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PubMed2002

Cloning and characterization of a divergent alpha-tubulin that is expressed specifically in dividing amebae of Naegleria gruberi.

A novel alpha-tubulin gene (alpha6) was cloned from a genomic library of Naegleria gruberi strain NB-1 and characterized. The open reading frame of alpha6 contained 1359 nucleotides encoding a protein of 452 amino acids (aa) with a calculated molecular weight of 50.5 kDa. The nucleotide sequence of the open reading frame of alpha6 showed considerable divergence (68.4% identity) when compared with previously cloned N. gruberi alpha-tubulin genes, which share about 97% identity in DNA sequences. The deduced aa sequence of alpha6-tubulin was 61.9% identical to that of alpha13-tubulin, which was cloned from the same strain, and showed similar identities to those of alpha-tubulins from other species (54 approximately 62%). These data showed that alpha6-tubulin is one of the most divergent alpha-tubulins so far known. Alpha6-tubulin was found to be expressed in actively growing cells and repressed quickly when these cells were induced to differentiate. Immunostaining with an antibody against alpha6-tubulin showed that alpha6-tubulin is present in the nuclei and mitotic spindle-fibers but absent in flagellar axonemes or cytoskeletal microtubules. These data finally established the presence of an alpha-tubulin that is specifically utilized for spindle-fiber microtubules and distinct from the flagellar axonemal alpha-tubulins in N. gruberi, hence confirmed the multi-tubulin hypothesis in this organism.

Amino Acid Sequence↗
PubMed2000

Transcriptional regulation of the divergent paa catabolic operons for phenylacetic acid degradation in Escherichia coli.

The expression of the divergently transcribed paaZ and paaABCDEFGHIJK catabolic operons, which are responsible for phenylacetic acid (PA) degradation in Escherichia coli, is driven by the Pz and Pa promoters, respectively. To study the transcriptional regulation of the inducible paa catabolic genes, genetic and biochemical approaches were used. Gel retardation assays showing that the PaaX regulator binds specifically to the Pa and Pz promoters were complemented with in vivo experiments that indicated a PaaX-mediated repression effect on the expression of Pa-lacZ and Pz-lacZ reporter fusions. The region within the Pa and Pz promoters that is protected by the PaaX repressor in DNase I footprinting assays contains a conserved 15-base pair imperfect palindromic sequence motif that was shown, through mutational analysis, to be indispensable for PaaX binding and repression. PA-coenzyme A (PA-CoA), but not PA, specifically inhibited binding of PaaX to the target sequences, thus confirming the first intermediate of the pathway as the true inducer and PaaX as the only bacterial regulatory protein described so far that responds to an aryl-CoA compound. Superimposed in the specific PaaX-mediated regulation is transcriptional activation by the cAMP receptor protein and the integration host factor protein. These global regulators may adjust the transcriptional output from Pa and Pz promoters to the overall growth status of the cell.

Acetyl Coenzyme A↗
PubMed2005

Distinct tissue-specificity of three zebrafish ext1 genes encoding proteoglycan modifying enzymes and their relationship to somitic Sonic hedgehog signaling.

Proteins of the EXT (Exostosin) 1 family are known for their role in human disease. Mutations in EXT1 cause hereditary multiple exostoses (HME), benign outgrowths of the bones, and therefore were classed as tumor suppressors. More recently, their role during embryonic development of Drosophila and mouse was addressed, revealing important functions of EXT1 genes in major signaling pathways. Here, we report the isolation of three zebrafish members of the EXT1 family, which we named ext1a, ext1b, and ext1c, respectively. They are expressed in restricted temporal and spatial domains during development. Both ext1a and ext1b are provided maternally and expressed during gastrulation: ext1a in the neurectoderm and ext1b in the embryonic midline and in the involuting mesendoderm of the germ ring. During somitogenesis stages, transcripts of all three ext genes can be found in the somitic mesoderm. Furthermore, ext1a is expressed in the dorsal neural tube. These expression domains become more pronounced at 24 hr postfertilization (hpf). At 48 hpf, ext1 genes are present in the brain, while somitic expression ceases. Zebrafish have three members of the EXT1 family, in contrast to only one EXT1 gene in mammals or Xenopus, consistent with the occurrence of partial genome duplications in the teleost lineage. Our expression analysis reveals that the three ext genes have distinct expression patterns, reflecting functional divergence after duplication. In addition, expression of ext1a and ext1c responds to elevated and reduced levels of Sonic hedgehog (shh) signaling in the somites, whereas expression of ext1b does not. This suggests a differential relationship between the shh pathway and individual ext gene function in zebrafish.

Amino Acid Sequence↗
PubMed1987

Verbal expression of right cerebrovascular accident patients: convergent and divergent language.

This investigation examined the role of the right hemisphere in language expression. Three groups of 12 subjects each--right CVAs, left CVAs, and controls--performed convergent and divergent language tasks of naming, function, and connected speech. For all convergent tasks and for number of words, number of message units, and fluency in divergent connected speech, controls surpassed both brain-damaged groups, who performed similarly. For the other divergent tasks, controls were superior to the brain-damaged groups, but the right CVAs outperformed the left CVAs. In general, verbal expression problems of right-hemisphere-damaged patients were almost as severe as those of left-hemisphere-damaged patients.

Adult↗
PubMed1999

Transcription of the beta-galactoside alpha2,6-sialyltransferase gene (SIAT1) in B-lymphocytes: cell type-specific expression correlates with presence of the divergent 5'-untranslated sequence.

A single gene, SIAT1, encodes ST6Gal I, the sialyltransferase that mediates transfer of alpha2,6-linked sialic acids to Galbeta1, 4GlcNAc termini of N-linked glycoproteins. In vivo, multiple SIAT1 mRNA forms, differing only in the 5'-untranslated region, are expressed in a tissue-specific manner. This mRNA heterogeneity has been attributed, at least in part, to transcription from a number of physically distinct promoter regions. In mature B-lymphocytes, SIAT1 transcription initiates at P2, a regulatory region known to function only in B-lineage cells. Bacterial chloramphenicol acetyltransferase (CAT) under the control of the P2 region encompassing 415 bp 5'- and 125 bp 3' of the transcriptional initiation site is efficiently expressed in Louckes, a mature B-lymphoblastoid cell line. In contrast, CAT expression in Reh, a T-null/B-null precursor line, and in HepG2, a hepatoma line, are 14-fold and >25-fold less than in Louckes, respectively. The data is consistent with the presence of cis -acting regulatory elements residing both 5' and 3' of the P2 transcriptional initiation site. At least 370 bp of 5'-flanking sequence, coinciding with the inclusion of AP2 and NF-kappaB sites, is necessary for high level expression in Louckes. Exon sequences 3' of the transcription start site are also important for expression. A segment from(+)32 to(+)125 (position(+)1 is transcription start site) is capable of exerting promoter-like activity in Louckes, but not in Reh or HepG2. CAT expression by P2 is negligible in Reh cells. However, enhanced CAT activity is not accompanied by elevated mRNA levels. This observation is consistent with the relief of translational restraints imposed by the(+)32 to(+)125 region. Together, the data demonstrate that efficient and cell-specific transcription regulation in mature B lymphocytes is contained in a 495 bp P2 segment that is comprised of 370 bp of 5'-flanking region and 125 bp of transcribed region of Exon X.

5' Untranslated Regions↗
PubMed2004

Variation in alternative splicing across human tissues.

BACKGROUND: Alternative pre-mRNA splicing (AS) is widely used by higher eukaryotes to generate different protein isoforms in specific cell or tissue types. To compare AS events across human tissues, we analyzed the splicing patterns of genomically aligned expressed sequence tags (ESTs) derived from libraries of cDNAs from different tissues. RESULTS: Controlling for differences in EST coverage among tissues, we found that the brain and testis had the highest levels of exon skipping. The most pronounced differences between tissues were seen for the frequencies of alternative 3' splice site and alternative 5' splice site usage, which were about 50 to 100% higher in the liver than in any other human tissue studied. Quantifying differences in splice junction usage, the brain, pancreas, liver and the peripheral nervous system had the most distinctive patterns of AS. Analysis of available microarray expression data showed that the liver had the most divergent pattern of expression of serine-arginine protein and heterogeneous ribonucleoprotein genes compared to the other human tissues studied, possibly contributing to the unusually high frequency of alternative splice site usage seen in liver. Sequence motifs enriched in alternative exons in genes expressed in the brain, testis and liver suggest specific splicing factors that may be important in AS regulation in these tissues. CONCLUSIONS: This study distinguishes the human brain, testis and liver as having unusually high levels of AS, highlights differences in the types of AS occurring commonly in different tissues, and identifies candidate cis-regulatory elements and trans-acting factors likely to have important roles in tissue-specific AS in human cells.

Alternative Splicing↗
PubMed1996

High frequency of somatic mutations in the VH genes expressed in prolymphocytic leukemia.

Prolymphocytic leukemia (PLL) is a chronic lymphoproliferative disorder, characterized by prominent splenomegaly, prolymphocytes accounting for more than 55% of circulating lymphocytes, and short-term survival. To better characterize the nature of the cellular origin in this disease, we analyzed lg heavy chain variable region (VH) genes in eleven cases of de novo PLL Leukemic cells expressed a skewed repertoire characterized by predominant use of the V3 family members (73%), with preferential use of the V3-23 gene (50% of the VH3 genes). All sequences from expressed VH genes diverged from their putative germline counterpart, and in eight cases the divergence was greater than 5%. In seven cases, which expressed the V3-23 gene and VH4 family members, nucleotide substitutions could be confidently attributed to somatic mutations. The type and distribution of these mutations clearly indicated that in three cases the cells had been subjected to an antigen selection process. Taken together, these results suggest that B-PLL cells display a skewed repertoire of lg VH regions and probably represent, at least in some instances, expansion of postgerminal center cells that have undergone antigen driven selection.

Adult↗
PubMed1996

Differential regulation of p53, c-Myc, Bcl-2 and Bax protein expression during apoptosis induced by widely divergent stimuli in human hepatoblastoma cells.

Apoptosis of HepG2 cells triggered by various agents is characterized in an attempt to delineate the common apoptosis signaling pathway in human hepatoma cells. Several hallmarks of apoptosis, including DNA laddering, chromatin condensation and fragmentation, and an apoptosis specific cleavage of 28S and 18S ribosomal RNA were observed after treatment with curcumin. Curcumin treatment however did not alter the expression levels of Bcl-2 and Bax proteins. p53 protein accumulated slowly and decreased abruptly after reaching the maximum. Conversely, c-Myc protein decreased initially and subsequently increased preceding the onset of apoptosis. The accumulation of p53 protein is not due to increased levels of p53 mRNA and does not result in growth arrest. Staurosporine, quinacrine, ultraviolet irradiation, hydrogen peroxide, and cyclohexamide are all capable of triggering apoptosis in HepG2 cells. While most of these agents affect the expression levels of p53 and c-Myc similarly, none of them altered the expression levels of the Bcl-2 and Bax proteins. In conclusion, these data suggest that p53 and c-Myc may play a more important role in the apoptosis signaling pathway in HepG2 cells, than the bcl-2 gene family.

Antineoplastic Agents↗
PubMed2006

Genes expressed in a turrid venom duct: divergence and similarity to conotoxins.

The toxoglossate mollusks are a large group of venomous animals (>10,000 species) conventionally divided into three groups, the cone snails, the auger snails, and the turrid snails; turrids account for >90% of the biodiversity of toxoglossans. Only the venoms of cone snails have been intensively investigated, with little work focused on turrids. We report the first broad characterization of genes expressed in venom ducts of any turrid species. Twenty-three different cDNA clones encoding putative toxins were characterized from the venom duct of the turrine species Lophiotoma olangoensis Olivera 2002 and belong to 16 different gene families. Of the 16 different Lophiotoma olangoensis gene families that encode putative toxins, for only 1 was there clear evidence of sequence similarity with any conotoxin gene family. The I-like gene family of Lophiotoma olangoensis was found to be related to the K channel-targeted I(2) conotoxin superfamily. Most putative Lophiotoma toxins are cysteine-rich polypeptides, with a significant fraction much larger (>80 amino acids) than the toxins from cone snails. A small number were not cysteine-rich but had hydrophobic amino acid clusters interspersed with arginine residues. This is only 1 of >10,000 different turrid venoms that needs to be characterized. From this study, a common origin with Conus for one family of putative turrid toxins is indicated.

Amino Acid Sequence↗
PubMed2000

Decoupled evolution of coding region and mRNA expression patterns after gene duplication: implications for the neutralist-selectionist debate.

The neutralist perspective on molecular evolution maintains that the vast majority of mutations affecting gene function are neutral or deleterious. After a gene duplication where both genes are retained, it predicts that original and duplicate genes diverge at clock-like rates. This prediction is usually tested for coding sequences, but can also be applied to another important aspect of gene function, the genes' expression pattern. Moreover, if both sequence and expression pattern diverge at clock-like rates, a correlation between divergence in sequence and divergence in expression patterns is expected. Duplicate gene pairs with more highly diverged sequences should also show more highly diverged expression patterns. This prediction is tested for a large sample of duplicated genes in the yeast Saccharomyces cerevisiae, using both genome sequence and microarray expression data. Only a weak correlation is observed, suggesting that coding sequence and mRNA expression patterns of duplicate gene pairs evolve independently and at vastly different rates. Implications of this finding for the neutralist-selectionist debate are discussed.

Biological Evolution↗
PubMed1991

Cloning of a human homeobox gene that resembles a diverged Drosophila homeobox gene and is expressed in activated lymphocytes.

A new homeobox gene, HB24, has been isolated from a human B-lymphocyte cDNA library. Northern blot analysis of polyadenylated RNA purified from activated human B cells revealed a single mRNA transcript of approximately 2.3 kb. Two cDNA clones were sequenced and provided 2,250 nucleotides (nt) of DNA sequence information. There is a single methionine codon-initiated open reading frame of 1,458 nt in frame with a homeobox and a CAX repeat, and the open reading frame is predicted to encode a protein of 51,659 daltons. When the homeodomain from HB24 was compared to known mammalian and Drosophila homeodomains it was found to be only moderately conserved, but when it was compared to a highly diverged Drosophila homeodomain, H2.0, it was found to be 80% identical. The HB24 mRNA was absent or present at low levels in normal B and T lymphocytes; however, with the appropriate activation signal HB24 mRNA was induced within several hours even in the presence of cycloheximide. Characterization of HB24 expression in lymphoid and select developing tissues was performed by in situ hybridization. Positive hybridization was found in thymus, tonsil, bone marrow, developing vessels, and in fetal brain. HB24 is likely to have an important role in lymphocytes as well as in certain developing tissues.

Amino Acid Sequence↗
PubMed2005

Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas.

Expression of neurotrophin receptors of the tyrosine kinase receptor (Trk) family is an important prognostic factor in solid tumors including neuroblastoma. High expression of TrkA (NTRK1) is associated with a favorable biology and outcome of neuroblastoma, whereas TrkB (NTRK2) is expressed on aggressive neuroblastomas with unfavorable outcome. To gain new insights into the global gene expression program resulting in these divergent biological phenotypes, we stably expressed either TrkA or TrkB in the human SH-SY5Y neuroblastoma cell line. Gene expression profiles were obtained from parental cells and transfectants activated by their ligands in a time course over 24 h using oligonucleotide microarrays. Basal activation of Trk receptors in the absence of exogenous ligand was sufficient to induce broad and divergent genetic changes. Global gene regulation following external ligand stimulation was surprisingly similar in SY5Y-TrkA and SY5Y-TrkB cells except for the differential expression of distinct novel target genes. Consistent with their divergent biological phenotype, SY5Y-TrkA cells were characterized by upregulation of proapoptotic genes and angiogenesis inhibitors, whereas SY5Y-TrkB cells demonstrated upregulation of genes involved in invasion or therapy resistance. We suggest that the transcriptional program of neuroblastoma cells is modulated by Trk-receptor expression and basal activation rather than by ligand-induced activation. Fine-tuning of the malignant phenotype may be achieved by additional ligand stimulation with subsequent activation of a few specific genes.

Cell Division↗
PubMed2002

Structure, expression, and developmental function of early divergent forms of metalloproteinases in hydra.

Metalloproteinases have a critical role in a broad spectrum of cellular processes ranging from the breakdown of extracellular matrix to the processing of signal transduction-related proteins. These hydrolytic functions underlie a variety of mechanisms related to developmental processes as well as disease states. Structural analysis of metalloproteinases from both invertebrate and vertebrate species indicates that these enzymes are highly conserved and arose early during metazoan evolution. In this regard, studies from various laboratories have reported that a number of classes of metalloproteinases are found in hydra, a member of Cnidaria, the second oldest of existing animal phyla. These studies demonstrate that the hydra genome contains at least three classes of metalloproteinases to include members of the 1) astacin class, 2) matrix metalloproteinase class, and 3) neprilysin class. Functional studies indicate that these metalloproteinases play diverse and important roles in hydra morphogenesis and cell differentiation as well as specialized functions in adult polyps. This article will review the structure, expression, and function of these metalloproteinases in hydra.

Animals↗
PubMed1998

Visceral endoderm-restricted translation of Otx1 mediates recovery of Otx2 requirements for specification of anterior neural plate and normal gastrulation.

Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, contribute to brain morphogenesis. In particular Otx1 null mice are viable and show spontaneous epileptic seizures and abnormalities affecting the dorsal telencephalic cortex. Otx2 null mice die early in development and fail in specification of the rostral neuroectoderm and proper gastrulation. In order to determine whether Otx1(-/- )and Otx2(-/-) highly divergent phenotypes reflect differences in temporal expression or biochemical activity of OTX1 and OTX2 proteins, the Otx2-coding sequence was replaced by a human Otx1 full-coding cDNA. Homozygous mutant embryos recovered anterior neural plate and proper gastrulation but failed to maintain forebrain-midbrain identities, displaying a headless phenotype from 9 days post coitum (d.p.c.) onwards. Unexpectedly, in spite of the RNA distribution in both visceral endoderm (VE) and epiblast, the hOTX1 protein was synthesized only in the VE. This VE-restricted translation was sufficient to recover Otx2 requirements for specification of the anterior neural plate and proper organization of the primitive streak, thus providing evidence that the difference between Otx1 and Otx2 null mice phenotypes originates from their divergent expression patterns. Moreover, our data lead us to hypothesize that the differential post-transcriptional control existing between VE and epiblast cells may potentially contribute to fundamental regulatory mechanisms required for head specification.

Animals↗
PubMed2003

The expression of calbindin in chicks that are divergently selected for low or high incidence of tibial dyschondroplasia.

Three experiments were conducted with broiler chicks that were divergently selected for low or high incidence of tibial dyschondroplasia (LTD and HTD, respectively) to determine if the expression of intestinal calbindin-28 kD mRNA and protein differed between the 2 strains. In addition, levels of intestinal vitamin D receptor mRNA and plasma thyroid hormone concentrations were also examined. In experiment 1, LTD and HTD chicks were fed a corn-soybean meal diet that was adequate in all nutrients except cholecalciferol (D3), which was titrated to 5 or 40 microg/kg diet in a completely randomized 2 x 2 factorial arrangement. At 4 and 8 d of age, HTD chicks fed 5 microg of D3/kg of diet had a lower (P < 0.05) expression level of calbindin-28 kD mRNA than the LTD chicks fed the same diet. At 4 and 8 d of age, HTD chicks fed 5 microg of D3 had the lowest intestinal expression of calbindin-28 kD protein. Expression of vitamin D receptor mRNA did not differ for broiler strains at either level of D3 supplementation. In experiment 2, there was no significant difference in the expression of calbindin-28 kD mRNA or vitamin D receptor mRNA between day-of-hatch LTD, HTD, and commercial broiler chicks. Experiment 3 was similar in design to the first experiment except that the birds were fed for 18 d. Calbindin-28 kD and vitamin D receptor mRNA expression levels at 18 d were similar to those observed in experiment 1. Plasma triiodothyronine and free-triiodothyronine concentrations were greater for LTD chicks, regardless of dietary D3 supplementation levels. These results suggest that divergent selection of broilers for LTD or HTD alters the physiological response to nutritionally inadequate levels of dietary D3.

Animals↗
PubMed2000

Estrogen modulates HNF-3beta mRNA levels in the developing chick oviduct.

Steroid hormones are involved in many physiological processes, including tissue-specific gene expression, homeostasis, and development. The chick oviduct represents an excellent system in which to study many of these events, as it is highly steroid responsive. Here, we report the cloning of chick HNF-3beta from an oviduct cDNA library and its expression pattern in adult tissues and in the developing oviduct in response to estrogen treatment. Overall, cHNF-3beta was expressed at high levels in the immature chick oviduct and lung and, to a lesser extent, in the liver, kidney, and muscle. This expression pattern is divergent from that of mammalian HNF-3beta, which is not expressed in kidney or muscle. Furthermore, several lengths of cHNF-3beta mRNA transcripts were detected that were expressed tissue specifically. Interestingly, cHNF-3beta mRNA levels were differentially influenced by estrogen as a result of a post-transcriptional effect on the cHNF-3beta message in some tissues. Finally, a role for cHNF-3beta is proposed in the estrogen-stimulated differentiation and development of the oviduct, as cHNF-3beta mRNA expression is induced in the early stages of oviduct development and declines as the animal becomes sexually mature.

Amino Acid Sequence↗
PubMed2004

Influences of sigmaB and agr on expression of staphylococcal enterotoxin B (seb) in Staphylococcus aureus.

In Staphylococcus aureus, enterotoxin B (SEB) is a superantigen that activates host interleukins and induces adverse responses, ranging from food poisoning to toxic shock. The alternate sigma factor, sigmaB (SigmaB), and agr are two known regulators of S. aureus. Northern blots of strain COL, a sigB-positive strain, showed an inverse correlation between sigmaB expression and seb message. seb expression was also measured as a function of a seb promoter linked to green fluorescent protein (GFP) expression in RN6390, COL, and Newman. In sigB mutants of RN6390, SH1000, COL, and Newman, seb promoter activities, as measured by GFP expression, increased relative to the respective parental types but at differing levels, suggesting alternate strain-specific regulation. In agr mutants of RN6390 and Newman, seb promoter activities were intermediate between the high level seen for the sigB mutant and the low level in the sigB active strains. A sigB agr double mutant of RN6390 displayed lower GFP expression than the agr mutant. These results suggest that while sigmaB and agr regulate seb expression in a divergent manner, other activator(s) of seb that depend on sigB expression may be present in S. aureus.

Bacterial Proteins↗