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H Albertsen

Publications and source records attributed to H Albertsen.

18 recordsLinked to original sources
PubMed1999

Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells.

Inhibitors of DNA methyltransferase, typified by 5-aza-2'-deoxycytidine (5-Aza-CdR), induce the expression of genes transcriptionally down-regulated by de novo methylation in tumor cells. We utilized gene expression microarrays to examine the effects of 5-Aza-CdR treatment in HT29 colon adenocarcinoma cells. This analysis revealed the induction of a set of genes that implicated IFN signaling in the HT29 cellular response to 5-Aza-CdR. Subsequent investigations revealed that the induction of this gene set correlates with the induction of signal transducer and activator of transcription (STAT) 1, 2, and 3 genes and their activation by endogenous IFN-alpha. These observations implicate the induction of the IFN-response pathway as a major cellular response to 5-Aza-CdR and suggests that the expression of STATs 1, 2, and 3 can be regulated by DNA methylation. Consistent with STAT's limiting cell responsiveness to IFN, we found that 5-Aza-CdR treatment sensitized HT29 cells to growth inhibition by exogenous IFN-alpha2a, indicating that 5-Aza-CdR should be investigated as a potentiator of IFN responsiveness in certain IFN-resistant tumors.

Antimetabolites, Antineoplastic↗
PubMed1997

The chromosome location of the human homolog of the mouse mammary tumor-associated gene INT6 and its status in human breast carcinomas.

The INT6 gene is a common integration site for the mouse mammary tumor virus in mouse mammary tumors. We have determined that the human homolog of INT6 is located on chromosome region 8q22-q23. A processed INT6 pseudogene is located on chromosome 6q. INT6 is composed of 13 exons that span 45 kb of genomic DNA. The deduced amino acid sequence of the gene product is identical to the mouse protein and contains three potential translation start signals. We have examined 100 primary breast carcinoma DNAs for evidence of genetic alteration affecting INT6. Loss of heterozyosity (LOH) was detected in 11 of 39 (28%) of the tumor samples informative for a polymorphic sequence in intron 7 of INT6. Since single-strand conformation and hybrid mismatch analysis of the remaining allele in these tumor DNAs failed to detect any mutations, we conclude that the target gene for LOH must be closely linked to INT6.

Animals↗
PubMed1996

Suppression of the malignant phenotype of human prostate cancer cell line PPC-1 by introduction of normal fragments of human chromosome 10.

Numerous studies have detected frequent losses of heterozygosity at polymorphic loci on chromosomal arms 10p and 10q in human prostate cancers. To confirm the presence of tumor suppressor genes in these chromosomal regions, fragments of normal human chromosome 10 tagged with a neomycin resistance gene were transferred into cells from a human prostate cancer cell line. PPC-1, by microcell-mediated chromosome transfer. Two of the six hybrid clones obtained showed decreased tumorigenicity in athymic nude mice and decreased efficiency of colony formation in soft agar compared with PPC-1; the other four retained fully malignant phenotypes. Analysis of polymorphic loci on chromosome 10 in these hybrid clones suggested that a tumor suppressor gene associated with prostate cancer is located within a 17-cM region at distal 10p.

Animals↗
PubMed1996

Isolation of a gene (DLG3) encoding a second member of the discs-large family on chromosome 17q12-q21.

The discs-large family is a collection of proteins that have a common structural organization and are thought to be involved in signal transduction and mediating protein-protein interactions at the cytoplasmic surface of the cell membrane. The defining member of this group of proteins is the gene product of the Drosophila lethal (1) discs large (dlg) 1 locus, which was originally identified by the analysis of recessive lethal mutants. Germline mutations in dlg result in loss of apical-basolateral polarity, disruption of normal cell-cell adhesion, and neoplastic overgrowth of the imaginal disc epithelium. We have isolated and characterized a novel human gene, DLG3, that encodes a new member of the discs-large family of proteins. The putative DLG3 gene product has a molecular weight of 66 kDa and contains a discs-large homologous region, a src oncogene homology motif 3, and a domain with homology to guanylate kinase. The DLG3 gene is located on chromosome 17, in the same segment, 17q12-q21, as the related gene, DLG2. The products of the DLG2 and DLG3 genes show 36% identity and 58% similarity to each other, and both show nearly 60% sequence similarity to p55, an erythroid phosphoprotein that is a component of the red cell membrane. We suggest that p55, DLG2, and DLG3 are closely related members of a gene family, whose protein products have a common structural organization and probably a similar function.

Amino Acid Sequence↗
PubMed1995

A gene (DLG2) located at 17q12-q21 encodes a new homologue of the Drosophila tumor suppressor dIg-A.

We have isolated a novel cDNA that maps distal to BRCA1 at 17q12-q21. The total sequence predicts a protein of 576 amino acids with three conserved regions: a 90-amino-acid repeat domain, a SH3 (src homology region 3) motif, and a guanylate kinase domain. These conserved regions are shared among members of the discs-large family of proteins that include human p55, a membrane protein expressed in erythrocytes, rat PSD-95/SAP90, a synapse protein expressed in brain, Drosophila dIg-A, a septate junction protein expressed in various epithelia, and human and mouse ZO-1 and canine ZO-2, two tight junction proteins. dIg-A has been shown to act as a tumor suppressor, and the other members may all be involved in signal transduction through specialized membrane domains with highly organized cytoskeletons and thus are potential tumor suppressors. Since allelic loss has been reported in the 17q12-q21 region in breast and ovarian cancer and it appears that BRCA1 is not the target of the losses, we looked for somatic alterations in DLG2 in sporadic breast tumors. No evidence for mutation was found, making it unlikely that DLG2 is involved in sporadic breast cancer.

Amino Acid Sequence↗
PubMed1995

Isolation and mapping of a gene encoding a novel human ADP-ribosylation factor on chromosome 17q12-q21.

A gene encoding a low-molecular-weight GTP-binding protein was isolated from a retinal cDNA library and mapped to human chromosome 17q12-q21. Comparison of the predicted protein with the protein databases revealed striking homology to the family of ADP-ribosylation factors (ARFs), which are thought to be involved in membrane trafficking and protein secretion. The greatest homology observed was with the rat ARF-like 4 protein (ARL4), with which it shared 58% identity, while the more highly conserved human ARF1 and ARF3 proteins each shared 46% identity. Inspection of the predicted new protein showed that it contained each of the six conserved motifs that are required for guanine nucleotide binding and hydrolysis, and thus it is probably a novel ARF isoform. We have designated the new protein and its corresponding gene ARF4L.

ADP-Ribosylation Factor 1↗
PubMed1995

A strategy for constructing high-resolution genetic maps of the human genome: a genetic map of chromosome 17p, ordered with meiotic breakpoint-mapping panels.

Genetic linkage analyses with genotypic data obtained from four CEPH reference families initially assigned 24 new PCR-based markers to chromosome 17 and located the markers at specific intervals of an existing genetic map of chromosome 17p. Each marker was additionally genotyped with an ordered set of obligate, phase-known recombinant chromosomes. The breakpoint-mapping panels for each family consisted of two parents, one sib with a nonrecombinant chromosome, and one or more sibs with obligate recombinant chromosomes. The relative order of markers was determined by sorting segregation patterns of new markers and ordered anchor markers and by minimizing double-recombination events. Consistency of segregation patterns with multiple flanking loci constituted support for order. A genetic map of chromosome 17p was completed with 39 markers in 23 clusters, with an average space of 3 cM between clusters. The collection of informative genotypes was highly efficient, requiring fivefold fewer genotypes than would be collected with all the CEPH families. Given the availability of large numbers of highly informative PCR-based markers, meiotic breakpoint mapping should facilitate construction of a human genomic map with 1-cM resolution.

Base Sequence↗
PubMed1995

Breakpoint analysis: precise localization of genetic markers by means of nonstatistical computation using relatively few genotypes.

Placing new markers on a previously existing genetic map by using conventional methods of multilocus linkage analysis requires that a large number of reference families be genotyped. This paper presents a methodology for placing new markers on existing genetic maps by genotyping only a few individuals in a selected subset of the reference panel. We show that by identifying meiotic breakpoint events within existing genetic maps and genotyping individuals who exhibit these events, along with one nonrecombinant sibling and their parents, we can determine precise location for new markers even within subcentimorgan chromosomal regions. This method also improves detection of errors in genotyping and assists in the observation of chromosome behavior in specific regions.

Algorithms↗
PubMed1994

Evidence for involvement of BRCA1 in sporadic breast carcinomas.

The hereditary breast cancer gene BRCA1 previously has been localized to chromosome 17q21. We looked for evidence of involvement of this region of chromosome 17 in 130 sporadic breast cancers. Seventeen polymorphic sequence tagged site markers were examined in these tumors between the D17S250 and D17S579 loci to screen for deletions as measured by loss of heterozygosity. The smallest common region that was deleted occurred in the approximately 120-kilobase interval between the D17S846 and D17S746 loci within the BRCA1 region. Delineation of this commonly deleted area should accelerate attempts to identify the involved gene(s) and its relationship to BRCA1.

Breast Neoplasms↗
PubMed1994

Localisation of the breast-ovarian cancer susceptibility gene (BRCA1) on 17q12-21 to an interval of < or = 1 cM.

A breast-ovarian cancer susceptibility gene, BRCA1, which is responsible for disease in approximately 45% of breast cancer families and most families that contain breast and ovarian cancer, has been assigned by genetic linkage to 17q12-21. Here, we report the analysis of three marker-disease recombinants in families that contain breast and ovarian cancer, two of which strongly suggest a location for BRCA1 telomeric to D17S702, a microsatellite polymorphism, and a third which suggests a location centromeric to EDH17B, the gene encoding estradiol-17B dehydrogenase. If the interpretation of these recombinants is correct, the results localise BRCA1 to an interval of < or = 1 cM.

Adult↗
PubMed1994

Genetic mapping of the BRCA1 region on chromosome 17q21.

Chromosome 17q21 harbors a gene (BRCA1) associated with a hereditary form of breast cancer. As a step toward identification of this gene itself we developed a number of simple-sequence-repeat (SSR) markers for chromosome 17 and constructed a high-resolution genetic map of a 40-cM region around 17q21. As part of this effort we captured genotypes from five of the markers by using an ABI sequencing instrument and stored them in a locally developed database, as a step toward automated genotyping. In addition, YACs that physically link some of the SSR markers were identified. The results provided by this study should facilitate physical mapping of the BRCA1 region and isolation of the BRCA1 gene.

Base Sequence↗
PubMed1994

A radiation hybrid map of the BRCA1 region.

A locus on chromosome 17q, designated "BRCA1," has been identified as a predisposition gene for breast cancer. A panel of chromosome 17-specific radiation-reduced somatic cell hybrid clones has been assembled for high-resolution mapping of chromosome 17. A series of 35 markers, known to span the BRCA1 locus, were tested against this hybrid panel by PCR assays. Statistical analysis of these data yields a BRCA1 radiation hybrid map at a density sufficient to initiate YAC cloning and pulsed-field gel electrophoretic mapping of the candidate region. In addition, many of the markers reveal genetic polymorphisms and may be tested in breast cancer families and in loss-of-heterozygosity studies of sporadic breast cancers to better define the BRCA1 gene candidate region.

Animals↗
PubMed1994

Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region.

To test the reliability of linkage-disequilibrium analysis for gene mapping, we compared physical distance and linkage disequilibrium among seven polymorphisms in the adenomatous polyposis coli (APC) region on chromosome 5. Three of them lie within the APC gene, and two lie within the nearby MCC (mutated in colon cancer) gene. One polymorphism lies between the two genes, and one is likely to be 5' of MCC. Five of these polymorphisms are newly reported. All polymorphisms were typed in the CEPH kindreds, yielding 179-205 unrelated two-locus haplotypes. Linkage disequilibrium between each pair of polymorphisms is highly correlated with physical distance in this 550-kb region (correlation coefficient -.80, P < .006). This result is replicated in both the Utah and non-Utah CEPH kindreds. There is a tendency for greater disequilibrium among pairs of polymorphisms located within the same gene than among other pairs of polymorphisms. Trigenic, quadrigenic, three-locus, and four-locus disequilibrium measures were also estimated, but these measures revealed much less disequilibrium than did the two-locus disequilibrium measures. A review of 19 published disequilibrium studies, including this one, shows that linkage disequilibrium nearly always correlates significantly with physical distance in genomic regions > 50-60 kb but that it does not do so in smaller genomic regions. We show that this agrees with theoretical predictions. This finding helps to resolve controversies regarding the use of disequilibrium for inferring gene order. Disequilibrium mapping is unlikely to predict gene order correctly in regions < 50-60 kb in size but can often be applied successfully in regions of 50-500 kb or so in size. It is convenient that this is the range in which other mapping techniques, including chromosome walking and linkage mapping, become difficult.

Adenomatous Polyposis Coli↗
PubMed1993

Polymorphic SSR (simple-sequence-repeat) markers for chromosome 20.

Chromosome 20-specific simple-sequence-repeat (SSR) markers were developed from a flow-sorted phage library (LL20NS01), subcloned in Bluescript, and screened with a tetranucleotide repeat, (AAAG)6, to identify potentially polymorphic loci. Of 100 clones sequenced, 39 were selected to construct primers. Of these 39, 22 were polymorphic. Reference to the CEPH linkage database (version 5) permitted genetic mapping of 16 of the new markers to specific regions of chromosome 20. Ten of the SSRs showed heterozygosity indices (above 70%) that would qualify them as potential index markers.

Base Sequence↗
PubMed1992

Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A.

Charcot-Marie-Tooth disease 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy, associated with a DNA duplication on chromosome 17p11.2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p. Recently, the peripheral myelin protein-22 (pmp-22) gene was identified as the likely Tr locus. We have constructed a partial yeast artificial chromosome contig spanning the CMT1A gene region and mapped the PMP-22 gene to the duplicated region. These observations further implicate PMP-22 as a candidate gene for CMT1A, and suggest that over-expression of this gene may be one mechanism that produces the CMT1A phenotype.

Animals↗
PubMed1991

Identification and characterization of the familial adenomatous polyposis coli gene.

DNA from 61 unrelated patients with adenomatous polyposis coli (APC) was examined for mutations in three genes (DP1, SRP19, and DP2.5) located within a 100 kb region deleted in two of the patients. The intron-exon boundary sequences were defined for each of these genes, and single-strand conformation polymorphism analysis of exons from DP2.5 identified four mutations specific to APC patients. Each of two aberrant alleles contained a base substitution changing an amino acid to a stop codon in the predicted peptide; the other mutations were small deletions leading to frameshifts. Analysis of DNA from parents of one of these patients showed that his 2 bp deletion is a new mutation; furthermore, the mutation was transmitted to two of his children. These data have established that DP2.5 is the APC gene.

Adenomatous Polyposis Coli↗
PubMed1991

Identification of deletion mutations and three new genes at the familial polyposis locus.

Small (100-260 kb), nested deletions were characterized in DNA from two unrelated patients with familial adenomatous polyposis coli (APC). Three candidate genes located within the deleted region were ascertained and a previous candidate gene, MCC, was shown to be located outside the deleted region. One of the new genes contained sequence identical to SRP19, the gene coding for the 19 kd component of the ribosomal signal recognition particle. The second, provisionally designated DP1 (deleted in polyposis 1), was found to be transcribed in the same orientation as MCC. Two other cDNAs, DP2 and DP3, were found to overlap, forming a single gene, DP2.5, that is transcribed in the same orientation as SRP19.

Adenomatous Polyposis Coli↗