PubMed Health⌕ Search

Biomedical subjects

S Weremowicz

Publications and source records attributed to S Weremowicz.

At least 55 records · Page 3Linked to original sources
PubMed1996

A gene similar to PKD1 maps to chromosome 4q22: a candidate gene for PKD2.

We report a partial cDNA sequence that encodes a protein, dubbed "polycystwin," with 21% identify and 46% similarity to amino acids 3688-4109 of the carboxyl terminus of polycystin, the gene product of the autosomal dominant polycystic kidney disease locus located on chromosome 16 at band p13 (PKD1). Northern analysis demonstrates that the R48321 gene is expressed in all tissues examined, including both adult and fetal kidneys. Finally, in situ hybridization studies localize this novel gene to 4q22, where PKD2, the second most common locus for ADPKD, is known to map. Therefore, R48321 is an excellent candidate gene for PKD2.

Amino Acid Sequence↗
PubMed1996

Cloning of human RTEF-1, a transcriptional enhancer factor-1-related gene preferentially expressed in skeletal muscle: evidence for an ancient multigene family.

Transcriptional Enhancer Factor-1 (TEF-1) is a transcription factor required for cardiac muscle gene activation. Since ablation of TEF-1 does not abolish cardiac gene expression, we sought to identify a human gene related to TEF-1 (RTEF-1) that might also participate in cardiac gene regulation. A human heart cDNA library was screened to obtain a full-length RTEF-1 cDNA. Fluorescence in situ hybridization assigned the RTEF-1 gene to chromosome 12p13.2-p13.3. In contrast, PCR screening of human/rodent cell hybrid panels identified TEF-1 on chromosome 11p15.2, between D11S1315 and D11S1334, extending a region of known synteny between human chromosomes 11 and 12 and arguing for an ancient divergence between these two closely related genes. Northern blot analysis revealed a striking similarity in the tissue distribution of RTEF-1 and TEF-1 mRNAs; skeletal muscle showed the highest abundance of both mRNAs, with lower levels detected in pancreas, placenta, and heart. Phylogenetic analysis of all known TEF-1-related proteins identified human RTEF-1 as one of four vertebrate members of this multigene family and further suggests that these genes diverged in the earliest metazoan ancestors.

Amino Acid Sequence↗
PubMed1996

The protein tyrosine phosphatase epsilon gene maps to mouse chromosome 7 and human chromosome 10q26.

We have mapped the mouse protein tyrosine phosphatase epsilon (PTP epsilon, gene symbol Ptpre) gene to the distal region of chromosome 7 by linkage analysis using two sets of multilocus genetic crosses. The human PTP epsilon gene (gene symbol PTPRE) was mapped to chromosome 10q26 by fluorescence in situ hybridization. We have previously documented the existence of two isoforms of PTP epsilon--a transmembranal, receptor-type isoform and a shorter, cytoplasmic one. Both isoforms have been suggested to arise from a single gene through the use of alternative promoters and 5' exons. The identification of a single PTP epsilon locus in both organisms is consistent with this suggestion.

Animals↗
PubMed1996

Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas.

Uterine leiomyomata are the most common pelvic tumors in women and are the indication for more than 200,000 hysterectomies annually in the United States. Rearrangement of chromosome 12 in bands q14-q15 is characteristic of uterine leiomyomata and other benign mesenchymal tumors, and we identified a yeast artificial chromosome (YAC) spanning chromosome 12 translocation breakpoints in a uterine leiomyoma, a pulmonary chondroid hamartoma, and a lipoma. Recently, we demonstrated that HMGIC, which is an architectural factor mapping within the YAC, is disrupted in lipomas, resulting in novel fusion transcripts. Here, we report on the localization of translocation breakpoints in seven uterine leiomyomata from 10 to > 100 kb upstream of HMGIC by use of fluorescence in situ hybridization. Our findings suggest a different pathobiologic mechanism in uterine leiomyomata from that in lipomas. HMGIC is the first gene identified in chromosomal rearrangements in uterine leiomyomata and has important implications for an understanding of benign mesenchymal proliferation and differentiation.

Chromosomes, Human, Pair 12↗
PubMed1996

Fluorescence in situ hybridization for the detection of aneuploidy from archived fetal cells.

BACKGROUND: In perinatal settings, fluorescence in situ hybridization has the potential to provide specific chromosome evaluation when full karyotype analysis is not possible because there are no dividing cells. CASE: Based on clinical features, cases of fetal and neonatal demise were selected for evaluation with chromosome-specific probes. Sources of nondividing cells included deparaffinated tissue sections, disaggregated tissue biopsies, and archived, Giemsa-stained slides. CONCLUSION: Diagnostic information was obtained by fluorescence in situ hybridization in three settings: 1) postmortem trisomy 21 identification from paraffin sections following unsuccessful tissue culture, 2) postmortem trisomy 18 confirmation in disaggregated cells from macerated fetal tissues, and 3) retrospective documentation of a cryptic deletion (22q-) in archived metaphase spreads. We encourage familiarity by obstetricians with fluorescence in situ hybridization for chromosomal assessment using archived fetal material.

Abnormalities, Multiple↗
PubMed1995

Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains.

Lipomas are one of the most common mesenchymal neoplasms in humans. They are characterized by consistent cytogenetic aberrations involving chromosome 12 in bands q14-15. Interestingly, this region is also the site of rearrangement for other mesenchymally derived tumors. This study demonstrates that HMGI-C, an architectural factor that functions in transcriptional regulation, has been disrupted by rearrangement at the 12q14-15 chromosomal breakpoint in lipomas. Chimeric transcripts were isolated from two lipomas in which HMGI-C DNA-binding domains (AT hook motifs) are fused to either a LIM or an acidic transactivation domain. These results, identifying a gene rearranged in a benign neoplastic process that does not proceed to a malignancy, suggest a role for HMGI-C in adipogenesis and mesenchyme differentiation.

Amino Acid Sequence↗
PubMed1995

Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11.

The mitogen-induced gene, DUSP2, encodes a nuclear protein, PAC1, that acts as a dual-specific protein phosphatase with stringent substrate specificity for MAP kinase. MAP kinase phosphorylation and consequent enzymatic activation is a central and often obligatory component in signal transduction initiated by growth factor stimulation or resulting from various types of oncogenic transformation. DUSP2 downregulates intracellular signal transduction through the dephosphorylation/inactivation of MAP kinases. To facilitate assessment of the possible role of DUSP2 in growth processes, the genomic structure and chromosomal location of the gene have been determined. DUSP2 has been localized to the pericentromeric region of human chromosome 2 (2p11.2-q11) by analysis of somatic cell hybrids, in situ chromosome hybridization, and genetic linkage analysis using a single-strand conformational polymorphism (SSCP) that has been identified in the 3' UTR of the gene. No consistent translocations or deletions at this chromosomal site have been reported in hematopoietic neoplasias or other tumors.

Base Sequence↗
PubMed1995

Identification of a YAC spanning the translocation breakpoints in uterine leiomyomata, pulmonary chondroid hamartoma, and lipoma: physical mapping of the 12q14-q15 breakpoint region in uterine leiomyomata.

Uterine leiomyomata are the most common tumors in women and can cause abnormal uterine bleeding, pelvic pain, and infertility. Approximately 200,000 hysterectomies are performed annually in the U.S. to relieve patients of the medical sequelae of these benign neoplasms. Our efforts have focused on cloning the t(12;14)(q14-q15;q23-q24) breakpoint in uterine leiomyoma to further our understanding of the biology of these tumors. Thirty-nine YACs and six cosmids mapping to 12q14-q15 have been mapped by fluorescence in situ hybridization to tumor metaphase chromosomes containing a t(12;14). One YAC spanned the translocation breakpoint and was mapped to tumor metaphases from a pulmonary chondroid hamartoma containing a t(12;14)(q14-q15;q23-q24) and a lipoma containing a t(12;15)(q15;q24); this YAC also spanned the breakpoint in these two tumors, suggesting that the same gene on chromosome 12 may be involved in the pathobiology of these distinct benign neoplasms.

Base Sequence↗
PubMed1995

Mapping of the human cone transducin alpha-subunit (GNAT2) gene to 1p13 and negative mutation analysis in patients with Stargardt disease.

We report localization of the human cone transducin (GNAT2) gene using fluorescence in situ hybridization on chromosome 1 in band p13. The recent assignment of a gene for Stargardt disease to the same chromosomal region by linkage analysis prompted us to investigate the possible role of GNAT2 in the pathogenesis of this disease. We investigated 66 unrelated patients for mutations in the coding region of the GNAT2 gene using polymerase chain reaction-single strand conformation polymorphism analysis (SSCP) and direct sequencing. No disease-specific mutations were found, indicating that GNAT2 is probably not involved in the pathogenesis of most cases of Stargardt disease.

Base Sequence↗
PubMed1995

RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation.

A novel pp90rsk Ser/Thr kinase (referred to as RSK3) was cloned from a human cDNA library. The RSK3 cDNA encodes a predicted 733-amino-acid protein with a unique N-terminal region containing a putative nuclear localization signal. RSK3 mRNA was widely expressed (but was predominant in lung and skeletal muscle). By using fluorescence in situ hybridization, the human RSK3 gene was localized to band q27 of chromosome 6. Hemagglutinin epitope-tagged RSK3 was expressed in transiently transfected COS cells. Growth factors, serum, and phorbol ester stimulated autophosphorylation of recombinant RSK3 and its kinase activity toward several protein substrates known to be phosphorylated by RSKs. However, the relative substrate specificity of RSK3 differed from that reported for other isoforms. RSK3 also phosphorylated potential nuclear target proteins including c-Fos and histones. Furthermore, although RSK3 was inactivated by protein phosphatase 2A in vitro, the enzyme was not activated by ERK2/mitogen-activated protein (MAP) kinase. In contrast, the kinase activity of another epitope-tagged RSK isoform (RSK-1) was significantly increased by in vitro incubation with ERK2/MAP kinase. Finally, we used affinity-purified RSK3 antibodies to demonstrate by immunofluorescence that endogenous RSK3 undergoes serum-stimulated nuclear translocation in cultured HeLa cells. These results provide evidence that RSK3 is a third distinct isoform of pp90rsk which translocates to the cell nucleus, phosphorylates potential nuclear targets, and may have a unique upstream activator. RSK3 may therefore subserve a discrete physiologic role(s) that differs from those of the other two known mammalian RSK isoforms.

Amino Acid Sequence↗
PubMed1995

Expression of two human skeletal calcitonin receptor isoforms cloned from a giant cell tumor of bone. The first intracellular domain modulates ligand binding and signal transduction.

Two distinct calcitonin (CT) receptor (CTR)-encoding cDNAs (designated GC-2 and GC-10) were cloned and characterized from giant cell tumor of bone (GCT). Both GC-2 and GC-10 differ structurally from the human ovarian cell CTR (o-hCTR) that we cloned previously, but differ from each other only by the presence (GC-10) or absence (GC-2) of a predicted 16-amino acid insert in the putative first intracellular domain. Expression of all three CTR isoforms in COS cells demonstrated that GC-2 has a lower binding affinity for salmon (s) CT (Kd approximately 15 nM) than GC-10 or o-hCTR (Kd approximately 1.5 nM). Maximal stimulatory concentrations of CT resulted in a mean accumulation of cAMP in GC-2 transfected cells that was greater than eight times higher than in cells transfected with GC-10 after normalizing for the number of receptor-expressing cells. The marked difference in maximal cAMP response was also apparent after normalizing for receptor number. GC-2 also demonstrated a more potent ligand-mediated cAMP response compared with GC-10 for both human (h) and sCT (the EC50 values for GC-2 were approximately 0.2 nM for sCT and approximately 2 nM for hCT; EC50 values for GC-10 were approximately 6 nM for sCT and approximately 25 nM for hCT). Reverse transcriptase PCR of GCT RNA indicated that GC-2 transcripts are more abundant than those encoding for GC-10. In situ hybridization on GCT tissue sections demonstrated CTR mRNA expression in osteoclast-like cells. We localized the human CTR gene to chromosome 7 in band q22. The distinct functional characteristics of GC-2 and GC-10, which differ in structure only in the first intracellular domain, indicate that the first intracellular domain of the CTR plays a previously unidentified role in modulating ligand binding and signal transduction via the G protein/adenylate cyclase system.

Animals↗
PubMed1995

Trinucleotide repeats at the rad locus. Allele distributions in NIDDM and mapping to a 3-cM region on chromosome 16q.

A 10-allele polymorphism was identified in rad (ras associated with diabetes), a gene that is overexpressed in non-insulin-dependent diabetes mellitus (NIDDM) muscle. The polymorphism, designated RAD1, consists of a variable number of trinucleotide repeats (GTT and ATT) located in the poly(A) region of an intronic Alu sequence. Based on the number of GTT and ATT repetitions, the alleles can be grouped into four classes (I-IV). RAD1 allele frequencies were determined in 210 NIDDM patients and 133 nondiabetic control subjects, all Caucasians. One allele (number 8, class III) accounted for > 80% of the chromosomes in both groups. However, an excess of minor alleles, all belonging to class I, II, or IV, was observed among NIDDM chromosomes (P < 0.025), suggesting a possible association between RAD1 and NIDDM predisposition. To promote further studies to test the hypothesis that genetic variability at the rad locus contributes to NIDDM, we mapped rad on the human genome. Using the fluorescence in situ chromosomal hybridization technique, rad was unequivocally assigned to chromosomal band 16q22. In families that were informative for RAD1, the rad locus was mapped within a 3-cM region defined by the markers D16S265, D16S186, and D16S397 (logarithm of odds scores = 10.08, 10.9, and 10.84 at recombination fractions of 0.024, 0.001, and 0.03, respectively). The high degree of heterozygosity of these markers will allow large-scale family studies to be performed to test the presence of linkage between rad and NIDDM.

Alleles↗
PubMed1994

Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene.

Nitric oxide (NO) is an important intercellular signaling molecule synthesized in diverse human tissues by proteins encoded by a family of NO synthase (NOS) genes. The similarity of sequence and cofactor binding sites has suggested that the NOS genes may also be related to cytochrome P450 reductase, as well as to plant and bacterial oxidoreductases. Endothelial NOS activity is a major determinant of vascular tone and blood pressure, and in several important (and sometimes hereditary) disease states, such as hypertension, diabetes, and atherosclerosis, the endothelial NO signaling system appears to be abnormal. To explore the relationship of the endothelial NOS gene to other similar genes, and to delineate the genetic factors involved in regulating endothelial NOS activity, we isolated the human gene encoding the endothelial NOS. Genomic clones containing the 5' end of this gene were identified in a human genomic library by applying a polymerase chain reaction (PCR)-based approach. Identification of the human gene for endothelial NOS (NOS3) was confirmed by nucleotide sequence analysis of the first coding exon, which was found to be identical to its cognate cDNA. The NOS3 gene spans at least 20 kb and appears to contain multiple introns. The transcription start site and promoter region of the NOS3 gene were identified by primer extension and ribonuclease protection assays. Sequencing of the putative promoter revealed consensus sequences for the shear stress-response element, as well as cytokine-responsive cis regulatory sequences, both possibly important to the roles played by NOS3 in the normal and the diseased cardiovascular system.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Identification of genetically aberrant cell lineages in Wilms' tumors.

Most Wilms' tumors contain several predominant cell types, of which a primitive blastemal population is often the most prominent. Other typical components include undifferentiated mesenchymal and epithelial cells, but it has not been demonstrated that these components are neoplastic. We used a combined cytogenetic and fluorescence in situ hybridization approach to determine the clonal relationship of different cell populations within six Wilms' tumors. Clonal numerical chromosome aberrations in three Wilms' tumors were found in blastemal cells, but not in mesenchymal cells. Loss of one WT1 allele in two other tumors was detected in both blastemal and mesenchymal cells. Tetrasomy 18 in a sixth case was observed in mesenchymal and epithelial cells; blastemal cells could not be evaluated in this tumor. These findings demonstrate that mesenchymal and epithelial cells in some Wilms' tumors are neoplastic. Different histologic components in some Wilms' tumors derive from a single chromosomally aberrant ancestor which is most likely to be the primitive blastemal cell.

Child↗
PubMed1994

Characterization of human and mouse cartilage oligomeric matrix protein.

Cartilage oligomeric matrix protein (COMP) is a 524,000-Da protein that is expressed at high levels in the territorial matrix of chondrocytes. The sequences of rat and bovine COMP indicate that it is a member of the thrombospondin gene family. In this study, we have cloned and sequenced human COMP. Phylogenetic analysis using progressive sequence alignment and two parsimony-based algorithms indicates that the COMP gene and a precursor of the thrombospondin-3 and -4 genes were produced by a gene duplication that occurred 750 million years ago. An interspecific backcross mapping panel has been used to map the murine COMP gene to the central region of mouse chromosome 8. Southern blot analysis of a somatic cell hybrid DNA panel and in situ hybridization to human metaphase chromosomes indicate that the human COMP gene is located on chromosome 19 in band p13.1. These data confirm and extend the known regions of homology between human and mouse chromosomes and establish that COMP, like thrombospondin-1, -2, -3, and -4, is present in the human and mouse genomes.

Animals↗
PubMed1994

Translocations in 7q22 define a critical region in uterine leiomyomata.

Rearrangements involving the long arm of chromosome 7 in uterine leiomyoma are widely recognized and comprise one of the major cytogenetic subgroups of these tumors. To approach a molecular genetic investigation of this subgroup for identification of a gene(s) involved in the biology of uterine leiomyomata we have analyzed breakpoints in the del(7q) subgroup in a series of myomas karyotyped in our laboratory. Herein we report the cytogenetic analysis of 11 uterine leiomyomata: eight with interstitial deletions in the long arm of chromosome 7 and three with translocations in 7q. These translocations provide further support for 7q22 as the critical band in the del(7q) subgroup.

Chromosome Deletion↗