LIM-kinase deleted in Williams syndrome.
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Animals↗
Biomedical subjects
D Sheer
Publications and source records attributed to D Sheer.
Assignment of the human and mouse LIM-kinase genes (LIMK1; Limk1) to chromosome bands 7q11.23 and 5G1, respectively, by in situ hybridization.
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Animals↗
Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q.
Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. HMPS appears to be inherited in an autosomal dominant manner. Genetic linkage analysis has been performed on a large family with HMPS. Data did not support linkage to the APC locus or to any of the loci for hereditary nonpolyposis colorectal cancer. Evidence that the HMPS locus lies on chromosome 6q was, however, provided by significant two-point LOD scores for linkage between HMPS and the D6S283 locus. Analysis of recombinants and multipoint linkage analysis suggested that the HMPS locus lies in a 4-cM interval containing the D6S283 locus and flanked by markers D6S468 and D6S301.
Adenoma↗
H-RYK, an unusual receptor kinase: isolation and analysis of expression in ovarian cancer.
BACKGROUND: Protein tyrosine kinases play an important role in cellular metabolism as key components of signal transduction pathways. They are involved in cellular growth, differentiation, and development. Receptor tyrosine kinases (EGF receptor and c-erbB2) have been shown to be important in the pathogenesis of cancer. In ovarian cancer, overexpression of c-erbB2, a type I receptor, has been correlated with an adverse effect on survival of patients. MATERIAL AND METHODS: An unusual receptor tyrosine kinase, H-RYK, has been isolated from a complimentary DNA library of SKOV-3, an epithelial ovarian cancer cell line, using a polymerase chain reaction-mediated approach. RESULTS: The primary structure of the predicted amino acid sequence of the protein shows a novel NH2-terminal region. The catalytic region shows homology to other tyrosine kinases, the closest homology being with v-sea (39%). A significant alteration in the catalytic domain is that the highly conserved "DFG" triplet in subdomain VII is altered to "DNA." The gene was mapped to chromosome 3q22. A single transcript of 3.0 kb is expressed in heart, brain, lung, placenta, liver, muscle, kidney, and pancreas by Northern analysis with maximal expression in skeletal muscle. In situ hybridization analysis on human tissues demonstrated localization of message in the epithelial and stromal compartment of tissues such as brain, lung, colon, kidney, and breast. There was minimal to absent expression of H-RYK on surface epithelium of ovaries. In benign (3) and borderline tumors of the ovary (5), there was expression in the stromal compartment. However, in malignant tumors (24) there was increased expression predominantly confined to the epithelium. Polyclonal antisera raised against synthetic peptides recognize a 100-kD protein in ovarian cancer cells and other cell lines. In contrast to other receptor tyrosine kinases, the receptor did not phosphorylate in an in vitro kinase assay. CONCLUSIONS: The expression of this unusual receptor tyrosine kinase in epithelial ovarian cancer suggests that it may be involved in tumor progression, which needs further investigation.
Adenocarcinoma↗
Molecular cloning and tissue expression of FAT, the human homologue of the Drosophila fat gene that is located on chromosome 4q34-q35 and encodes a putative adhesion molecule.
FAT, a new member of the human cadherin super-family, has been isolated from the T-leukemia cell line J6. The predicted protein closely resembles the Drosophila tumor suppressor fat, which is essential for controlling cell proliferation during Drosophila development. The gene has the potential to encode a large transmembrane protein of nearly 4600 residues with 34 tandem cadherin repeats, five EGF-like repeats, and a laminin A-G domain. The cytoplasmic sequence contains two domains with distant homology to the cadherin catenin-binding region. Northern blotting analysis of J6 mRNA demonstrated full-length, approximately 15-kb, FAT message in addition to several 5'-truncated transcripts. In addition to its presence in J6 cells, in situ hybridization revealed FAT mRNA expression in epithelia and in some mesenchymal compartments. Furthermore, higher levels of expression were observed in fetal, as opposed to adult, tissue, suggesting that its expression may be developmentally regulated in these tissues. FAT shows homologies with a number of proteins important in developmental decisions and cell:cell communication and is the first fat-like protein reported in vertebrates. The gene encoding FAT was located by in situ hybridization on chromosome 4q34-q35. We propose that this family of molecules is likely to be important in mammalian developmental processes and cell communication.
Amino Acid Sequence↗
Is prostate cancer worth diagnosing?
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Humans↗
The eukaryotic cofactor for the human immunodeficiency virus type 1 (HIV-1) rev protein, eIF-5A, maps to chromosome 17p12-p13: three eIF-5A pseudogenes map to 10q23.3, 17q25, and 19q13.2.
The eukaryotic initiation factor 5A (eIF-5A) has been identified as an essential cofactor for the HIV-1 transactivator protein Rev. Rev plays a key role in the complex regulation of HIV-1 gene expression and thereby in the generation of infectious virus particles. Expression of eIF-5A is vital for Rev function, and inhibition of this interaction leads to a block of the viral replication cycle. In humans, four different eIF-5A genes have been identified. One codes for the eIF-5A protein and the other three are pseudogenes. Using a panel of somatic rodent-human cell hybrids in combination with fluorescence in situ hybridization analysis, we show that the four genes map to three different chromosomes. The coding eIF-5A gene (EIF5A) maps to 17p12-p13, and the three pseudogenes EIF5AP1, EIF5AP2, and EIF5AP3 map to 10q23.3, 17q25, and 19q13.2, respectively. This is the first localization report for a eukaryotic cofactor for a regulatory HIV-1 protein.
Base Sequence↗
Fusion of the EWS gene to a DNA segment from 9q22-31 in a human myxoid chondrosarcoma.
Southern blot analyses revealed a rearrangement of the EWS gene in a skeletal human myxoid chondrosarcoma. Interphase fluorescence in situ hybridization (FISH) studies, using cosmid clones F7 and G9 that flank the EWS locus on 22q12, confirmed the presence of this EWS gene abnormality. Cloning the rearranged EWS DNA fragment and mapping by FISH demonstrated that the EWS gene is joined to DNA sequences localised in 9q22-31. These findings are consistent with previous cytogenetic reports of a recurrent t(9;22)(q22-31;q11-12) in the myxoid variant of chondrosarcoma and reveal involvement of the EWS gene in a fourth type of human sarcoma.
Adult↗
Characterization of a t(10;11)(p13-14;q14-21) in the monoblastic cell line U937.
Previous analysis of the monoblastic cell line U937 has shown that several sublines contain a rearranged chromosome arm 11q. In order to determine the true nature of the rearrangement, fluorescence in situ hybridization (FISH) was carried out with various combinations of single copy anonymous markers, clones containing genes, a chromosome 10 paint, and an 11 centromere specific sequence. The rearrangement was deduced to be a reciprocal translocation between chromosomes 10 and 11 described as t(10;11)(p13-14;q14-21). The breakpoint on chromosome 11 is telomeric to the INT2 gene and the pHS11 probe at 11q13, and centromeric to the marker D11S36 localized to 11q14.3-q22.1 and the MLL gene at 11q23. Similar translocations have been reported in various acute leukemias, principally of the monocytic lineage, and also in T-cell precursor acute lymphocytic leukemias. Further characterization of the genetic rearrangements in U937 may lead to the isolation of genes important in leukemogenesis and provide an in vitro system for their study.
Chromosome Mapping↗
The small cell lung cancer antigen cluster-4 and the leukocyte antigen CD24 are allelic isoforms of the same gene (CD24) on chromosome band 6q21.
Cluster-4 and CD24 cDNA's have recently been cloned from the small cell lung carcinoma (SCLC) cell line SW2 and from the erythroleukemia cell line K562, respectively. The only difference in the coding sequence, between cluster-4 and CD24 antigens is the substitution of a single base pair leading to a substitution of Val by Ala near the putative glycosylphosphatidylinositol (GPI) anchorage sites of the mature protein. Here we demonstrate that the nucleotide substitution which distinguishes the cluster-4 and CD24 antigen genes is due to an allelic polymorphism on chromosome band 6q21. In addition, we identified by Southern blotting and PCR of DNA from somatic human x hamster hybrid cell lines homologues of cluster-4/CD24 on the Y chromosome and chromosome 15. We suggest, however, that the gene on 6q21 is the active locus since the mRNA of cell lines always represents the allelic variants found on chromosome 6. The distribution pattern of this allelic polymorphism in SCLC cell lines and leukocytes of healthy donors did not reveal any obvious relationship with disease. However, it is noteworthy that homozygosity for cluster-4 was found in only one case whereas heterozygosity and homozygosity for CD24 both contribute up to 50% of the samples examined.
Alleles↗
Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins.
BACKGROUND: Intracellular proteins are processed into small peptides that bind HLA class I molecules of the major histocompatibility complex (MHC) in order to be presented to T lymphocytes. The proteasome, a multi-subunit protease, has recently been implicated in the generation of these peptides. Two genes encoding proteasome subunits, LMP2 and LMP7, are tightly linked to the TAP peptide transport loci in the class II region of the human MHC. Inclusion of the LMP subunits may alter proteasome activity, biasing it towards the production of peptides with carboxyl termini appropriate for binding HLA class I molecules. Nevertheless, mutant cells that lack the LMP genes are able to process and present antigens at the cell surface at similar levels to wild-type cells. These results raise questions about the role of the proteasome, and in particular of the LMP subunits, in antigen processing. RESULTS: We have cloned the genes encoding a new proteasome subunit, MB1, which is closely related to LMP7, and that encoding a second subunit, Delta, which is closely related to LMP2. Expression of the MB1 and delta genes is reciprocal to that of the LMP genes: MB1 and delta are up-regulated in mutant cell lines lacking LMPs and down-regulated in the presence of gamma-interferon. The MB1 and delta genes are found to be located on chromosomes 14 and 17, respectively, raising interesting evolutionary questions about how the LMP genes independently became incorporated into the MHC. CONCLUSIONS: We suggest that the subtle phenotype of LMP-deficient cell lines results from the compensatory expression in these lines of two other proteasome subunits, MB1 and Delta.
Amino Acid Sequence↗
The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts.
BACKGROUND: Precise diagnosis of small-round-cell tumors is often a challenge to the pathologist and the clinical oncologist. In Ewing's sarcomas and related peripheral primitive neuroectodermal tumors, a t(11;22) translocation or a (21,22) rearrangement is associated with hybrid transcripts of the EWS gene with the FLI1 or ERG gene. To investigate the diagnostic implication of this observation, we searched for these hybrid transcripts in tumors from patients with clinical and radiologic features of Ewing's sarcoma or peripheral primitive neuroectodermal tumors. METHODS: Samples of RNA from 114 tumors were reverse transcribed and subjected to the polymerase chain reaction with primers designed to amplify the relevant chimeric transcripts. All amplified products were sequenced. RESULTS: In-frame hybrid transcripts were observed in 89 cases. A hybrid transcript was found in 83 of 87 cases (95 percent) of Ewing's sarcoma or peripheral primitive neuroectodermal tumors. Samples of RNA from all of 12 tumors that had been proved to be other than Ewing's sarcoma or neuroectodermal tumors had no hybrid transcript. However, 6 of 15 undifferentiated tumors whose type was ambiguous (nonsecreting, poorly differentiated neuroblastoma or undifferentiated sarcoma) contained a hybrid transcript, suggesting that they might have to be reclassified. CONCLUSIONS: A subgroup of small-round-cell tumors identified as belonging to the Ewing family of tumors can be defined according to a specific molecular genetic lesion that is detectable by a rapid, reliable, and efficient method. This approach can be applied to small specimens obtained by fine-needle biopsies.
Adolescent↗
Mapping of the genes encoding human inducible and endothelial nitric oxide synthase (NOS2 and NOS3) to the pericentric region of chromosome 17 and to chromosome 7, respectively.
Nitric oxide (NO) is an important molecular messenger regulating the functions of a wide variety of cells and tissues. NO is synthesized from L-arginine by a variety of isoforms of the enzyme nitric oxide synthase (NOS). We have used Southern blotting analysis on DNAs obtained from a panel of human-rodent hybrid cell lines to map the gene encoding the inducible NOS (NOS2) to chromosome 17cen-17q11 and the gene encoding the endothelial form of NOS (NOS3) to chromosome 7. Fluorescence in situ hybridization using a NOS2 probe gave several signals in the 17p11-q11 pericentromeric region.
Amino Acid Oxidoreductases↗
The human gene for xeroderma pigmentosum complementation group G (XPG) maps to 13q33 by fluorescence in situ hybridization.
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Animals↗
Molecular analysis of simple variant translocations in acute promyelocytic leukemia.
The primary cytogenetic abnormality in acute promyelocytic leukemia (APL; FAB M3) is a reciprocal translocation, t(15;17)(q22;q12), which serves to fuse the PML gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17. A PML-RARA fusion message transcribed from the der(15) is thought to mediate leukemogenesis. Two APL patients with simple variants of this translocation, t(3;15)(q21;q22) and t(X;15)(p11;q22), have previously been reported who lack cytogenetic involvement of chromosome 17, although their breakpoint positions on chromosome 15 still suggest the involvement of the PML gene. Here we report on a combined analysis by molecular genetics and in situ hybridization of these two patients, in which we wanted to determine whether the PML gene has alternative fusion partners or whether cryptic rearrangement of the RARA locus has occurred instead. A cryptic involvement of RARA was demonstrated in both patients by a combination of Southern analysis, reverse transcription coupled to PCR (RT-PCR), and fluorescence in situ hybridization. The results indicate an absolute requirement for the rearrangement of the RARA gene in the pathogenesis of APL and underline the importance of RARA during normal myeloid differentiation.
Adolescent↗
Mapping of the human SAP1 (SRF accessory protein 1) gene and SAP2, a gene encoding a related protein, to chromosomal bands 1q32 and 12q23, respectively.
SAP1, SAP2, and ELK1 form a related subgroup of ETS-domain proteins that can form ternary complexes with the transcription factor SRF at the c-fos serum response element (SRE). SAP1 was identified by a genetic screen for proteins interacting with SRF expressed in yeast, and SAP2 by its homology with SAP1; ELK1 was previously identified by its homology to the ETS domain. cDNA probes were used to isolate cosmid and phage clones harboring genes encoding SAP1 and SAP2. These clones were subsequently used to map the genes to 1q32 and 12q23, respectively, by fluorescence in situ hybridization.
Chromosome Mapping↗
The CL100 gene, which encodes a dual specificity (Tyr/Thr) MAP kinase phosphatase, is highly conserved and maps to human chromosome 5q34.
Expression of the human CL100 gene is induced in skin fibroblasts in response to oxidative/heat stress and growth factors. The CL100 gene encodes a dual specificity (Tyr/Thr) protein phosphatase that specifically inactivates mitogen-activated protein (MAP) kinase in vitro. In addition, CL100 is able to suppress the activation of MAP kinase by oncogenic ras in extracts of Xenopus oocytes. Thus, the CL100 phosphatase may play an important role in the negative regulation of cellular proliferation and is a likely candidate for a tumour-suppressor gene. Here, we show that DNA sequences homologous to CL100 are present in genomic DNA isolated from mouse, chicken, Xenopus and Drosophila, indicating that the CL100 gene is highly conserved. Using an assay based on the polymerase chain reaction, in conjunction with genomic DNA obtained from human-rodent somatic-cell hybrids, we have determined that the CL100 gene is situated on chromosome 5. Fluorescence in situ hybridisation using a CL100 genomic probe confirms that the CL100 mRNA is transcribed from a single genetic locus and maps the gene to 5q34.
Animals↗
Cloning and characterization of human phosphatase inhibitor-2 (IPP-2) sequences.
cDNA clones similar to rabbit muscle phosphatase inhibitor-2 (IPP-2) were isolated from human libraries. On Northern blots two transcripts of approximately 2kbp and approximately 4kbp were detected in all tissues tested. Analysis of cDNA sequences showed that the longer transcripts were similar to the shorter clones but contained extended 3' ends. The human nucleotide sequence was highly homologous (94% identity) to the rabbit IPP-2 sequence and encoded a peptide of 205 amino acids. IPP-2 sequences were highly conserved throughout vertebrates. Southern hybridization results were consistent with the existence of a family of related IPP-2 sequences in the human genome. Most of these are likely to be pseudogenes, since all of the cDNA clones examined could have originated from a single gene. By in situ hybridization IPP-2 sequences were mapped to several different human chromosomes. We sequenced one gene located in the major histocompatibility complex (MHC) on Chromosome (Chr) 6 that contained the entire coding region of IPP-2.
Amino Acid Sequence↗