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Results for “multigene typing”

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PubMed1997

Structure and function of the CD94 C-type lectin receptor complex involved in recognition of HLA class I molecules.

A multigene family of immunoglobulin superfamily (Ig-SF) killer cell inhibitory receptors (KIRs) specifically recognize HLA class I molecules, while the interaction with H-2 products is mediated by members of the murine Ly49 C-type lectin family. A common structural feature of these receptors with inhibitory function is the presence of cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that couple them to SHP phosphatases. Strong support for the involvement of the CD94 C-type lectin receptor complex in NK cell-mediated recognition of Bw6+ HLA-B, HLA-A and HLA-C alleles has been obtained. The cloned CD94 molecule covalently assembles with at least two different glycoproteins (43 kDa and 39 kDa) to form functional receptors. NK cells inhibited upon HLA recognition express the CD94/p43 dimer, whose specificity for HLA molecules partially overlaps the Ig-SF receptor system. By contrast, NK clones bearing the homologous CD94/p39 receptor are triggered upon its ligation by CD94-specific mAbs. Remarkably, a set of Ig-SF receptors (p50) homologous to p58 KIRs also display an activating function. CD94-associated molecules belong to the NKG2 family of C-type lectins; the NKG2-A gene encodes for the p43 subunit, which contains cytoplasmic ITIMS. Expression of the different CD94 heterodimeric receptors will enable precise analysis of their putative interaction with HLA class I molecules.

Antigens, CD↗

PubMed1987

A small multigene family encodes Gi signal-transduction proteins.

The guanine nucleotide-binding regulatory proteins known as G proteins are receptor-associated signal-transduction molecules that are implicated in the control of a variety of metabolic processes. Recent evidence suggests that G proteins may mediate B-lymphocyte responses to bacterial lipopolysaccharide and may also transduce signals from the T-cell antigen receptor. Since these receptors are uniquely expressed on lymphoid cells, we used molecular cloning strategies to ask whether lymphocytes contain specialized G-protein alpha subunits to assist in signal transduction. Comparison of our two deduced human alpha i amino acid sequences with those previously determined for bovine and rodent G proteins permits the identification of three closely related but distinct types of alpha i molecules that comprise a small multigene family. Using gene-specific probes, we found that both of our alpha i genes are expressed in most cell types but in differing ratios. Our data support the view that a modest repertoire of extremely closely related G proteins mediates the transduction of signals derived from multiple different receptor molecules.

Animals↗

PubMed1998

Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family.

Voltage-activated Ca2+ channels exist as multigene families that share common structural features. Different Ca2+ channels are distinguished by their electrophysiology and pharmacology and can be classified as either low or high voltage-activated channels. Six alpha1 subunit genes cloned previously code for high voltage-activated Ca2+ channels; therefore, we have used a database search strategy to identify new Ca2+ channel genes, possibly including low voltage-activated (T-type) channels. A novel expressed sequence-tagged cDNA clone of alpha1G was used to screen a cDNA library, and in the present study, we report the cloning of alpha1H (or CavT.2), a low voltage-activated Ca2+ channel from human heart. Northern blots of human mRNA detected more alpha1H expression in peripheral tissues, such as kidney and heart, than in brain. We mapped the gene, CACNA1H, to human chromosome 16p13.3 and mouse chromosome 17. Expression of alpha1H in HEK-293 cells resulted in Ca2+ channel currents displaying voltage dependence, kinetics, and unitary conductance characteristic of native T-type Ca2+ channels. The alpha1H channel is sensitive to mibefradil, a nondihydropyridine Ca2+ channel blocker, with an IC50 of 1.4 micromol/L, consistent with the reported potency of mibefradil for T-type Ca2+ channels. Together with alpha1G, a rat brain T-type Ca2+ channel also cloned in our laboratory, these genes define a unique family of Ca2+ channels.

Amino Acid Sequence↗

PubMed1994

Molecular analysis of wild-type and mutant alleles at the Opaque-2 regulatory locus of maize reveals different mutations and types of O2 products.

The expression of the various members of the zein multigene family in maize endosperm is controlled by different regulatory loci. One of these loci, Opaque-2, coding for a bZIP transcriptional factor, controls the expression of a subset of zein genes. Analysis of genomic DNA from plants carrying wild-type (O2) or mutant o2 alleles shows specific DNA restriction patterns that correlate with transcript types and their various gene products. Northern and western analyses show the presence in different wild types of a 1.7 kb transcript coding for different sizes of normal O2 proteins that migrate as doublets in the 68-72 kDa range. Among the various o2 mutants analysed we showed the occurrence of various null-transcript alleles, the presence of alleles with a normal size transcript which, however, produce a different-sized o2 protein, and a mutant producing both a normal size transcript and a longer transcript, but generating only a single o2 product migrating around 40 kDa. Analysis of other mutations (o7, fl2) known to affect zein polypeptide synthesis shows no interference of these mutations in the expression of the O2 gene products. The overall results indicate the occurrence of micro heterogeneity in the O2 wild-type genes and a broad spectrum of o2 mutations, both producing different sizes of O2 or o2 proteins. A nomenclature of the O2 and o2 genes based on the RFLP, transcripts and products of the various alleles is presented.

Alleles↗

PubMed2006

Structural organization and expression of human MTUS1, a candidate 8p22 tumor suppressor gene encoding a family of angiotensin II AT2 receptor-interacting proteins, ATIP.

The Mitochondrial Tumor suppressor 1 (MTUS1) gene is a newly identified candidate tumor suppressor gene at chromosomal position 8p22. We report here that MTUS1 encodes a family of proteins whose leader member (ATIP1) was previously isolated in our laboratory as a novel interacting partner of the angiotensin II AT2 receptor involved in growth inhibition (Nouet, JBC 279: 28989-97, 2004). The MTUS1 gene contains 17 coding exons distributed over 112 kb of genomic DNA. Alternative exon usage generates three major transcripts (ATIP1, ATIP3 and ATIP4), each showing different tissue distribution. ATIP polypeptides are identical in their carboxy-terminal region carrying four coiled-coil domains. In their amino-terminal portion, ATIP polypeptides exhibit distinct motifs for localisation in the cytosol, nucleus or cell membrane, suggesting that MTUS1 gene products may be involved in a variety of intracellular functions in an AT2-dependent and independent manner. ATIP1 is ubiquitous and highly expressed in the brain. ATIP3 is the major transcript in tissues (prostate, bladder, breast, ovary, colon) corresponding to cancer types with frequent loss of heterozygosity at 8p22. Interestingly, ATIP4 is a brain-specific transcript highly abundant in the cerebellum and fetal brain. High evolutionary conservation of ATIP amino-acid sequences suggests important biological roles for this new family of proteins in tumor suppression and/or brain function.

Alternative Splicing↗

PubMed2005

Structural and functional aspects of the Ly49 natural killer cell receptors.

Natural killer cells are part of the first line of innate immune defence against virus-infected cells and cancer cells in the vertebrate immune system. They are called 'natural' killers because, unlike cytotoxic T cells, they do not require a previous challenge and preactivation to become active. The Ly49 NK receptors are type II transmembrane glycoproteins, structurally characterized as disulphide-linked homodimers. They share extensive homology with C-type lectins, and they are encoded by a multigene family that in mice maps on chromosome 6. A fine balance between inhibitory and activating signals regulates the function of NK cells. Inhibitory Ly49 molecules bind primarily MHC class I ligands, whereas the ligands for activating Ly49 molecules may include MHC class I, but also interestingly MHC class I-like molecules expressed by viruses, as is the case for Ly49H, which binds the m157 gene product of murine cytomegalovirus. In this study, we review the function and X-ray crystal structure of the Ly49 NK cell receptors hitherto determined (Ly49A, Ly49C and Ly49I), and the structural features of the Ly49/MHC class I interaction as revealed by the X-ray crystal structures of Ly49A/H-2Dd and the recently determined Ly49C/H-2Kb.

Animals↗

PubMed1994

Structure of the gene coding for the human early lymphocyte activation antigen CD69: a C-type lectin receptor evolutionarily related with the gene families of natural killer cell-specific receptors.

CD69 is the earliest inducible cell surface glycoprotein acquired during lymphoid activation. CD69 functions as a signal transmitting receptor involved in cellular activation events including proliferation and the induction of specific genes. This molecule is a member of a supergene family of type-II integral membrane proteins with C-type lectin domains. We have herein studied the genomic structure of the human gene encoding CD69. The coding sequence is divided into five exons separated by four introns. The first two exons corresponded to separate functional domains of the protein (cytoplasmic tail and the transmembrane region), while the final three exons encoded the carbohydrate-recognition domain (CRD). The conserved intron position between the exons encoding the CRD indicated that this protein is closely related to other type-II receptor groups with the C-type CRD, such as the asialoglycoprotein receptors, the low-affinity IgE receptor (CD23), and natural killer cell-specific receptors, NKR-P1 and Ly49. In contrast to the broad NKR-P1 and Ly-49 gene families, CD69 is a single-copy gene, as demonstrated by Southern blot analyses. The major transcription initiation site has been located, by amplification of cDNA 5' ends, 30 nucleotides downstream of a consensus TATA box. Comparison of human CD69 and mouse NKR-P1 gene structures indicates that the first intron maintains a conserved position, suggesting that CD69 and this gene family may diverge from a common ancestor gene. A possible evolutionary pathway of these genes is proposed.

Antigens, CD↗

PubMed2005

The genes and gene organization of the Ly49 region of the rat natural killer cell gene complex.

We here report the cDNA sequences of 11 new rat Ly49 genes with full and three with incomplete open reading frames. Although obtained from different inbred rat strains, these as well as six previously published cDNA represent non-allelic genes matching different loci in the Brown Norway (BN) rat genome, which is predicted to contain 34 Ly49 loci distributed over the distal part of the NK cell gene complex. Some of the cloned genes appear to be mutated to non-function in the BN genome, which harbors additional genes with full open reading frames, suggesting at least 26 non-allelic functional Ly49 genes in the rat. Of the encoded receptors, 13 are predicted to be inhibitory, eight to be activating, whereas five may be both ('bifunctional'). Phylogenetic analysis bears evidence of a highly dynamic genetic region, in which only the most distally localized Ly49 gene has a clear-cut mouse ortholog. In phylograms, the majority of the genes cluster into three subgroups with the genes mapping together, defining three chromosomal regions that seem to have undergone recent expansions. When comparing the lectin-like domains, the receptors form smaller subgroups, most containing at least one inhibitory and one activating or 'bifunctional' receptor, where close sequence similarities suggest recent homogenization events.

Alleles↗

PubMed1994

The activation antigen CD69.

One of the earliest cell surface antigens expressed by T cells following activation is CD69, which is detectable within one h of ligation of the T cell receptor/CD3 complex. Once expressed, CD69 acts as a costimulatory molecule for T cell activation and proliferation. In addition to mature T cells, CD69 is inducibly expressed by immature thymocytes, B cells, natural killer (NK) cells, monocytes, neutrophils and eosinophils, and is constitutively expressed by mature thymocytes and platelets. Recently, cDNA clones encoding human and mouse CD69 were isolated and showed CD69 to be a member of the C-type lectin superfamily. Gene mapping studies have placed CD69 on distal mouse chromosome 6 and human chromosome 12p13, close to, if not in, the NK gene complex. The structure, chromosomal localization, expression and function of CD69 suggest that it is likely a pleiotropic immune regulator, potentially important not only in NK cell function but also in the activation and differentiation of a wide variety of hematopoietic cells.

Animals↗

PubMed2003

Developmental expression of XEEL, a novel molecule of the Xenopus oocyte cortical granule lectin family.

We have isolated cDNA clones from a Xenopus laevis embryo library that encode a predicted translation product of 342 amino acids containing a signal sequence for secretion. The predicted protein has 62-70% amino acid identity with the Xenopus oocyte cortical granule lectin (XCGL), the mouse intelectin, the human HL-1/intelectin and HL-2. Onset of gene expression occurs by gastrulation, and the transcripts localize in non-ciliated epidermal cells all over the tailbud embryos. The results suggest that the molecule, designated XEEL ( Xenopus embryonic epidermal lectin), is a novel XCGL family molecule secreted from the embryonic epidermis.

Animals↗

PubMed1988

Regulation of cytosine methylation in ribosomal DNA and nucleolus organizer expression in wheat.

Cytosine methylation has been studied in wheat rRNA genes at nucleolar organizers displaying different activities. The methylation pattern within a specific multigene locus is influenced by the number and type of rRNA genes in other rDNA loci in the cell. One CCGG site 164 base-pairs upstream from the start of transcription is preferentially unmethylated in some genes. Dominant, very active loci have a higher proportion of rRNA genes with unmethylated cytosine residues in comparison with recessive and inactive loci. It is concluded that cytosine methylation in rDNA is regulated and that the methylation pattern correlates with the transcription potential of an rRNA gene.

Binding Sites↗

PubMed1992

Candidate natural killer cell receptors.

Among the high points of immunological discovery has been the identification of antigen-recognizing receptors on B and T cells. Of the lymphocyte populations, only the NK cell receptor remains unknown. Consequently, any newly-recognized, cell-surface molecules expressed selectively on NK cells, especially ones that can transmit a signal to the cell upon appropriate ligand interaction, are possible candidates. This article describes such candidates.

Animals↗

PubMed1992

DNA topoisomerases.

DNA topoisomerases play an important role in regulating DNA structure, thus affecting many aspects of chromosome function inside cells. Recent progress in this field raises exciting questions regarding the distinct and critical functions of multiple topoisomerases, and the roles of DNA topoisomerases in the processes of chromosome condensation, decondensation, and segregation.

Antineoplastic Agents↗

PubMed1999

Domain organization, genomic structure, evolution, and regulation of expression of the aggrecan gene family.

Proteoglycans are complex macromolecules, consisting of a polypeptide backbone to which are covalently attached one or more glycosaminoglycan chains. Molecular cloning has allowed identification of the genes encoding the core proteins of various proteoglycans, leading to a better understanding of the diversity of proteoglycan structure and function, as well as to the evolution of a classification of proteoglycans on the basis of emerging gene families that encode the different core proteins. One such family includes several proteoglycans that have been grouped with aggrecan, the large aggregating chondroitin sulfate proteoglycan of cartilage, based on a high number of sequence similarities within the N- and C-terminal domains. Thus far these proteoglycans include versican, neurocan, and brevican. It is now apparent that these proteins, as a group, are truly a gene family with shared structural motifs on the protein and nucleotide (mRNA) levels, and with nearly identical genomic organizations. Clearly a common ancestral origin is indicated for the members of the aggrecan family of proteoglycans. However, differing patterns of amplification and divergence have also occurred within certain exons across species and family members, leading to the class-characteristic protein motifs in the central carbohydrate-rich region exclusively. Thus the overall domain organization strongly suggests that sequence conservation in the terminal globular domains underlies common functions, whereas differences in the central portions of the genes account for functional specialization among the members of this gene family.

Aggrecans↗

PubMed1992

Localization of the expression of type I, II, III collagen, and aggrecan core protein genes in developing human articular cartilage.

The expression of mRNAs for collagen types I, II, III and for aggrecan core protein was studied in developing human femoral cartilage by in situ hybridization, with special attention given to the cartilage covered by the perichondrium and to the articular surface. In parallel, the synthesis of the related proteins was monitored by immunohistochemistry. The cells metabolically active for type I and type III collagen expression were identified by hybridization using [32P]-labeled cDNA clones coding for human alpha 1(I) and alpha 1(III), respectively. Type II collagen and core protein mRNAs were detected by hybridization with specific [32P]-labeled oligonucleotide probes. In the femoral heads of one 22-week old fetus and of one newborn, our in situ hybridization and immunohistochemical analysis revealed that chondrocytes located immediately subjacent to the perichondrium produced collagen types I, II, III as well as aggrecan; whereas only type II collagen and aggrecan gene expression was detected deeper in the cartilage covered by the perichondrium. This observation supports the hypothesis that the inner cell layers of perichondrium are chondrogenic, with a transient state where cells express all the markers studied here. At the articular surface different patterns of expression were observed at the two developmental stages. After 22 weeks of fetal development only collagen types I and III were expressed by the surface zone cells while in the newborn cartilage, these cells expressed all the molecules studied (collagen types I, II, III and cartilage proteoglycan). At both ages the underlying cartilage cells expressed only the cartilage-specific molecules (type II collagen and aggrecan). Thus a progressive transformation of cartilaginous matrix occurs with time from the deep cartilage up to the surface by addition of new components, i.e. aggrecan and type II collagen. These results supplemented by an immunofluorescence analysis on 20-, 26- and 38-week old fetal femoral heads suggest that expression of collagen and aggrecan in the cartilage covered by the perichondrium and in the cartilage at the articular surface are subject to different regulatory mechanisms during development. Furthermore, the appearance of hybridizable core protein and type II collagen mRNAs at the articular surface, closely followed by the appearance of the proteins for which they code, indicates that core protein and type II collagen expression is regulated primarily at the transcriptional level in this region. Finally, the similar topography observed for the expression of these two proteins suggests that the genes for these two major constituents of cartilage matrix are coordinately regulated during growth of articular cartilage.

Aggrecans↗

PubMed2005

Direct sequence comparison of two divergent class I MHC natural killer cell receptor haplotypes.

The murine Ly49 gene family encoding natural killer cell receptors for class I MHC is an example of a rapidly evolving cluster of immune response genes. Determining the genomic sequence of the 129S6/SvEvTac (129S6) Ly49 cluster and comparing it to the known sequence of the C57BL/6 (B6) region provided insight into the mechanisms of Ly49 gene evolution. 129S6 contains 20 Ly49, many of which are pseudogenes and 40% of the genes have no counterpart in the B6 genome. The difference in gene content between these two strains is primarily the result of distinct patterns of gene duplication. Phylogenetic analyses of individual exons showed that Ly49 genes form distinct sub-families and an ancestral haplotype can be surmised. Dotplot analysis supports limited allelism in the two haplotypes; however, large regions of variation punctuate these islands of co-linearity. These variable regions contain a high concentration of repetitive elements that are predicted to contribute to the dynamic evolution of this cluster. The extreme variation in Ly49 haplotype content between mouse strains provides a genetic explanation for the documented differences in natural killer cell phenotype, and also indicates that differences in natural killer cell function observed between B6 and 129-derived gene-targeted mice should be interpreted with caution.

Amino Acid Sequence↗

PubMed1986

A single gene in mast cells encodes the core peptides of heparin and chondroitin sulfate proteoglycans.

The diversity of the genes encoding mammalian proteoglycan peptide cores was explored using a cDNA clone that encodes the partial sequence of a cell surface/pericellular matrix-localized chondroitin sulfate proteoglycan. Thus we were able to detect the expression of the gene(s) encoding the intracellular chondroitin sulfate proteoglycan produced by a variety of rat and mouse mucosal-like mast cells and the intracellular heparin proteoglycan synthesized by rat serosal mast cells. The cDNA from the proteoglycan cDNA clone pPG-1 was fractionated into two discrete fragments, one of which contained the nucleotides encoding the serine-glycine repeat sequence (pPG-B) and the other of which contained sequences on the 3' side of the repeat (pPG-M). As assessed by Southern blot analysis, pPG-B identified a large gene family, whereas pPG-M identified a single DNA fragment in the rat genome. When the pPG-1 insert and the two subcloned probes pPG-B and pPG-M were used to analyze RNA extracted from the rat and mouse mucosal-like mast cells and the rat serosal mast cells, the same major RNA species was detected at 1.3 kilobases with both probes. These data suggest that the gene responsible for the peptide core of the extracellular chondroitin sulfate proteoglycan synthesized by the rat yolk sac cell line is also the gene that encodes the core peptides of the secretory granule-localized chondroitin sulfate and heparin proteoglycans.

Aggrecans↗

PubMed2003

Positive and negative control of virus-induced interferon-A gene expression.

Transcriptional regulation is a consequence of the combination of both activation and repression for establishing specific patterns of eukaryotic gene expression. The regulation of the expression of type I interferon (IFN-A and -B) multigene family is controlled primarily at the transcriptional level and has been widely studied as a model to understand the mechanisms of stable repression, transient expression and postinduction repression of genes. The positive and negative regulatory elements required for this on/off switch have been defined within a complex 5' upstream region of their transcription start site. The differential expression pattern of IFN-A genes is thought to involve both substitutions in the virus responsive element (VRE-A) and presence or absence of the distal negative regulatory element (DNRE) which is delimited upstream of the VRE-A. The interferon regulatory factors (IRF)-3 and -7 binding to the VRE-A and interacting as homodimers or heterodimers participate in the virus-induced transcriptional activation of IFN-A family. This data and the presence of homeodomain protein pituitary homeobox 1 (Pitx1) binding to the distal DNRE, negatively regulating the IRF-3 and IRF-7 activities and interacting physically with IRF-3 and IRF-7 contribute to our understanding of the complex differential transcriptional activation and repression of the IFN-A genes.

Amino Acid Sequence↗