A MspI polymorphism and linkage mapping of the human protein-tyrosine phosphatase G (PTPRG) gene.
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Chromosome Mapping↗
Biomedical subjects
K Huebner
Publications and source records attributed to K Huebner.
YAC-assisted cloning of transcribed sequences from the human chromosome 3p21 region.
The region surrounding the ZNF35 zinc finger protein gene on 3p21 is of particular interest, as this region of chromosome 3 is frequently involved in rearrangements and/or deletions associated with various human tumors including lung and renal carcinoma. We have analyzed yeast artificial chromosomes (YACs), identified by PCR screening, using oligonucleotides derived from the ZNF35 gene. PFGE and Southern blot/hybridization analysis revealed that the clones cover 750-kb including the ZNF35 gene. The use of specific somatic cell hybrids have allowed us to locate the YAC contig telomeric to the D3F15S2 locus, in a region which is frequently deleted in lung carcinomas. In addition, we have developed a novel cDNA hybridization protocol allowing the isolation of transcribed sequences present in the overlapping YAC clones. Using the cDNA hybridization selection, we have isolated and characterized one transcribed sequence (D3S1362E) from the 3p21 YAC contig and the corresponding cDNA has been isolated. DNA sequencing analysis indicated that the D3S1363E cDNA codes for a putative transcription factor. Northern blot analysis indicated that the D3S1362E sequence hybridized to multiple transcripts in skeletal muscle, and weakly hybridizing transcripts of similar sizes were detected in other tissues.
Amino Acid Sequence↗
Identification of a carbonic anhydrase-like domain in the extracellular region of RPTP gamma defines a new subfamily of receptor tyrosine phosphatases.
The tyrosine phosphatase RPTP gamma is a candidate tumor suppressor gene since it is located on human chromosome 3p14.2-p21 in a region frequently deleted in certain types of renal and lung carcinomas. In order to evaluate its oncogenic potential and to explore its normal in vivo functions, we have isolated cDNAs and deduced the complete sequences of both human and murine RPTP gamma. The murine RPTP gamma gene has been localized to chromosome 14 to a region syntenic to the location of the human gene. Northern (RNA) blot analysis reveals the presence of two major transcripts of 5.5 and 8.5 kb in a variety of murine tissues. In situ hybridization analysis reveals that RPTP gamma mRNA is expressed in specific regions of the brain and that the localization of RPTP gamma changes during brain development. RPTP gamma is composed of a putative extracellular domain, a single transmembrane domain, and a cytoplasmic portion with two tandem catalytic tyrosine phosphatase domains. The extracellular domain contains a stretch of 266 amino acids with striking homology to the zinc-containing enzyme carbonic anhydrase (CAH), indicating that RPTP gamma and RPTP beta (HPTP zeta) represent a subfamily of receptor tyrosine phosphatases. We have constructed a model for the CAH-like domain of RPTP gamma based upon the crystal structure of CAH. It appears that 11 of the 19 residues that form the active site of CAH are conserved in RPTP gamma. Yet only one of the three His residues that ligate the zinc atom and are required for catalytic activity is conserved. On the basis of this model we propose that the CAH-like domain of RPTP gamma may have a function other than catalysis of hydration of metabolic CO2.
Amino Acid Sequence↗
Retroposition in a family of carcinoma-associated antigen genes.
The gene encoding the carcinoma-associated antigen defined by the monoclonal antibody GA733 is a member of a family of at least two type I membrane proteins. This study describes the mechanism of evolution of the GA733-1 and GA733-2 genes. A full-length cDNA clone for GA733-1 was obtained by screening a human placental library with a genomic DNA probe. Comparative analysis of the cDNA sequence with the previously determined genomic sequence confirmed that GA733-1 is an intronless gene. The GA733-2 gene encoding the monoclonal antibody-defined antigen was molecularly cloned with a cDNA probe and partially sequenced. Comparison of GA733-2 gene sequences with the previously established cDNA sequence revealed that this gene consists of nine exons. The putative promoter regions of the GA733-1 and GA733-2 genes are unrelated. These findings suggest that the GA733-1 gene was formed by the retroposition of the GA733-2 gene via an mRNA intermediate. Prior to retroposition, the GA733-2 gene had been affected by exon shuffling. Analysis of GA733-2 exons revealed that many delineate structural motifs. The GA733-1 retroposon was localized either to chromosome region 1p32-1p31 or to 1p13-1q12, and the GA733-2 founder gene was localized to chromosome 4q.
Amino Acid Sequence↗
The human ryk cDNA sequence predicts a protein containing two putative transmembrane segments and a tyrosine kinase catalytic domain.
The human ryk tyrosine kinase cDNA was originally identified as a PCR-amplified cDNA fragment (JTK5) from K562 leukemia cells and found to represent a ubiquitously expressed gene (Partanen et al., 1990). The open reading frame of human ryk, reported here, encodes a novel type of putative tyrosine kinase of 607 amino acid residues, having two potential transmembrane domains and homology to receptor tyrosine kinases, such as met (HGF/SF-R) and IGF-1R, in its catalytic domain. The gene maps to human chromosome 3q11-25. Expression of the 3.4 kb ryk mRNA was found in all human adult tissues examined.
Amino Acid Sequence↗
A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system.
We report the isolation of a novel human POU domain encoding gene named RDC-1. The POU domain of the RDC-1 encoded protein is highly related to the POU domain potentially encoded by the rat brain-3 sequence and to that of the Drosophila I-POU protein; outside of the POU region, RDC-1 is unrelated to any previously characterized protein. The RDC-1 gene is expressed almost exclusively in normal tissues and transformed cells of neural origin. In the developing mouse and human fetus, RDC-1 is expressed in a spatially and temporally restricted pattern that suggests a critical role in the differentiation of neuronal tissues. In addition, RDC-1 is expressed in a unique subset of tumors of the peripheral nervous system including neuroepitheliomas and Ewing's sarcomas but not neuroblastomas. Based on its unique structural characteristics and expression pattern, we discuss potential functions for the RDC-1 protein.
Amino Acid Sequence↗
Molecular cloning of cDNAs for the human granulocyte colony-stimulating factor receptor from HL-60 and mapping of the gene to chromosome region 1p32-34.
Early studies examining the effects of purified or recombinant granulocyte colony-stimulating factor (G-CSF) on human leukemia cell lines demonstrated that some cell lines, such as HL-60, could be induced to differentiate in response to G-CSF. In two recent studies reporting the cloning of the human G-CSF receptor (hGCSFR), four classes of receptor cDNA were identified and, surprisingly, the message for this receptor was reportedly expressed by HL-60 at either very low levels or not at all. Using a mouse G-CSF receptor probe, we cloned and sequenced a cDNA for hGCSFR from an HL-60 cDNA library in plasmid and used it to identify 31 additional clones from an HL-60 cDNA library in phage. Polymerase chain reaction analysis of the 31 phage clones established that 29 were derived from class I hGCSFR mRNA, one was derived from class III mRNA, and one was derived from class IV mRNA. In addition, the hGCSFR gene was chromosomally localized by Southern blot analysis of its segregation pattern in a panel of rodent-human hybrid DNAs using the radiolabeled cDNA probe. The hGCSFR locus was present in hybrids retaining the distal short arm of human chromosome 1 and absent in hybrids that did not retain this region. Chromosomal in situ hybridization refined the localization of the hGCSFR gene to region 1p32-p34. The combination of hybrid DNA analysis and in situ hybridization places the hGCSFR gene telomeric to the CSF1, JUN, and TCL-5 loci.
Base Sequence↗
FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter.
The receptors for at least two hematopoietic growth factors, namely the stem cell factor and colony-stimulating factor 1, belong to class III receptor tyrosine kinases. Here we describe cloning of a partial complementary DNA for FLT4, an additional member of this gene family from human leukemia cells. The FLT4 tyrosine kinase domain is 79% homologous with the previously cloned FLT1 (M. Shibuya et al., Oncogene, 5: 519-524, 1990) tyrosine kinase and maps to the chromosomal region 5q33-qter. We have found FLT4 expression in human placenta, lung, heart, and kidney, whereas the pancreas and brain appeared to contain very little if any FLT4 RNA. The results suggest that FLT4 functions in multiple adult tissues.
Adult↗
Localization of the fibroblast growth factor receptor-4 gene to chromosome region 5q33-qter.
Our polymerase chain reaction cloning of novel tyrosine kinases expressed in the K562 chronic myeloid leukemia cells has revealed a novel fibroblast growth factor receptor, FGFR4. We have here mapped the FGFR4 gene by analysis of somatic cell hybrids and in situ hybridization to the 5q33-qter chromosomal region. This finding is of interest in that the FGFR4 gene is expressed in several leukemia cell lines and the 5q33-qter region is involved in nonrandom chromosomal translocations in acute myelogenous leukemias and Ki-I lymphomas.
Chromosome Mapping↗
A human histone H2B.1 variant gene, located on chromosome 1, utilizes alternative 3' end processing.
A variant human H2B histone gene (GL105), previously shown to encode a 2300 nt replication independent mRNA, has been cloned. We demonstrate this gene expresses alternative mRNAs regulated differentially during the HeLa S3 cell cycle. The H2B-Gl105 gene encodes both a 500 nt cell cycle dependent mRNA and a 2300 nt constitutively expressed mRNA. The 3' end of the cell cycle regulated mRNA terminates immediately following the region of hyphenated dyad symmetry typical of most histone mRNAs, whereas the constitutively expressed mRNA has a 1798 nt non-translated trailer that contains the same region of hyphenated dyad symmetry but is polyadenylated. The cap site for the H2B-GL105 mRNAs is located 42 nt upstream of the protein coding region. The H2B-GL105 histone gene was localized to chromosome region 1q21-1q23 by chromosomal in situ hybridization and by analysis of rodent-human somatic cell hybrids using an H2B-GL105 specific probe. The H2B-GL105 gene is paired with a functional H2A histone gene and this H2A/H2B gene pair is separated by a bidirectionally transcribed intergenic promoter region containing consensus TATA and CCAAT boxes and an OTF-1 element. These results demonstrate that cell cycle regulated and constitutively expressed histone mRNAs can be encoded by the same gene, and indicate that alternative 3' end processing may be an important mechanism for regulation of histone mRNA. Such control further increases the versatility by which cells can modulate the synthesis of replication-dependent as well as variant histone proteins during the cell cycle and at the onset of differentiation.
Amino Acid Sequence↗
Localization of 11q13 loci with respect to regional chromosomal breakpoints.
We have employed two strategies to map 13 markers located at 11q13. First, we used pulsed-field gel electrophoresis of DNA fragments obtained with methylation-sensitive restriction enzymes. The markers used in this study were scattered over 8.4 Mb and, for most of them, could not be linked one to another. A second mapping strategy employed hybridization to either DNA of somatic hybrids containing various parts of the long arm of chromosome 11 or metaphase chromosomes of a B-cell line containing the t(11;14)(q13;q32) translocation. We were able to sort out the centromeric from the telomeric probes with respect to translocation breakpoints taken as reference chromosomal landmarks by this approach. BCL1, which corresponds to the region where the t(11;14)(q13;q32) translocation breakpoints are clustered, appears as a boundary between two areas of human/mouse homology present in conserved syntenic regions on mouse chromosomes 7 and 19.
Animals↗
Chromosomal assignment of a gene encoding a new collagen type (COL15A1) to 9q21 --> q22.
The collagens constitute a large family of extracellular matrix components primarily responsible for maintaining the structure and biological integrity of connective tissue. These proteins exhibit considerable diversity size, sequence, tissue distribution, and molecular composition. Fourteen types of homo- and/or heterotrimeric molecules, thus far reported, are encoded by a minimum of 27 genes. Nineteen of these genes, including several that are closely linked, have been assigned to 10 separate autosomes, and one collagen gene has been mapped to the X chromosome. We have isolated a 2.1-kb human cDNA clone coding for a collagen molecule different in sequence and structure from types I-XIV collagens. This polypeptide has been designated the alpha 1 chain of type XV collagen. To determine the location of the corresponding gene, the cDNA clone was hybridized to rodent-human hybrid DNAs and to human metaphase chromosomes. The results obtained using the hybrid cell lines showed that this newly identified collagen gene, COL15A1, is present in the pter --> q34 region of chromosome 9. In situ hybridization allowed sublocalization to 9q21 --> q22, a region to which no other collagen genes had previously been assigned. Our data further demonstrate the complex arrangement of the many collagen genes in the human genome.
Amino Acid Sequence↗
Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5.
IL12 (formerly NKSF or CLMF) is a unique cytokine composed of two unrelated disulfide-linked subunits. The larger 40-kDa subunit (p40) is a member of the cytokine receptor family, and the smaller 35-kDa subunit (p35) is related to IL6 and GCSF. The chromosomal localization of these two subunits was determined by PCR analysis of DNA from rodent-human hybrids. More refined mapping was obtained by PCR analysis of hybrids containing translocation chromosomes and for p40, by analysis of radiation hybrids. The subunits map to different chromosomes: p40 (IL12B) to 5q31-q33 and p35 (IL12A) to 3p12-3q13.2.
Animals↗
A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains.
Endothelial cell surfaces play key roles in several important physiological and pathological processes such as blood clotting, angiogenic responses, and inflammation. Here we describe the cloning and characterization of tie, a novel type of human endothelial cell surface receptor tyrosine kinase. The extracellular domain of the predicted tie protein product has an exceptional multidomain structure consisting of a cluster of three epidermal growth factor homology motifs embedded between two immunoglobulinlike loops, which are followed by three fibronectin type III repeats next to the transmembrane region. Additionally, a cDNA form lacking the first of the three epidermal growth factor homology domains was isolated, suggesting that alternative splicing creates different tie-type receptors. Cells transfected with tie cDNA expression vector produce glycosylated polypeptides of 117 kDa which are reactive to antisera raised against the tie carboxy terminus. The tie gene was located in chromosomal region 1p33 to 1p34. Expression of the tie gene appeared to be restricted in some cell lines; large amounts of tie mRNA were detected in endothelial cell lines and in some myeloid leukemia cell lines with erythroid and megakaryoblastoid characteristics. In addition, mRNA in situ studies further indicated the endothelial expression of the tie gene. The tie receptor tyrosine kinase may have evolved for multiple protein-protein interactions, possibly including cell adhesion to the vascular endothelium.
Amino Acid Sequence↗
The c-src tyrosine kinase (CSK) gene, a potential antioncogene, localizes to human chromosome region 15q23----q25.
We have previously reported the cloning of a novel cytoplasmic tyrosine kinase, CSK. This tyrosine kinase has been shown to downregulate the tyrosine kinase activity of the c-src oncoprotein through tyrosine phosphorylation of the c-src carboxyl terminus. Cell transformation by src oncoproteins is caused by several oncogenic mechanisms, which interfere with this phosphorylation. The CSK gene could therefore potentially function as an antioncogene. We have here mapped the CSK gene to 15q23----q25 by in situ hybridization.
CSK Tyrosine-Protein Kinase↗
The human platelet-derived growth factor alpha chain (PDGFA) gene maps to chromosome 7p22.
The human PDGFA gene has been mapped previously to two different sites on chromosome 7 (7p21----p22 and 7q11.2----q21.1). Using in situ hybridization and human x mouse somatic cell hybrid lines we present data which confirm the localization of PDGFA to the terminal short arm of chromosome 7, at 7p22.
Blotting, Southern↗
A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells.
Tre is a recombinant gene isolated from NIH3T3 cells transfected with human Ewing's sarcoma DNA. It is composed of three major genetic elements derived, 5' to 3', from human chromosomes 5, 18 and 17. We report here on transcripts from the 3' domain of tre. The transcripts were cloned from a cDNA library of cytoplasmic poly(A)+ RNA from tre-transfected NIH3T3 tumor cells. The complete cDNA sequence, 8201 nucleotides, possessed an unusually long non-coding region and a translatable region with two open reading frames. In one cDNA clone, the presence of two insertions suggested the possibility of alternative splicing. The sequence mapped to the centromere-proximal region of 17q. Transfection-tumorigenicity assays with the open reading frames subcloned into expression vectors were positive for the reading frame adjacent to the 5' non-coding region and negative for the second, downstream, reading frame and the possible alternatively spliced versions of both reading frames. Analysis of the 786 amino acid sequence deduced from the 5' reading frame predicted a highly hydrophilic protein with two charge clusters suggesting nucleic acid-binding properties. When used as probe, the cloned sequence detected RNA transcripts in a wide variety of human cancer cells regardless of their lineage of origin from different tissues, but not in human cells from normal tissue.
3T3 Cells↗
B-raf and a B-raf pseudogene are located on 7q in man.
The B-raf gene was localized to human chromosome region 7p11-7qter by Southern blot analysis of its segregation in a panel of rodent-human hybrids, using a B-raf cDNA clone. Chromosomal in situ hybridization refined the localization to 7q33-36. Analysis of genomic B-raf clones identified a B-raf pseudogene in addition to the active gene. Based on the chromosomal mapping data we conclude that the pseudogene is located near the active gene.
Base Sequence↗