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Biomedical subjects

O Mor

Publications and source records attributed to O Mor.

13 recordsLinked to original sources
PubMed1998

The human Surfeit locus.

The organization of the human Surfeit locus containing the six sequence-unrelated housekeeping genes Surf-1 to Surf-6 (HGMW-approved symbols SURF1-SURF6) has been determined. The human surfeit locus occupies about 60 kb of DNA, and the tightly clustered gene organization and the juxtaposition of the human genes are similar to the mouse and chicken surfeit loci with the 5' end of each gene associated with a CpG-rich island. Whereas in the mouse the Surf-2 and Surf-4 genes overlap at their 3' ends, the human Surf-2 and Surf-4 genes have been found to be separated by 302 bp due to a much shorter 3' untranslated region in the human Surf-2 gene. The distance between the 3' ends of the human Surf-1 and Surf-3 genes is 374 bp, and the distance between the 5' ends of the human Surf-3 and Surf-5 genes is only 112 bp. Unusually the human Surf-5 gene contains an intron in its 5' untranslated region not found in the mouse or rat Surf-5 genes. This additional intron is also found in the Surf-5 gene of both Old and New World monkeys, being generated before the divergence of human and prosimians but after the divergence of primates and rodents. A contig of 200 kb containing the human Surfeit locus has been constructed from overlapping cosmid, P1, and PAC clones. Approximately 40 kb proximal to the 3' end of the Surf-6 gene, the 5' region of the ABO glycosyltransferase gene has been detected. This allows us to determine the orientation of the Surfeit and ABO loci with respect to each other and to the telomere and centromere of human chromosome 9.

Animals↗
PubMed1997

p53 in polyoma virus transformed REF52 cells.

While cellular transformation by small DNA tumour viruses usually involves targeting the product of the p53 tumour suppressor gene by a virally encoded protein, none of the three polyoma virus (Py) specified T antigens have been observed to interact with p53. We show that primary mouse embryo fibroblasts and REF52 cells, which resemble primary cells in requiring co-operating oncogenes for transformation, cannot be transformed by the Py oncogene, middle T-antigen (PyMT), alone. These cells can be transformed by the complete Py early region, which encodes the Py large, middle and small T-antigens. We find that PyMT can transform rodent cells lacking a functional p53 protein (p53 null mouse embryo fibroblasts and DN-REF52 cells which contain a dominant negative p53). In Py transformed REF52 cells (Py-REF52) there is no significant accumulation of p53 protein, as opposed to SV40 transformed REF52 cells (SV-REF52) in which the amount of steady state p53 protein is elevated. However accumulation of p53 is observed following exposure of Py-REF52 cells to u.v. Treatment of Py-REF52 cells with X-rays results in a rapid increase in the levels of the p53-induced proteins p21/WAF1 and MDM2. In untransformed REF52 cells, X-irradiation causes p53 activation, which results in induction of both G1/S and G2/M blocks. In SV-REF52 and DN-REF52 cells, p53 abrogation results in the absence of both the G1/S and G2/M blocks. Only the absence of a G1/S block is observed in Py-REF52 cells exposed to X-irradiation. Together these results indicate that in contrast to most other DNA tumour viruses, Py does not appear to interfere with the DNA damage induced transactivation activities of the p53 protein but absence of a functional p53 protein can mediate transformation by the PyMT oncogene in the absence of other co-operating oncogenes. Possible modes of transformation by Py are discussed.

Animals↗
PubMed1997

Absence of p53 mutations in malignant mesotheliomas.

Mutations in the p53 gene are the most common genetic alterations found in human malignancies. In this study, a search was done for mutations in the conserved regions of the p53 gene in malignant mesotheliomas. Thirteen malignant mesotheliomas collected over the preceding 12 yr and maintained in paraffin blocks were examined by polymerase chain reaction (PCR) followed by both single-strand conformation polymorphism (SSCP) and denaturing gradient-gel electrophoresis (DGGE). Direct sequence analysis was performed in cases suspected for mutations. No mutations in exons 5 to 8 of the p53 gene were detected. Our results suggest that malignant transformation of human mesothelioma cells does not require inactivation of p53 by point mutations in the conserved regions of the gene.

Adult↗
PubMed1995

Analysis of microsatellite repeats in pediatric brain tumors.

Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor suppressor genes. However, investigation of genomic instability of microsatellites has disclosed a new mechanism for human carcinogenesis, which is involved not only in hereditary nonpolyposis colon cancer (HNPCC) but also in a number of other malignancies. To determine whether microsatellite instability is involved in pediatric brain tumors, we screened 15 such tumors using seven microsatellite marker loci on six chromosomes 4, 5, 9p, 9q, 11, 14, and 17. Using the polymerase chain reaction method, DNA samples from the tumors and from normal peripheral blood leukocytes from each patient were compared for the allelic pattern produced at each locus. Our preliminary results indicate loss of heterozygosity at the fatty acid binding protein (FABP) locus, located on chromosomal arm 4q28-q31, the only trinucleotide repeat in the panel of markers used, for 3 of 15 cases, suggesting the presence of previously unidentified sequences relevant to brain tumorigenesis at or in the vicinity of this locus. We did not observe any microsatellite instability in these samples, indicating that the mechanisms operating in HNPCC are not active in this subset of pediatric brain tumors.

Brain Neoplasms↗
PubMed1993

DNA amplification in human gastric carcinomas.

We recently identified a genomic domain at chromosome 10q26 that is highly amplified in the gastric carcinoma cell lines KATO III and SNU-16 and contains the BEK/K-sam gene, which encodes several growth factor receptors. A contiguous segment of 200 kb spanning this gene was amplified in five of 139 (3.6%) primary gastric carcinomas, all of them classified as poorly differentiated tumors. There was no amplification of this genomic region in a variety of other solid tumors. The overall frequency of gene amplification among the gastric carcinomas rose to 19.4% when MYC, ERBB2, and INT2 were included in the analysis, with significant association with advanced tumor stage. Amplification of various genomic regions in solid tumors may be more frequent than previously estimated.

Carcinoma↗
PubMed1992

Detection of amplified DNA sequences in human tumor cell lines by fluorescence in situ hybridization.

An unambiguous and rapid characterization of amplified DNA sequences in tumor cells is important for the understanding of neoplastic progression. This study was conducted to evaluate the potential of fluorescence in situ hybridization (FISH) to identify such amplified DNA sequences in human tumor cell lines. Applying this technique, we followed the metaphase location and interphase position of amplified DNA sequences corresponding to the SAMK, MYC, and MYCN genes in four cell lines derived from human tumors: two gastric carcinoma lines (KATO III and SNU-16), a neuroblastoma (NUB-7), and a neuroepithelioma (NUB-20) line. In metaphase cells of KATO III, NUB-7, and NUB-20 lines, the amplified regions were clearly visible and easily identified at an intrachromosomal location: in KATO III and NUB-7 at a terminal position and in NUB-20 at an interstitial position. In SNU-16, on the other hand, the amplified SAMK and MYC sequences were identified in extrachromosomal double minute chromosomes (DMs). In this line, the SAMK and MYC sequences were coamplified in the same cells and were colocated on the same DMs. FISH also allowed the identification of amplified DNA sequences in nondividing cells, enabling us to distinguish, at interphase, whether the amplification gave rise to intrachromosomal amplified regions (IARs) or to extrachromosomal DMs. The FISH technique also allowed us to determine at metaphase as well as at interphase the extent of amplification and the size of the IARs.

DNA Probes↗
PubMed1992

DNA sequences amplified in cancer cells: an interface between tumor biology and human genome analysis.

There is growing evidence that amplification of specific genes is associated with tumor progression. While several proto-oncogenes are known to be activated by amplification, it is clear that not all the genes involved in DNA amplification in human tumors have been discovered. Our approach to the identification of such genes is based on the 'reverse genetics' methodology. Anonymous amplified DNA fragments are cloned by virtue of their amplification in a given tumor. These sequences are mapped in the normal genome and hence define a new genetic locus. The amplified domain is isolated by long-range cloning and analyzed along three lines of investigation: new genes are sought that can explain the biological significance of the amplification; the structure of the domain is studied in normal cells and in the amplification unit in the cancer cell; attempts are made to identify molecular probes of diagnostic value within the amplified domain. This application of genome technology to cancer biology is demonstrated in our study of a new genomic domain at chromosome 10q26 which is amplified specifically in human gastric carcinomas.

Blotting, Southern↗
PubMed1991

Novel DNA sequences at chromosome 10q26 are amplified in human gastric carcinoma cell lines: molecular cloning by competitive DNA reassociation.

Molecular cloning of genomic sequences altered in cancer cells is believed to lead to the identification of new genes involved in the initiation and progression of the malignant phenotype. DNA amplification is a frequent molecular alteration in tumor cells, and is a mode of proto-oncogene activation. The cytologic manifestation of this phenomenon is the appearance of chromosomal homogeneously staining regions (HSRs) or double minute bodies (DMs). The gastric carcinoma cell line KATO III is characterized by a large HSR on chromosome 11. In-gel renaturation analysis confirmed the amplification of DNA sequences in this cell line, yet none of 42 proto-oncogenes that we tested is amplified in KATO III DNA. We employed the phenol-enhanced reassociation technique (PERT) to isolate 21 random DNA fragments from the amplified domain, and used 6 of them to further clone some 150 kb from that genomic region. While in situ hybridization performed with some of these sequences indicated that in KATO III they are indeed amplified within the HSR on chromosome 11, somatic cell hybrid analysis and in situ hybridization to normal lymphocyte chromosomes showed that they are derived from chromosome 10, band q26. The same sequences were found to be amplified in another gastric carcinoma cell line, SNU-16, which contains DMs, but were not amplified in other 70 cell lines representing a wide variety of human neoplasms. One of these sequences was highly expressed in both KATO III and SNU-16. Thus, the cloned sequences supply a starting point for identification of novel genes which might be involved in the pathogenesis of gastric cancers, and are located in a relatively unexplored domain of the human genome.

Adult↗
PubMed1990

Importance of phenotypic and molecular characterization for identification of a neuroepithelioma tumor cell line, NUB-20.

A neuroblastic-like cell line (NUB-20) was derived from a case of histopathologically diagnosed metastatic neuroblastoma. The metastatic tumor and nude mouse heterotransplant resembled neuroblastoma by histological criteria, in contrast to the primary tumor, which was differentially classified as Ewing's sarcoma. However, the cell line demonstrated a unique phenotype in culture with respect to morphology, immunohistochemical markers, and sensitivity to a battery of differentiation modulators. These characteristics, together with the presence of a chromosomal translocation (11;22),(q24;q12) and amplification with enhanced expression of the c-myc protooncogene rather than N-myc, established this tumor as neuroepithelioma. Neuroepithelioma is a tumor type distinct from, but related to, neuroblastoma in its development from the neural crest lineage. These results emphasize the growing importance of cytogenetic and molecular markers in the classification and characterization of human tumors.

Bucladesine↗