumor cells with the anti-p53 antibody DO7. A positive correlation was found between p53-positive staining and p53 mutation (P < 0.001). A strong association was observed between p53 mutation and LOH at the TP53 locus but not between p53 expression and LOH on 17p. In breast tumors without a detectable p53 mutation but with LOH on 17p, the 17p13.3 region is always involved and, in some cases, even exclusively involved. These results suggest that a second tumor suppressor gene, located distal to TP53, is targeted by LOH on 17p in some breast tumors and that a substantial number of breast tumors stabilize p53 through mechanisms other than mutation.

Alleles↗
PubMed1994

At least two different regions are involved in allelic imbalance on chromosome arm 16q in breast cancer.

Loss of heterozygosity (LOH) or allelic imbalance, the latter term referring to both loss and gain of an allele, on the long arm of chromosome 16 has been repeatedly found in cancers of, e.g., the breast and prostate. This indicates the presence of one or more tumor suppressor genes on 16q. To locate the gene(s) more precisely, a detailed allelic imbalance map of 20 polymorphic markers on this chromosome arm was made for 79 sporadic breast carcinomas. LOH of one or more markers was found in 63% of the tumors. Some had allelic imbalance on a region of 16q which failed to overlap with the LOH in other tumors. We therefore assigned two separate "smallest regions of overlap" to 16q and suggest that this chromosome arm contains at least two different tumor suppressor genes.

Alleles↗
PubMed1994

Instability of short tandem repeats (microsatellites) in human cancers.

The allele sizes of polymorphic microsatellite repeats in DNA from human cancers were compared to normal DNA from the same patients. In 16 out of 196 paired samples (8%), we found evidence of an extra allele of a different size in the tumour which was not present in the normal DNA. Sequence analysis confirmed that the extra allele originates from the appropriate locus and that the size change is attributable to alteration in the number of repeat units. This form of instability was more common in tri- and tetranucleotide repeats than in dinucleotide repeats. In any single tumour sample only one repeat in the set examined was abnormal, the remainder showing identical patterns in normal and tumour DNA or evidence of allele loss. The pattern of instability in diverse types of cancer differs from that reported in colorectal neoplasms.

Alleles↗
PubMed1993

Evidence for limited molecular genetic heterogeneity as defined by allelotyping and clonal analysis in nine metastatic breast carcinomas.

To investigate genetic intratumor heterogeneity, 42 samples of nine primary breast carcinomas and 29 related lymph node metastases were examined for DNA ploidy status, allelotype, and X chromosome inactivation pattern. Two primary breast carcinomas showed DNA index heterogeneity and five contained a single DNA aneuploid tumor stemline, whereas the two remaining primary tumors were solely DNA diploid. Most primary DNA tumor stemlines recurred in lymph node metastases (9 of 11). The allelotype, constructed with 31 different probes mapping to 23 different chromosome arms showed allelic imbalances on nearly all chromosome arms investigated. All tumors contained multiple allelic imbalances (range, 3-12). An allelic imbalance present in a primary tumor was consistently present in all DNA samples of that primary tumor and also in all DNA samples of related lymph node metastases, irrespective of DNA index heterogeneity. X chromosome inactivation pattern analysis with probe M27 beta (DXS255) confirmed the presence of clonal tumor cell populations in these tumors at the time of diagnosis. Densitometry of autoradiograms, which by eye showed retention of heterozygosity, revealed a narrow clustering of allelic imbalance factors between 1.0 and 1.4. In contrast, autoradiograms visually showing an allelic imbalance exhibited a marked interprobe, intertumor and intratumor variation in allelic imbalance factors. No relation between densitometry results and DNA ploidy status was found. Thus, at the time of diagnosis, an advanced primary breast carcinoma consists of a clonal tumor cell population with an established complement of allelic imbalances in all parts of the primary tumor and in the related lymph node metastases. Secondary to the establishment of allelic imbalances, intratumor heterogeneity for the copy number of involved alleles may develop, which in turn probably precedes metastasis.

Adult↗
PubMed1991

A single amino acid substitution changes the substrate specificity of quinoprotein glucose dehydrogenase in Gluconobacter oxydans.

Gluconobacter oxydans contains pyrroloquinoline quinone-dependent glucose dehydrogenase (GDH). Two isogenic G. oxydans strains, P1 and P2, which differ in their substrate specificity with respect to oxidation of sugars have been analysed. P1 can oxidize only D-glucose, whereas P2 is also capable of the oxidation of the disaccharide maltose. To investigate the nature of this maltose-oxidizing property we cloned the gene encoding GDH from P2. Expression of P2 gdh in P1 enables the latter strain to oxidize maltose, indicating that a mutation in the P2 gdh gene is responsible for the change in substrate specificity. This mutation could be ascribed to a 1 bp substitution resulting in the replacement of His 787 by Asn.

Amino Acid Sequence↗
PubMed1990

Cloning, mapping, and sequencing of the gene encoding Escherichia coli quinoprotein glucose dehydrogenase.

Escherichia coli contains pyrroloquinoline quinone-dependent glucose dehydrogenase. We cloned and sequenced the gene (gcd) encoding this enzyme and showed that the derived amino acid sequence is highly homologous to that of the gdhA gene product of Acinetobacter calcoaceticus. Stretches of homology also exist between the amino acid sequence of E. coli glucose dehydrogenase and other pyrroloquinoline quinone-dependent dehydrogenases from several bacterial species. The position of gcd on the chromosomal map of E. coli was determined to be at 3.1 min.

Amino Acid Sequence↗
PubMed1989

Cloning of the genes encoding the two different glucose dehydrogenases from Acinetobacter calcoaceticus.

Glucose dehydrogenase (GDH) is a PQQ dependent bacterial enzyme which converts aldoses to their corresponding acids. A. calcoaceticus contains two different PQQ dependent glucose dehydrogenases designated GDH-A which is active in vivo and GDH-B of which only in vitro activity can be shown. We cloned the genes coding for the two GDH enzymes. The DNA sequences of both gdh genes were determined. There is no obvious homology between gdhA and gdhB. Both GDH enzymes oxidize D-glucose in vitro but disaccharides are specific GDH-B substrates and 2-deoxyglucose is specifically oxidized by GDH-A.

Acinetobacter↗
PubMed1989

Cloning, characterization and DNA sequencing of the gene encoding the Mr 50,000 quinoprotein glucose dehydrogenase from Acinetobacter calcoaceticus.

Recently we described the cloning of the gene coding for a Mr 87,000 glucose dehydrogenase (GDH-A) from Acinetobacter calcoaceticus. In this report we describe the cloning of a gene coding for a second GDH (GDH-B) with a Mr of 50,000 from the same organism. This gene was isolated using a 20-mer synthetic oligonucleotide, derived from the N-terminal amino acid sequence of purified GDH-B as a probe to screen a genomic bank. From the DNA sequence of the gdhB gene, a protein can be derived of Mr 52,772 with a 24 amino acid signal peptide which is removed, resulting in the mature protein with a Mr 50,231. In vitro transcription-translation of the gdhB clone shows the mature and the precursor protein. The derived amino acid sequence has no obvious homology with GDH-A of A. calcoaceticus. We show that disaccharides are specific GDH-B substrates and that 2-deoxyglucose is specific for GDH-A.

Acinetobacter↗
PubMed1988

Cloning of the gene encoding quinoprotein glucose dehydrogenase from Acinetobacter calcoaceticus: evidence for the presence of a second enzyme.

We cloned the gene coding for the quinoprotein glucose dehydrogenase from Acinetobacter calcoaceticus. This clone complements gdh mutations in A. calcoaceticus, Pseudomonas aeruginosa, and Escherichia coli. The gene codes for a protein with an Mr of 83,000. Evidence is presented for the presence of two different glucose dehydrogenase enzymes in A. calcoaceticus: a protein with an Mr of 83,000 and a dimer of two identical subunits with an Mr of 50,000.

Acinetobacter↗
PubMedDate not supplied

Genomic structure and expression analysis of the spastic paraplegia gene, SPG7.

SPG7 is a newly identified gene involved in an autosomal recessive form of hereditary spastic paraplegia (HSP), a genetically heterogeneous group of neurodegenerative disorders. This gene encodes a protein characterized as a nuclear-encoded mitochondrial metalloprotease. The present report describes the genomic structure of the SPG7 gene. It is organized into 17 exons ranging from 78 to 242 bp and spans approximately 52 kb within three overlapping cosmids. The exon/intron boundaries and all splice junctions are consistent with the published consensus sequences for donor and acceptor sites. The provided genomic structure of SPG7 should facilitate the screening for mutations in this gene in patients with HSP and other related mitochondrial disease syndromes. SPG7 has been mapped to chromosome 16q24.3, a region of frequent loss of heterozygosity (LOH) seen in sporadic breast and prostate cancer. We have performed single-strand conformation polymorphism analysis of ten exons of this gene in a number of sporadic breast cancer samples showing LOH at 16q24.3. No mutations were detected; only single nucleotide polymorphisms were observed in exon 11, intron 7, intron 10 and intron 12. An expression analysis study has revealed the differential expression of SPG7 mRNA in various tissues and at different developmental stages.

ATPases Associated with Diverse Cellular Activitie↗