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PubMed1997

Primary structure and evolution of the ATP-binding domains of the P-type ATPases in Tetrahymena thermophila.

The P-type ATPases (e.g., Na+-K+-ATPase and Ca2+-ATPase) occur widely in living cells of fungi, Protozoa, plants, and animals. These ion pumps show a high degree of divergence in their primary structures but share a limited number of common amino acid residues for their ATP-catalytic function. Particularly, the amino acid sequences for the phosphorylation site (DKTGTLT) and the binding site for ATP (and its analogs; GDGVND) are conserved throughout evolution. Using two degenerate oligonucleotides corresponding to these regions, we applied a polymerase chain reaction (PCR) technique to the search for P-type ATPase isoforms, which will provide a clue to the evolutionary mechanisms of ion pumps in Tetrahymena thermophila. A total of 12 distinct P-type ATPase genes were identified. Sequence comparisons revealed that seven of them can be compiled into a multigene family, which is similar to animal Na+-K+- and H+-K+-ATPase genes. One of them is close to the sarco(endo)plasmic reticulum Ca2+-ATPase gene, and the other four share a significant homology with the gene encoding Plasmodium ATPase-1 whose function is unknown. A Northern blot analysis and reverse transcriptase-PCR demonstrated that all identified genes are expressed, but the expression levels vary widely under different culture conditions. A Southern blot analysis after pulse-field gel electrophoresis showed that all of these genes exist in T. thermophila macronuclei. The Na+-K+- and H+-K+-ATPase gene family has a high multiplicity (at least 10 different genes detected on genomic Southern blot analysis) and is distributed on four different macronuclear chromosomes. On the basis of a calculation with the amino acid sequences of the cloned cytoplasmic loop region (between the phosphorylation and the gamma-[4-(N-2-chloroethyl-N-methylamino)]-benzylamido ATP sites), the genes with >80% identity form a cognate linkage group within the same macronuclei chromosome, whereas the genes with <70% identity are separated in different chromosomes. The phylogenetic analysis showed that this multigene family is the result of a series of gene duplications.

Adenosine Triphosphatases↗

PubMed1983

The evolution and complexity of the genes encoding the cytoskeletal proteins of human epidermal cells.

In order to explore the differential expression and evolutionary conservation of the genes encoding the cytoskeletal proteins for human epidermal cells, we have constructed a library of bacterial plasmids containing inserts of double-stranded cDNAs complementary to the mRNAs of cultured human epidermal cells. Cloned hybrid plasmids containing 45-95% of the sequences present in keratin, actin, and tubulin mRNAs were isolated and characterized. To identify the cDNAs encoding the four major keratins of human epidermal cells, the clones were initially screened for their ability to hybridize strongly with 32P-labeled cDNA prepared from unfractionated epidermal mRNA (about 30% keratin mRNA). Strongly hybridizing clones were further characterized by positive hybrid selection. Two distinct classes of clones were identified: One class hybridized specifically to the 56 and 58kd keratin mRNAs and one class hybridized specifically to the 46 and 50kd keratin mRNAs. Each class is encoded by a separate multigene family of about 10 genes. The two classes of sequences are conserved throughout vertebrate evolution, indicating the functional importance of each class in filament assembly. Clones containing human cDNA sequences encoding a cytoplasmic actin and alpha-tubulin were selected by hybridization screening using 32P-labeled cloned cDNAs for the mRNAs of beta-actin and alpha-tubulin of embryonic chick brain. The identity of these clones was established by positive hybrid selection and by DNA sequence analysis. Similar to the keratins, the actins and tubulins are also encoded by multigene families which are highly evolutionarily conserved. The availability of cloned cDNAs specific for each of three types of epithelial cytoskeletal proteins allows us to investigate the coordinate expression of their mRNAs during terminal differentiation in human epidermis.

Actins↗

PubMed1996

Subunit composition of AMPD varies in response to changes in AMPD1 and AMPD3 gene expression in skeletal muscle.

Adenosine monophosphate deaminase (AMPD), a central enzyme in energy metabolism in skeletal muscle, is encoded by a multigene family in higher eukaryotes. Denervation was used as a stimulus to induce a change in fiber type composition of rat gastrocnemius muscle and, consequently, gene expression. Specific antisera and nucleic acid probes were used to assess changes in expression of the AMPD1 and AMPD3 genes. Total AMPD activity in denervated skeletal muscle increased by 34%. The composition of the AMPD tetrameric holoenzyme was altered in two ways: The percentage of AMPD holoenzyme molecules consisting of one or more AMPD3 subunits increased three-fold, and the percentage of AMPD1 mRNA that excludes exon 2-encoded sequences doubled. These results suggest that expression of the AMPD1 and AMPD3 genes may be coordinated in myocytes to effect production of an AMPD holoenzyme of varying subunit composition.

AMP Deaminase↗

PubMed2001

Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro.

The amyloidoses are a large group of protein misfolding diseases. Genetic and biochemical evidence support the hypothesis that amyloid formation from wild-type or 1 of 80 sequence variants of transthyretin causes the human amyloid diseases senile systemic amyloidosis or familial amyloid polyneuropathy, respectively. The late onset and variable penetrance of these diseases has led to their designation as multigenic--implying that the expression levels and alleles of multiple gene products influence the course of pathology. Here we show that the binding stoichiometry of three interacting molecules, retinol-binding protein, vitamin A, and L-thyroxine, notably influenced transthyretin amyloidogenicity in vitro. At least 70 genes control retinol-binding protein, vitamin A, and L-thyroxine levels in plasma and have the potential to modulate the course of senile systemic amyloidosis or familial amyloid polyneuropathy.

Amyloidosis↗

PubMed2001

Comparative analysis of HD2 type histone deacetylases in higher plants.

Zea mays (L.) histone deacetylase HD2 was identified as a new type of histone deacetylase (HDAC) unrelated to the well-known Rpd3p and Hdalp families but with sequence homology to peptidyl-prolyl cis-trans isomerases (PPIases). Here we show that HD2 is a multigene family with highly related members in various plant species. Gene analysis revealed a similar exon/intron structure in Arabidopsis thaliana (L.) Heynh. and Z. mays, and most of the sequences analyzed were demonstrated to possess an intron of the very rare AT-AC type.

Amino Acid Sequence↗

PubMed1998

Type I interferons: expression and signalization.

Type I interferon (IFN-A and IFN-B) genes encode a large family of multifunctional secreted proteins involved in antiviral defence, cell growth regulation and immune activation. These cytokines, as a consequence of their biological activities, have been established as effective therapeutic molecules for malignant and viral diseases. Virus infection is the main inducer leading to transient expression of type I IFN (A and B) and the antiviral response appears to proceed through a two-step pathway requiring, first, induction of type I IFN gene expression and, second, transcriptional activation by the synthesized IFN proteins, binding to their specific cell surface receptors, of a large number of genes. The proteins they encode are responsible, in part, for the pleiotropic multiple biological activities of the IFN. In this two-step pathway, the virus-induced IFN genes and the IFN-stimulated gene (ISG) expression seem to share common factors. Even if IFN-A genes are structurally related and very often coordinately induced in virus-infected cells, differences in the expression of the individual IFN-A messenger RNAs of the multigenic IFN-A gene family are observed in human as well as in murine cells, reflecting, in a particular cell type, the transcriptional activity of the corresponding promoter regions. Important studies on interferon regulatory factors and ISG factors have been made in the last decade. However, some factors involved in IFN-A gene regulation remain to be identified. Our goal has been to review the factors involved in the control of the type I IFN gene expression to understand the mechanisms of induction and repression of their transcription and to explain the properties of these cytokines through their signal transduction pathway.

Animals↗

PubMed1992

Murine serum amyloid A3 is a high density apolipoprotein and is secreted by macrophages.

The serum amyloid A (SAA) proteins make up a multigene family of apolipoproteins associated with high density lipoproteins. They are of ancient origin; the finding of a highly homologous protein in mammals and ducks indicates that SAAs have been in existence for at least 300 million years. The interspecies similarity among the SAAs makes the mouse, in which they have been most thoroughly studied, a reasonable model to use for defining the function(s) of this family of proteins in humans. Originally it was observed that the SAA proteins were made in the liver and represented a set of proteins belonging to acute-phase reactants. SAA3 is a unique member of the SAA multigene family in mice in that its mRNA is also expressed in extrahepatic tissues by a variety of cell types, mainly macrophages and adipocytes. To date, nothing has been reported regarding the fate or function of the SAA3 translation product. To identify the SAA3 protein, we developed SAA3-specific antibodies by immunizing rabbits against a portion of SAA3 protein synthesized in a bacterial fusion protein expression system. Electroimmunoblot analysis of serum and lipoprotein fractions of it showed SAA3 to be associated with high density lipoproteins of mice treated with lipopolysaccharide. Furthermore, a continuous mouse macrophage cell line (J-774.1), when exposed to lipopolysaccharide, expressed SAA3 mRNA in a dose-dependent manner and secreted SAA3 protein. The expression and secretion of SAA3 by macrophages stimulated with lipopolysaccharide suggest a role for this SAA in local responses to injury and inflammation.

Animals↗

PubMed1996

[Etiopathogenesis of type 1 diabetes mellitus].

Type 1 diabetes mellitus results from an autoimmune disease which specifically destroys the pancreatic beta cells. The disease presents a multigenic susceptibility and the activation of autoreactive T lymphocytes plays a major role in its pathogenesis. Environmental factors may initiate or modulate the immune response. Several mechanisms are probably involved in the ultimate beta cell destruction. The antigens which are first recognized by the immune system are still unknown. Humoral and cellular specific markers of the disease can be detected long before the onset of diabetes. Understanding the mechanisms which trigger the disease should allow a treatment of the autoimmune disease before the clinical expression of diabetes.

Autoimmune Diseases↗

PubMed2005

Role of beta-cells in type 1 diabetes pathogenesis.

Whether autoimmunity results primarily from a defect of the immune system, target organ dysfunction, or both remains an open issue in most human autoimmune diseases. The highly multigenic background on which diabetes develops in the NOD mouse and in the human suggests that numerous gene variants associate in contributing to activation of autoimmunity to beta-cells. Both immune genes and islet-related genes are involved. The presence of beta-cells is required for initiation of diabetes autoimmunity to proceed. Available experiments in the NOD mouse and epidemiological evidence in the human point to proinsulin as a key autoantigen in diabetes. The functional importance of insulin, the high number of autoantigens characterized at different stages of diabetes, and their clustering within beta-cell subparticles point to the islet as a starting point in the initiation phase of the disease. Genes that direct the autoimmune reaction toward the beta-cell target, autoantigens that are recognized by autoreactive B- and T-cells along the autoimmune process, the importance of beta-cells in the activation of autoreactive lymphocytes, and the expression level of key beta-cell molecules along diabetes development are successively considered in this review.

Animals↗

PubMed1989

An oocyte-expressed alpha-tubulin gene in Xenopus laevis; sequences required for the initiation of transcription.

We have studied the expression of X alpha T14, a member of the alpha-tubulin multigene family in Xenopus laevis. Small amounts of X alpha T14 RNA are detectable in a range of cell types, but much higher levels are present in ovary and tissue culture cells. In oocytes X alpha T14 transcripts accumulate during early vitellogenesis but their level declines in more advanced stages. Faithful and efficient initiation of transcription occurred on cloned X alpha T14 injected into oocytes even at low template levels. We have examined the amount of transcript produced by various deletion mutants relative to a co-injected control gene. The presence of 200bp of DNA 5' and 53bp of DNA 3' to the initiation site sufficed for high levels of promoter activity, although maximum activity required 560 bp of 5' flanking DNA. The DNA between -200 and -60 was necessary for transcription in oocytes and contains several sequence motifs implicated in transcriptional regulation including three CCAAT boxes and a sequence resembling a heat shock element. An 8 bp deletion that removed the latter element from 5kb of 5'-flanking DNA reduced promoter activity by 60%.

Animals↗

PubMed1997

Identification of members of gene families in Arabidopsis thaliana by contig construction from partial cDNA sequences: 106 genes encoding 50 cytoplasmic ribosomal proteins.

Partial cDNA sequencing to obtain expressed sequence tags (ESTs) has led to the identification of tags to about 8,000 of the estimated 20,000 genes on Arabidopsis thaliana. This figure represents four to five times the number of complete coding sequences from this organism available in international databases. In contrast to mammals, many proteins are encoded by multigene families in A. thaliana. Using ribosomal protein gene families as an example, it is possible to construct relatively long sequences from overlapping ESTs which are of sufficiently high quality to be able to unambiguously identify tags to individual members of multigene families, even when the sequences are highly conserved. A total of 106 genes encoding 50 different cytoplasmic ribosomal protein types have been identified, most proteins being encoded by at least two and up to four genes. Coding sequences of members of individual gene families are almost always very highly conserved and derived amino acid sequences are almost, if not completely, identical in the vast majority of cases. Sequence divergence is observed in untranslated regions which allows the definition of gene-specific probes. The method can be used to construct high-quality tags to any protein.

Amino Acid Sequence↗

PubMed1998

The activating form of CD94 receptor complex: CD94 covalently associates with the Kp39 protein that represents the product of the NKG2-C gene.

Inhibitory receptor complexes formed by CD94 and NKG2-A (Kp43) molecules have been implicated in HLA class I recognition by human natural killer (NK) cells. Additional forms of CD94 receptors have recently been described in NK cells characterized by the lack of NKG2-A expression. These CD94 receptors were shown to display activating functions. Immunoprecipitation with anti-CD94 monoclonal antibodies (mAb) led to the identification, in these cells, of a 39-kDa (Kp39) molecule that was originally believed to represent an activating isoform of the CD94 molecules. In the present study we show that the Kp39 molecule is covalently associated with CD94 and displays a protein backbone (26 kDa) similar to that of NKG2-A (Kp43) glycoproteins. Peptide mapping analysis indicates that Kp39 and NKG2-A glycoproteins belong to the same molecular family. A novel NKG2-specific mAb (termed P25) has been generated that specifically reacts with both NKG2-A and NKG2-C molecules, but fails to recognize NKG2-E molecules. Analysis of polyclonal and clonal NK cells shows that P25 mAb reacts with all NKG2-A+ cells and with a fraction of CD94+ cells lacking the expression of NKG2-A. These data indicate that NKG2-C molecules are indeed expressed only in a subset of cells lacking the expression of NKG2-A. The CD94-associated Kp39 molecule can be detected only in NKG2-A- P25+ cells, i.e. cells expressing NKG2-C molecules. Indeed, reverse transcription-polymerase chain reaction analysis performed on a large panel of NK clones indicates that NKG2-A- P25+ NK clones express the NKG2-C transcript. Notably, the cytolytic activity of these clones can be triggered by the P25 mAb in redirected killing analysis. Finally, biochemical analysis of COS7 cells cotransfected with CD94 and NKG2-C demonstrates the identity between Kp39 and NKG2-C molecules. Altogether, our data demonstrate that NKG2-C molecules associate with CD94 to form an activating receptor complex in a subset of human NK cells.

Amino Acid Sequence↗

PubMed1991

Mapping of the duplicated rabbit immunoglobulin kappa light chain locus.

The rabbit has two isotypic forms of the immunoglobulin kappa light chain, K1 and K2, which probably arose by duplication. In the normal rabbit, only traces of K2 light chains are produced. However, K2 levels are elevated in allotype-suppressed rabbits and in the Basilea strain which does not produce K1 because of a K1 mRNA splice site mutation. Previous cloning and sequencing showed that each isotype has its own set of J kappa genes but it was not known whether the two isotypes utilize shared or separate sets of V kappa genes. In addition, although genetic linkage of allotypes associated with the K1 and K2 genes has been demonstrated, physical linkage had not been previously demonstrated by overlapping cosmid or phage clones. We used pulsed field and transverse alternating field electrophoresis to obtain megabase maps and to estimate the size of the duplication of the rabbit kappa light chain locus. We found that the two C kappa genes are about 1 megabase apart. One explanation for the poor expression of K2, could be great physical distance from V kappa genes. However, we found that there are V kappa, J kappa and C kappa 2 genes within a approximately 105-kb fragment. Thus, physical distance of V kappa from C kappa 2 may not be the basis for poor K2 expression.

Animals↗

PubMed2001

Dosage-dependent gene regulation in multicellular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits.

Evidence from a variety of data suggests that regulatory mechanisms in multicellular eukaryotes have evolved in such a manner that the stoichiometric relationship of the components of regulatory complexes affects target gene expression. This type of mechanism sets the level of gene expression and, as a consequence, the phenotypic characteristics. Because many types of regulatory processes exhibit dosage-dependent behavior, they would impact quantitative traits and contribute to their multigenic control in a semidominant fashion. Many dosage-dependent effects would also account for the extensive modulation of gene expression throughout the genome that occurs when chromosomes are added to or subtracted from the karyotype (aneuploidy). Moreover, because the majority of dosage-dependent regulators act negatively, this property can account for the up-regulation of genes in monosomics and hemizygous sex chromosomes to achieve dosage compensation.

Aneuploidy↗

PubMed1992

Methylation status of ribosomal RNA gene clusters in the flow-sorted human acrocentric chromosomes.

Southern blot analysis of the human acrocentric chromosomes that were flow-sorted from B-lymphoblastoid cell line GM130B revealed that the sensitivity of the ribosomal RNA (rDNA) gene clusters to the restriction enzyme NotI differs among these rDNA-containing chromosomes: the rDNA clusters of Chromosomes (Chr) 13, 14, and 15 are much more sensitive to NotI digestion than those of Chrs 21 and 22 in this particular cell line. Detailed analysis by use of methylation-sensitive enzymes HpaII and HhaI and methylation-insensitive enzyme MspI confirmed the significant variation in the methylation status of rDNA clusters among these chromosomes. Quantitative analysis by fluorescent in situ hybridization (FISH) indicated that copy number of rDNA varies among individual chromosomes, but the average copy number in the acrocentric Chrs 21 and 22 is significantly greater than that of the Chrs 13, 14, and 15 in GM130B cells. Similar analysis reveals that the methylation status of rDNA clusters in another B-lymphoblastoid cell line GM131 was different from that of GM130B. These data together indicate that the copy number and methylation patterns of rDNA clusters differ among individual acrocentric chromosomes in a given cell line, and they are different among cell lines.

Blotting, Southern↗

PubMed2003

Phylogenetic analysis of vertebrate fibrillar collagen locates the position of zebrafish alpha3(I) and suggests an evolutionary link between collagen alpha chains and hox clusters.

Type I collagen in tetrapods is usually a heterotrimeric molecule composed of two alpha1 and one alpha2 chains. In some teleosts, a third alpha chain has been identified by chromatography, suggesting that type I collagen should also exist as an alpha1(I)alpha2(I)alpha3(I) heterotrimer. We prepared, from zebrafish, three distinct cDNAs identified to be those of the collagen alpha1(I), alpha2(I), and alpha3(I) chains. In this study on the evolution of fibrillar collagen alpha chains and their relationships, an exhaustive phylogenetic analysis, using vertebrate fibrillar collagen sequences, showed that each alpha chain constitutes a monophyletic cluster. Results obtained with the newly isolated sequences of the zebrafish showed that the alpha3(I) chain is phylogenetically close to the alpha1(I) chain and support the hypothesis that the alpha3(I) chain arose from a duplication of the alpha1(I) gene. The duplication might occur during the duplication of the actinopterygian genome, soon after the divergence of actinopterygians and sarcopterygians, a hypothesis supported by the demonstration of a syntenic evolution between a set of fibrillar collagen genes and Hox clusters in mammals. An evolutionary scenario is proposed in which phylogenetic relationships of the alpha chains of fibrillar collagens of vertebrates could be related to Hox cluster history.

Amino Acid Sequence↗

PubMed2000

Evolution of cis-acting elements in 5' flanking regions of vertebrate actin genes.

Regulation of the vertebrate actin multigene family involves the recognition of various regulatory sequences (cis-acting elements) that specify the distinct tissue type and developmental program of expression for each actin paralogue, which implies that the distribution of cis-acting elements may be unique for each paralogue gene. To elucidate the evolution of these unique distribution patterns, we improved a method to scan for cis-acting elements in the 5' flanking regulatory region of genes and used it to analyze five cis-acting elements (SRE, MyoD binding site, Elk-1 binding site, positive and negative YY1 binding sites) of six actin paralogue genes (beta and gamma cytoplasmic actins, alpha and gamma smooth muscle actins, and alpha skeletal and alpha cardiac actins) among various vertebrates. It was shown that although an element(s) may exist in all paralogue genes of the same species, its numbers, compositions, and distribution patterns or even sequences vary remarkably among paralogues, which contributes to their different tissue- and developmental-specific expression. However, each pair of coexpressed paralogues has some certain similarity in distribution patterns. Furthermore, among various orthologues of actin genes derived from diverse vertebrates, the sequences, numbers, and distribution patterns of these cis-acting elements are highly conserved or even identical in the long run of phylogeny of vertebrates. Taken together, the results described above strongly indicate that not only the structures of actins but also their expression patterns are essential in both the phylogeny and the physiology of vertebrates. The distribution patterns of cis-acting elements of various actin genes can be regarded as indicators of both horizontal (paralogues) and vertical (orthologous) evolution of actins.

Actins↗

PubMed1997

AICL: a new activation-induced antigen encoded by the human NK gene complex.

The NK gene complex on mouse chromosome 6 and its human homologue on chromosome 12 encode type II transmembrane proteins with a C-type lectin domain which trigger or inhibit target cell lysis by NK cells (NKR-P1, Ly49, NKG2, CD94) or function as cellular activators of various hematopoietic cells (CD69). We herein report the cDNA cloning of a new molecule, designated activation-induced C-type lectin (AICL), whose gene maps to the human NK gene complex proximal to the CD69 gene. AICL is a 149-amino acid (aa) polypeptide with a short cytoplasmic part of seven aa and a C-type lectin domain separated from the transmembrane region by only nine aa. The highest sequence similarity is found to the C-type lectin domains of CD69 and the chicken lectin 17.5. The presence of AICL transcripts in different cell types of hematopoietic origin, a rapid increase of gene transcription during lymphocyte activation, and a short half-life of the mRNA characterize AICL as a new, broadly expressed activation antigen.

Amino Acid Sequence↗