A novel Sp1-family-related cis-acting element for transcription of type VII collagen gene (COL7A1).
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Collagen Type VII↗
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Results for “multigene typing”
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The centromeric part of the human natural killer (NK) receptor complex: lectin-like receptor genes expressed in NK, dendritic and endothelial cells.
The human natural killer (NK) receptor complex encompasses a region of about 2 Mb on the short arm of chromosome 12. It contains at least 18 lectin-like receptor genes, of which some are expressed in NK and NK/T cells and function as NK receptors. Close to the CD94 and NKG2 NK receptor genes in the centromeric part, a novel family of genes, expressed in myeloid, dendritic and/or endothelial cells, recently became evident. These genes encode a receptor for oxidized low density lipoprotein in endothelial cells and three other receptors potentially serving regulatory functions in dendritic cells. Although the overall structure of the human NK receptor complex is similar to the syntenic rodent regions, the centromeric part lacks the cluster of Ly49 genes. This supports the notion that recognition of MHC class Ia molecules has evolved separately in rodents and humans in the lectin-like Ly49 and the killer immunoglobulin-like receptors, respectively. In the telomeric part, other lectin-like genes expressed in different hematopoietic lineages are found. The receptors of the NK receptor complex apparently serve important functions in several leukocytes and in endothelial cells, and the exact role of these receptors, their ligands, and their distinct and co-ordinate regulation in different cell lineages warrants further investigation.
Animals↗
Genes for the trophoblast interferons and their distribution among mammals.
The trophoblast interferons (IFN), ovine and bovine trophoblast protein-1 (oTP-1 and bTP-1 respectively), possess many properties in common with other Type I IFN, including antiviral and antiproliferative activities. However, they differ from other IFN subtypes in terms of their specific pattern of expression and poor responsiveness to viral stimulation. We describe here data that suggest that the trophoblast IFN genes are also distinct from other Type I IFN genes with respect to species distribution, promoter organization and transcriptional regulation. These results have important implications in terms of trophoblast IFN gene evolution and add credence to the concept that the trophoblast IFN genes are a distinct IFN gene subtype well suited for their role in early pregnancy.
Animals↗
Primary structure and cellular localization of chicken brain myosin-V (p190), an unconventional myosin with calmodulin light chains.
Recent biochemical studies of p190, a calmodulin (CM)-binding protein purified from vertebrate brain, have demonstrated that this protein, purified as a complex with bound CM, shares a number of properties with myosins (Espindola, F. S., E. M. Espreafico, M. V. Coelho, A. R. Martins, F. R. C. Costa, M. S. Mooseker, and R. E. Larson. 1992. J. Cell Biol. 118:359-368). To determine whether or not p190 was a member of the myosin family of proteins, a set of overlapping cDNAs encoding the full-length protein sequence of chicken brain p190 was isolated and sequenced. Verification that the deduced primary structure was that of p190 was demonstrated through microsequence analysis of a cyanogen bromide peptide generated from chick brain p190. The deduced primary structure of chicken brain p190 revealed that this 1,830-amino acid (aa) 212,509-D) protein is a member of a novel structural class of unconventional myosins that includes the gene products encoded by the dilute locus of mouse and the MYO2 gene of Saccharomyces cerevisiae. We have named the p190-CM complex "myosin-V" based on the results of a detailed sequence comparison of the head domains of 29 myosin heavy chains (hc), which has revealed that this myosin, based on head structure, is the fifth of six distinct structural classes of myosin to be described thus far. Like the presumed products of the mouse dilute and yeast MYO2 genes, the head domain of chicken myosin-V hc (aa 1-764) is linked to a "neck" domain (aa 765-909) consisting of six tandem repeats of an approximately 23-aa "IQ-motif." All known myosins contain at least one such motif at their head-tail junctions; these IQ-motifs may function as calmodulin or light chain binding sites. The tail domain of chicken myosin-V consists of an initial 511 aa predicted to form several segments of coiled-coil alpha helix followed by a terminal 410-aa globular domain (aa, 1,421-1,830). Interestingly, a portion of the tail domain (aa, 1,094-1,830) shares 58% amino acid sequence identity with a 723-aa protein from mouse brain reported to be a glutamic acid decarboxylase. The neck region of chicken myosin-V, which contains the IQ-motifs, was demonstrated to contain the binding sites for CM by analyzing CM binding to bacterially expressed fusion proteins containing the head, neck, and tail domains. Immunolocalization of myosin-V in brain and in cultured cells revealed an unusual distribution for this myosin in both neurons and nonneuronal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
In vivo expression of an interferon-alpha gene by intramuscular injection of naked DNA.
Acid-stable type I interferons belong to a multigene family. The biologic relevance of each subtype in vivo remains unknown. We have developed an experimental model in which muscles were transfected in situ with naked DNA plasmids encoding an IFN transgene to assess the roles of individual IFN subtypes in vivo. Murine IFN-alpha 9 gene was subcloned into several mammalian expression vectors. Adult C57BL/6 mice were injected bilaterally in regenerating tibialis anterior muscles with naked DNA 5 days after muscle injury to enhance DNA uptake and expression. In the muscles of mice given the IFN-alpha 9 plasmid constructs, acid-stable IFNs were detected by bioassay using reduction in cytopathic effect of encephalomyocarditis virus-infected L929 cells. In these same muscles, IFN-alpha 9 transcripts were identified by RT-PCR, indicating that transcription had occurred. Acid-stable IFNs were detected from days 7 to 28 post-DNA inoculation. Furthermore, these proteins were found in the sera of DNA-inoculated mice. Control groups of mice given the blank expression vectors did not produce detectable IFNs in muscle or sera as determined by bioassay, nor were transcripts detected by RT-PCR. This approach now allows investigation of the effector function of individual subtypes in various murine disease models.
Animals↗
A 3-Mb sequence-ready contig map encompassing the multiple disease gene cluster on chromosome 11q13.1-q13.3.
Despite the presence of several human disease genes on chromosome 11q13, few of them have been molecularly cloned. Here, we report the construction of a contig map encompassing 11q13.1-q13.3 using bacteriophage P1 (P1), bacterial artificial chromosome (BAC), and P1-derived artificial chromosome (PAC). The contig map comprises 32 P1 clones, 27 BAC clones, 6 PAC clones, and 1 YAC clone and spans a 3-Mb region from D11S480 to D11S913. The map encompasses all the candidate loci of Bardet-Biedle syndrome type I (BBS1) and spinocerebellar ataxia type 5 (SCA5), one-third of the distal region for hereditary paraganglioma 2 (PGL2), and one-third of the central region for insulin-dependent diabetes mellitus 4 (IDDM4). In the process of map construction, 61 new sequence-tagged site (STS) markers were developed from the Not I linking clones and the termini of clone inserts. We have also mapped 30 ESTs on this map. This contig map will facilitate the isolation of polymorphic markers for a more refined analysis of the disease gene region and identification of candidate genes by direct cDNA selection, as well as prediction of gene function from sequence information of these bacterial clones.
Chromosome Mapping↗
Directed replacement of mt A by mt a-1 effects a mating type switch in Neurospora crassa.
To test the functions of a mating type genes, we developed an efficient strategy to select transformants of Neurospora crassa in which resident A mating type DNA was replaced by cloned DNA from the mt a idiomorph. Cloned a idiomorphic DNA could specify all functions, including fertility, of a mating type, but only when it replaced A DNA at the mating type locus. Only the mt a-1 region of the a idiomorph was necessary in order to specify a mating type. Gene replacement events involved the homologous sequences flanking the unique mating type idiomorphic DNA, resulting in apparently isogenic a and A strains. These isogenic strains were fertile when crossed with one another, indicating that no determinants outside the transforming DNA are necessary for fertility as a and that no host sequences of A strains interfere with fertility as a. One a replacement strain bore a duplication of the transforming mt a-1 and hph DNA. The duplication strain had unexpected properties. Although mating type segregated 1:1 in crosses of this strain to A, the duplicated regions were efficiently altered during the sexual process to generate a single copy in the progeny. No progeny were recovered that had undergone RIP (repeat induced point mutation) sufficient to inactivate the mt a-1 gene. We infer that the mt a-1 gene is necessary and sufficient to specify a mating type identity in all vegetative and sexual activities. Mt a-1 may also play an essential role in ascosporogenesis after fertilization.
Cloning, Molecular↗
Type I interferon genes in cattle: restriction fragment length polymorphisms, gene numbers and physical organization on bovine chromosome 8.
Multiple, superimposed Type I interferon (IFN) restriction fragments were resolved following 72-92 h of horizontal electrophoresis. Restriction fragment length polymorphisms (RFLPs) for alpha IFN (IFNA), beta IFN (IFNB), omega IFN (IFNW) and trophoblast IFN (IFNT) genes were identified in HindIII, EcoRI and TaqI digestions from 313 cattle. RFLPs with codominant segregation in cattle pedigrees were considered alleles, and 19 distinct polymorphic Type I IFN loci (5 IFNA, 4 IFNB, 8 IFNW and 2 IFNT) were identified. Allele frequencies and observed heterozygosity values were calculated for each locus and several loci were considered highly informative for linkage analysis. Bovine IFN gene numbers (10 IFNA, 6 IFNB, 20 IFNW and 6 IFNT) were estimated from the number of polymorphic loci plus additional monomorphic hybridizing bands present in EcoRI and HindIII digestions. Physical linkage of the Type I IFN gene families on bovine chromosome 8 was demonstrated by pulsed field gel electrophoresis (PFGE). Hybridization of two or more IFN probes to similarly sized PFGE fragments suggested the tentative gene family order: IFNA/IFNW-IFNT-IFNB. These studies provide a basis for the development of more detailed genetic and physical maps of the bovine Type I IFNs.
Alleles↗
Within-individual variation in serum cholesterol levels: association with DNA polymorphisms at the apolipoprotein B and AI-CIII-AIV loci in patients with peripheral arterial disease.
We have examined the association between variation at the apolipoprotein (apo) B gene and apo AI-CIII-AIV gene cluster and within-individual variation in serum cholesterol levels. Annual measurements were available over a period of 5-10 years in a group of 117 male patients with peripheral arterial disease. The overall within-individual coefficient of variation in cholesterol levels over time was 13.9%. For all patients, Restriction Fragment Length Polymorphism (RFLP) genotype at the apo B gene (XbaI and EcoRI) and apo AI-CIII-AIV gene cluster (XmnI, PstI and PvuII-CIII) had previously been determined. At the apo B locus, individuals heterozygous for either the XbaI or EcoRI RFLP showed significantly greater within-individual variability over time compared to individuals of other genotypes. At the apo AI-CIII-AIV gene cluster, individuals homozygous for the common allele of either the PstI or PvuIIA RFLPs showed the greatest within-individual variability over time but there was no difference in this estimate associated with XmnI genotype. Our observations suggest that variation at both the apo B and apo AI-CIII-AIV loci interacts with unidentified environmental factors to determine individual variability in serum cholesterol levels over time.
Apolipoprotein A-I↗
The Ly-49 family: genes, proteins and recognition of class I MHC.
The Ly-49 family consists of at least nine members, of which Ly-49A and C have been found to be NK-cell inhibitory receptors specific for class I MHC. The functions of other Ly-49 molecules are still unclear. Further analysis of Ly-49 is complicated by the cross-reactivities of some anti-Ly-49 antibodies initially thought to be specific for individual Ly-49 molecules. Studies on the role of Ly-49 in hybrid resistance as well as on allelic exclusion are also complicated by our recent finding that a novel Ly-49CB6 gene is the likely allelic form of Ly-49CBALB as opposed to a previously reported highly related but distinct gene in B6 mice. In cell-cell binding assays, only Ly-49A and C show significant binding to class I MHC. Ly-49A and C also bind some polysaccharides, and carbohydrates on class I MHC seem to be important for its binding to Ly-49. However, this interaction involves not only the carbohydrate recognition domain of Ly-49 but also a part of the stalk region, suggesting that both carbohydrates and peptide backbone of class I MHC may be recognized by Ly-49. It is likely that additional Ly-49 molecules yet to be identified function as NK-inhibitory receptors specific for class I MHC.
Animals↗
Uterine NK cells and trophoblast HLA class I molecules.
PROBLEM: To investigate the proposal that NK cells in decidua may control trophoblast migration during implantation of the human placenta. METHOD: Use Mab specific for HLA-G and for HLA-C in association with flow cytometry and immunoprecipitation to determine the expression of these HLA molecules by trophoblast. Expression of Killer inhibitory/activatory receptors (KIR/KAR) and the CD94 receptor by decidual NK cells was also studied. RESULTS: Extravillous trophoblast expressed HLA-G and HLA-C in both beta2m-associated form and as free heavy chains. KIR and KAR are expressed by decidual NK cells. The repertoire of receptors varied between different women and also between blood and decidual NK cells from the same women. The expression of CD94 was also different between blood and decidual NK cells. CONCLUSION: The recognition of HLA-G/HLA-C by KIR/KAR and CD94 could provide a mechanism by which decidual NK cells control trophoblast migration.
Antibodies, Monoclonal↗
Schizosaccharomyces pombe ras1 and byr1 are functionally related genes of the ste family that affect starvation-induced transcription of mating-type genes.
We have further investigated the function of the ras1 and byr1 genes, which were previously shown to be critical for sexual differentiation in fission yeast cells. Several physiological similarities between strains containing null alleles of these genes supports the idea that ras1 and byr1 are functionally closely related. Furthermore, we have found that byr1 is allelic to ste1, one of at least 10 genes which when mutated can cause sterility. Since ras1 had previously been found to be allelic to ste5, both ras and byr genes are now clearly shown to be a part of the ste gene family, thus confirming their close functional relationship. The observation that the mating-type loci could overcome the sporulation block of ras1 and byr1 mutant strains prompted investigation of the role of the ras-byr pathway in the induction of the mating-type gene transcripts upon nitrogen starvation. By Northern analysis of RNA preparations from strains carrying wild-type or mutant ras1 alleles and grown to different stages of the growth cycle, we have shown that ras1 plays an important role in inducing the Pi transcript of the mating-type loci and the mei3 gene transcript. These observations provide a molecular basis for the role of the ste gene family, including ras1 and byr1, in meiosis and indicate that further characterization of other ste genes would be very useful for elucidating the mechanism of ras1 function in fission yeast cells.
Alleles↗
[PPARgamma variants and complex diseases].
Peroxisome proliferator-activated receptor gamma is a member of the nuclear hormone receptor superfamily. Mainly expressed in adipose tissue, PPARgamma promotes the differentiation of adipocytes and modulates the expression of many genes involved in the synthesis of adipocytokines in the adipose tissue. It is also the target molecule of the thiazolidinediones. Polymorphisms of the PPARgamma gene may influence pancreatic beta-cell function and result in changes in insulin secretion and insulin sensitivity of the peripheral tissues. They are also associated with risks of type 2 diabetes, obesity, cardiovascular diseases and cancer. Elucidation of its mechanism could be of major importance to the diagnosis, prevention and treatment of complex diseases.
Animals↗
Isolation and characterization of ribosomal DNA variants from Sciara coprophila.
The ribosomal RNA multigene family in the fungus fly Sciara coprophila contains a total of only 65 to 70 repeat units. We explored the types and frequencies of variant repeats in this small multigene family by characterizing different cloned rDNA variants from Sciara. Although we did not observe any intergenic spacer length variants in Sciara, we found a variant due to the insertion of a putative mobile element (lambda Bc11), and variants containing ribosomal insertion elements. By DNA sequence analysis of rDNA/non-rDNA junctions, there are three distinct types of ribosomal insertion elements found in Sciara rDNA: two correspond to the R1 and R2 insertion elements found in other dipterans (clones lambda Bc5 and pBc1L1, respectively), and one is a novel class of ribosomal insertion elements (R3, exemplified by clone pBc6D6) which so far is unique to Sciara. Together, the several different rDNA variants make up from 12 to 20% of the rDNA in Sciara. These results are discussed in the context of evolution of the ribosomal RNA multigene family.
Animals↗
A rhoptry-protein-associated mechanism of clonal phenotypic variation in rodent malaria.
The recognition and invasion of host cells are mediated by components of the apical complex of the ookinete, sporozoite and merozoite stages of Plasmodium parasites. The paired rhoptries (organelles involved in host-cell recognition) in the apical complex contain many proteins of as-yet unknown function. In the rodent malaria agent P. yoelii yoelii, a multigene family codes for merozoite rhoptry proteins of relative molecular mass 235,000 (p235 proteins); these proteins are thought to determine the subset of erythrocytes that the parasites invade. Further support for this idea came from the identification of a region in p235 with weak but significant homology to reticulocyte-binding protein-2 of P. vivax and the demonstration that at least one p235 member binds to the erythrocyte surface membrane. Here, using single, micromanipulated P.y.yoelii parasites, we describe a new mechanism of gene expression by which the merozoites originating from a single schizont each express a distinct member of this multigene family. We propose that this new type of clonal phenotypic variation provides the parasite with a survival strategy in the mammalian host; this strategy contributes to the observed chronicity of malarial infections. This phenomenon is genetically and functionally distinct from classical antigenic variation, which is mediated by the var multigene family of P. falciparum.
Animals↗
Two types of MGDG synthase genes, found widely in both 16:3 and 18:3 plants, differentially mediate galactolipid syntheses in photosynthetic and nonphotosynthetic tissues in Arabidopsis thaliana.
In Arabidopsis, monogalactosyldiacylglycerol (MGDG) is synthesized by a multigenic family of MGDG synthases consisting of two types of enzymes differing in their N-terminal portion: type A (atMGD1) and type B (atMGD2 and atMGD3). The present paper compares type B isoforms with the enzymes of type A that are known to sit in the inner membrane of plastid envelope. The occurrence of types A and B in 16:3 and 18:3 plants shows that both types are not specialized isoforms for the prokaryotic and eukaryotic glycerolipid biosynthetic pathways. Type A atMGD1 gene is abundantly expressed in green tissues and along plant development and encodes the most active enzyme. Its mature polypeptide is immunodetected in the envelope of chloroplasts from Arabidopsis leaves after cleavage of its transit peptide. atMGD1 is therefore likely devoted to the massive production of MGDG required to expand the inner envelope membrane and build up the thylakoids network. Transient expression of green fluorescent protein fusions in Arabidopsis leaves and in vitro import experiments show that type B precursors are targeted to plastids, owing to a different mechanism. Noncanonical addressing peptides, whose processing could not be assessed, are involved in the targeting of type B precursors, possibly to the outer envelope membrane where they might contribute to membrane expansion. Expression of type B enzymes was higher in nongreen tissues, i.e., in inflorescence (atMGD2) and roots (atMGD3), where they conceivably influence the eukaryotic structure prominence in MGDG. In addition, their expression of type B enzymes is enhanced under phosphate deprivation.
Amino Acid Sequence↗
Type I and type II keratins have evolved from lower eukaryotes to form the epidermal intermediate filaments in mammalian skin.
We have traced the evolutionary origins of keratin-like sequences to the genomes of lower eukaryotes. The proteins encoded by these genes have evolved to form the intermediate filaments that comprise the backbone of vertebrate skin cells. Two related but distinct types of keratins encoded by two separate multigene subfamilies are expressed in the epidermal keratinocytes of vertebrate species from fish to human. Both at the level of protein and at the level of DNA, these two classes of keratins are coordinately conserved throughout vertebrate evolution, indicating the central role that both types of keratins must play in the assembly and structure of the 8-nm filament.
Animals↗
Membrane-type metalloproteinases in tumor invasion.
Matrix metalloproteinases (MMPs) are members of a multigene family of zinc-dependent enzymes involved in the degradation of numerous extracellular matrix (ECM) components. Among these enzymes, membrane-type MMPs (MT-MMPs) play a major role in the activation of progelatinase A (MMP-2). The molecular structure of these enzymes is characterized by a transmembrane domain and the presence of an insertion of 11 amino-acids between the pro-peptide and the catalytic domains, which may be cleaved by furin-like enzymes leading to the activated form of the enzymes. MT1-MMP appears to play a dual role in extracellular matrix remodeling through activation of progelatinase A and procollagenase 3 and direct cleavage of some ECM macromolecules such as gelatin, type I collagen and fibronectin. Tissue inhibitor of MMPs-2 (TIMP-2) serves as an intermediate in progelatinase A activation by binding to MT1-MMP and progelatinase A on the plasma membrane. In vivo, MT1-MMP is overexpressed in malignant tumor tissues in which it was mainly localized in stromal cells surrounding the neoplastic tissue. These peritumoral fibroblasts, under particular stimuli, would be induced to overexpress MT1-MMP and consequently activate gelatinase A leading to ECM degradation. The expression of MT1-MMP is however observed in vitro in the invasive tumor cells which might represent an late stage of tumor progression. All these data confirm the important role of MT-MMPs in tumor invasion and highlight a cooperation between tumor and stromal cells for the production of these enzymes. The contribution of MMPs in a metastatic process leads to the development of novel therapies using inhibitors of these enzymes. Among a multitude of synthetic inhibitors generated, Marimastat is already clinically employed in cancer treatment.
Animals↗