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PubMed2002

Gene therapy and reproductive medicine.

OBJECTIVE: To review the literature on the principles of gene therapy and its potential application in reproductive medicine. DESIGN: Literature review. SETTING: Gene therapy involves transfer of genetic material to target cells using a delivery system, or vector. Attention has primarily focused on viral vectors. Significant problems remain to be overcome including low efficacy of gene transfer, the transient expression of some vectors, safety issues with modified adenoviruses and retroviruses, and ethical concerns. If these issues can be resolved, gene therapy will be applicable to an increasing spectrum of single and multiple gene disorders, as the Human Genome Project data are analyzed, and the genetic component of human disease becomes better understood. Gynecologic gene therapy has advanced to human clinical trials for ovarian carcinoma, and shows potential for the treatment of uterine leiomyomata. Obstetric applications of gene therapy, including fetal gene therapy, remain more distant goals. CONCLUSION(S): Concerns about the safety of human gene therapy research are being actively addressed, and remarkable progress in improving DNA transfer has been made. The first treatment success for a genetic disease (severe combined immunodeficiency disease) has been achieved, and ongoing research efforts will eventually yield clinical applications in many spheres of reproductive medicine.

Adenoviridae↗
PubMed2004

Characterization of gains, losses, and regional amplification in testicular germ cell tumor cell lines by comparative genomic hybridization.

We have performed comparative genomic hybridization on 12 testicular germ cell tumor (TGCT) cell lines and one paraffin-embedded surgical specimen to identify and characterize genome-wide gains and losses of chromosomes in these specimens. All specimens demonstrated overrepresentation of 12p. Other significant chromosomal gains, apart from 12p, included the X chromosome and chromosome arms 1q and 20q. Chromosomal losses were observed for chromosomes 4 and 18 and chromosome arms 2q, 9q, and 13q. Genomic differences were observed between an embryonal carcinoma component of a mixed tumor, 833K, and its cisplastin-resistant derivative line, 64CP, including losses of 6q23 approximately qter and 9p22 approximately q21. Five lines also demonstrated gain of 12p and additional 12p12 approximately p13 material. Similarly, two lines demonstrated gain of 12p and additional 12p11.2 approximately p12 material. The data supports the consistent gain of 12p in adult TGCT cell lines and additional regional amplification of 12p in some lines. This regional amplification has been observed in both primary tumor specimens and TGCT cell lines and may support a hypothesis that at least two different regions of 12p, one proximal and one distal, harbor genes important for the pathogenesis of testicular germ cell neoplasia.

Cell Line, Tumor↗
PubMed2001

RNA delivery into mitochondria.

Mitochondria, though containing their own genome, import the vast majority of their macromolecular components from the cytoplasm. If the mechanisms of pre-protein import are well understood, the import of nuclear-coded RNAs into mitochondria was investigated to a much lesser extent. This targeting, if not universal, is widely spread among species. The origin and the mechanisms of RNA import seem to differ from one system to another and striking differences are observed even in closely related species. We describe data concerning the various experimental systems of studying RNA import with emphasis on the model of the yeast Saccharomyces cerevisiae, which was studied in our laboratory. We compare various requirements of RNA import into mitochondria in different species and demonstrate that this pathway can be transferred from yeast to human cells, in which tRNAs normally are not imported. We speculate on the possibility to use RNA import for biomedical purposes.

Animals↗
PubMed1998

Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin.

BACKGROUND: Many pathogenic bacteria secrete iron-chelating siderophores as virulence factors in the iron-limiting environments of their vertebrate hosts to compete for ferric iron. Mycobacterium tuberculosis mycobactins are mixed polyketide/nonribosomal peptides that contain a hydroxyaryloxazoline cap and two N-hydroxyamides that together create a high-affinity site for ferric ion. The mycobactin structure is analogous to that of the yersiniabactin and vibriobactin siderophores from the bacteria that cause plague and cholera, respectively. RESULTS: A ten-gene cluster spanning 24 kilobases of the M. tuberculosis genome, designated mbtA-J, contains the core components necessary for mycobactin biogenesis. The gene products MbtB, MbtE and MbtF are proposed to be peptide synthetases, MbtC and MbtD polyketide synthases, MbtI an isochorismate synthase that provides a salicylate activated by MbtA, and MbtG a required hydroxylase. An aryl carrier protein (ArCP) domain is encoded in mbtB, and is probably the site of siderophore chain initiation. Overproduction and purification of the mbtB ArCP domain and MbtA in Escherichia coli allowed validation of the mycobactin initiation hypothesis, as sequential action of PptT (a phosphopantetheinyl transferase) and MbtA (a salicyl-AMP ligase) resulted in the mbtB ArCP domain being activated as salicyl-S-ArCP. CONCLUSIONS: Mycobactins are produced in M. tuberculosis using a polyketide synthase/nonribosomal peptide synthetase strategy. The mycobactin gene cluster has organizational homologies to the yersiniabactin and enterobactin synthetase genes. Enzymatic targets for inhibitor design and therapeutic intervention are suggested by the similar ferric-ion ligation strategies used in the siderophores from Mycobacteria, Yersinia and E. coli pathogens.

Bacterial Proteins↗
PubMed2000

Identification of Photosystem I components from a glaucocystophyte, Cyanophora paradoxa: The PsaD protein has an N-terminal stretch homologous to higher plants.

Thylakoid membranes and Photosystem I (PS I) complexes were isolated from a glaucocystophyte, Cyanophora paradoxa, which is thought to have the most primitive 'plastids', and the proteins related to PS I were examined. The intrinsic light-harvesting chlorophyll protein complexes of PS I (LHC I) were not detected by an immunological method. The PS I complexes consisted of at least eight low-molecular-mass proteins in addition to PS I reaction center proteins. The N-terminal sequence of the PsaD protein has higher homology to that of Chlamydomonas reinhardtii and land plants, than to that of other algae or cyanobacteria. On the other hand, the PsaL sequence has the highest homology to those of cyanobacteria. Taking into account the other sequences of PS I components whose genes are encoded in the cyanelle genome, and the fact that LHC I is not detected, it is concluded that PS I of C. paradoxa has chimeric characteristics of both 'green' lineages and cyanobacteria.

Journal Article↗
PubMed2003

Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme.

Since it has been widely demonstrated that platinum-based drugs, like cisplatin, carboplatin and oxaliplatin, bind preferentially to guanine in N7 position and that telomerase assemblage includes a RNA portion rich in guanine, we previously designed and synthesized a series of new complexes with a cytotoxic [Pt(II)Cl2] moiety, with the aim of selecting carrier ligands able to inhibit telomerase enzyme. Among these compounds, [cis-dichloropyridine-5-isoquinolinesulfonic acid Pt(II)], named Ptquin8, showed the most significant inhibition of telomerase in a cell-free biochemical assay. In this paper, we report the biological effects of Ptquin8 on in vitro tumor model (MCF-7). This complex is able to reduce telomerase activity from 12 to 46%, in a concentration range between 10(-9) and 10(-5) M after 24 h continuous treatment. Moreover, Ptquin8 shows significant cytotoxicity after 10 days of continuous treatment only at concentrations higher than 10(-5) M. The determination of residual telomere length confirmed the inhibition of telomerase action. This induced a progressive reduction of the cell proliferative capacity, and the appearance of an elevated number of apoptotic cells after 18 days. RT-PCR analysis of telomerase RNA components excluded any interaction of the compound at genomic level. The biochemical effects of Ptquin8 were also evaluated on non-neoplastic NIH3T3 cells, that are able to down-regulate telomerase activity as a consequence of the confluence contact inhibition. In this cell model, the reactivation of telomerase due to re-seeding at lower density was significantly inhibited by Ptquin8 in a dose-dependent manner. These results highlight a possible role of Ptquin8 as a selective anti-telomerase tool for cancer treatment.

Cell Division↗
PubMedDate not supplied

Repeat sequence families derived from mammalian tRNA genes.

Short interspersed repetitive DNA sequences (SINEs) are the major component of dispersed repetitive DNA in all mammalian genomes. Most SINEs contain an intragenic RNA polymerase III promoter that initiates transcription at the 5' end of the repeated DNA sequence and which has been proposed to facilitate the transposition and amplification of these sequences by an RNA-intermediate mechanism. We have discovered several SINE families in the prosimian Galago crassicaudatus which have promoter regions similar to transfer RNA genes. To determine the relationship between Galago SINEs and mammalian tRNA genes, we have compared their sequences. Here, we demonstrate that the Galago monomer and type II SINE families are 68 and 62% homologous, respectively, with a human methionine tRNA gene. We have extended our analysis to include the rat identifier and mouse B2 families and show that their sequences are closely related to alanine and serine tRNA genes, respectively. Our observations suggest that many mammalian SINE families are amplified tRNA pseudogenes.

Animals↗
PubMed1988

Effect of 1,25-dihydroxyvitamin D3 on cytosolic calcium in dispersed parathyroid cells.

We examined the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on cytosolic calcium ([Ca]i) of dispersed bovine parathyroid cells, using the fluorescent dye indo-1. The addition of 10(-8) M 1,25-(OH)2D3 caused an increase in [Ca]i by 23.4 +/- 2.7% over a 10 minute period. There was a significant increase in [Ca]i within two minutes of the addition of 1,25-(OH)2D3. 1,25-(OH)2D3 increased [Ca]i in a dose-dependent manner and this occurred with as little as 10(-10) M. Neither 10(-7) M 25-(OH)D3 nor 10(-7) M 24, 25-(OH)2D3 caused a significant increase in [Ca]i. Chelation of extracellular calcium with EGTA blocked the 1,25-(OH)2D3-induced increase in [Ca]i, suggesting that the increase was mainly from extracellular calcium. Neither 10(-5) M verapamil nor 10(-4) M diltiazem blocked the 1,25-(OH)2D3-induced increase in [Ca]i. The present data suggest that 1,25-(OH)2D3 might modify membrane permeability to calcium independent of voltage-dependent calcium channels sensitive to verapamil or diltiazem. The rapid effect of 1,25-(OH)2D3 raises the possibility that its mechanism is independent of genome activation, perhaps attributable to direct interaction with components of the parathyroid cell plasma membrane.

Animals↗
PubMed2004

A genome scan among Nigerians linking resting energy expenditure to chromosome 16.

Energy requirements at rest account for 50% to 75% of total energy expenditure. Interindividual variation in resting energy expenditure (REE) has been studied for potential links to obesity and hypertension. REE is a modestly heritable trait, and yet virtually nothing is known about the genetic factors that might influence the familial patterns. The objectives of this study were to identify the genomic regions showing genetic linkage to REE variation in a Nigerian population. For linkage analysis across the genome, three hundred seventy-seven microsatellite markers were typed on DNA from 995 individuals in 153 families. A genome scan was performed using a multipoint variance component method. Heritability of REE was 0.30 after adjustment for body size. The strongest linkage signal was detected on chromosome 16 (16q22.3) with a likelihood of odds of 2.96 (p = 0.08). Linkage evidence (likelihood of odds > 1) was detected on another three chromosomal regions, namely 2q12.1, 8q21.2, and 15p11.2.

Adult↗
PubMed2005

Chromatin regulation and sumoylation in the inhibition of Ras-induced vulval development in Caenorhabditis elegans.

In Caenorhabditis elegans, numerous 'synMuv' (synthetic multivulval) genes encode for chromatin-associated proteins involved in transcriptional repression, including an orthologue of Rb and components of the NuRD histone deacetylase complex. These genes antagonize Ras signalling to prevent erroneous adoption of vulval fate. To identify new components of this mechanism, we performed a genome-wide RNA interference (RNAi) screen. After RNAi of 16 757 genes, we found nine new synMuv genes. Based on predicted functions and genetic epistasis experiments, we propose that at least four post-translational modifications converge to inhibit Ras-stimulated vulval development: sumoylation, histone tail deacetylation, methylation, and acetylation. In addition, we demonstrate a novel role for sumoylation in inhibiting LIN-12/Notch signalling in the vulva. We further show that many of the synMuv genes are involved in gene regulation outside the vulva, negatively regulating the expression of the Delta homologue lag-2. As most of the genes identified in this screen are conserved in humans, we suggest that similar interactions may be relevant in mammals for control of Ras and Notch signalling, crosstalk between these pathways, and cell proliferation.

Animals↗
PubMed2006

Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14.

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.

Autistic Disorder↗
PubMedDate not supplied

[Mechanisms of cell division: lessons from a nematode].

The mechanisms orchestrating spatial cell division control remain poorly understood. In animal cells, the position of the mitotic spindle dictates cleavage furrow placement, and thus plays a key role in governing spatial relationships between resulting daughter cells. The one-cell stage Caenorhabditis elegans embryo is an attractive model system to investigate the mechanisms underlying spindle positioning in metazoans. In this review, the experimental advantages of this model system for an in vivo dissection of cell division processes are first discussed. Next, three lines of experiments that were conducted to dissect the mechanisms governing spindle positioning in one-cell stage C. elegans embryos are summarized. First, localized laser micro-irradiations were utilized to identify the forces acting on spindle poles during anaphase. This work revealed that there is a precise imbalance of pulling forces acting on the two spindle poles, with the forces acting on the posterior spindle pole being in slight excess, thus explaining the asymmetric spindle position achieved by the end of anaphase. Second, an RNAi-based functional genomic screen was carried out to identify novel components required for generating these pulling forces. This uncovered that gpr-1/gpr-2, which encode GoLoco-containing proteins, as well as the previously identified Ga subunits goa-1/gpa-16, are required for generation of pulling forces on the spindle poles. Third, the zyg-8 locus was identified by mutational analysis to play a distinct role during anaphase spindle positioning. zyg-8 was found to encode a protein related to human Doublecortin, which is affected in patients with neuronal migration disorders. Moreover, ZYG-8 is a microtubule-associated protein that stabilizes microtubules against depolymerization. Together, these experimental approaches contribute to a better understanding of the mechanisms orchestrating spatial cell division control in metazoan organisms.

Animals↗
PubMed2002

Suppressors of transcriptional transgenic silencing in Chlamydomonas are sensitive to DNA-damaging agents and reactivate transposable elements.

In the unicellular green alga Chlamydomonas reinhardtii, the epigenetic silencing of transgenes occurs, as in land plants, at both the transcriptional and posttranscriptional levels. In the case of single-copy transgenes, transcriptional silencing takes place without detectable cytosine methylation of the introduced DNA. We have isolated two mutant strains, Mut-9 and Mut-11, that reactivate expression of a transcriptionally silenced single-copy transgene. These suppressors are deficient in the repression of a DNA transposon and a retrotransposon-like element. In addition, the mutants show enhanced sensitivity to DNA-damaging agents, particularly radiomimetic chemicals inducing DNA double-strand breaks. All of these phenotypes are much more prominent in a double mutant strain. These observations suggest that multiple partly redundant epigenetic mechanisms are involved in the repression of transgenes and transposons in eukaryotes, presumably as components of a system that evolved to preserve genomic stability. Our results also raise the possibility of mechanistic connections between epigenetic transcriptional silencing and DNA double-strand break repair.

Animals↗
PubMed2002

Malignant worms: what cancer research can learn from C. elegans.

Developmental processes in the nematode C. elegans are controlled by pathways of gene functions that are analogous to those used in mammals. Hence, genetic studies in C. elegans have helped build the frameworks for these regulatory pathways. Many homologs of human genes that are targets for mutation in cancer have been found to function at distinct steps within such genetic pathways. This way, studies in C. elegans have provided important clues about the functions of human oncogenes and tumor suppressors. Understanding how human cancer genes function and act in signaling cascades is of great importance. This information reveals what kind of molecular changes contribute to the process of cell transformation. Moreover, additional candidate oncogenes and tumor suppressors may be revealed by identifying the functional partners of genes with an established role in cancer. Furthermore, identifying a cascade of gene functions increases the number of potential targets for therapeutic intervention, as blocking either one of multiple genes may interfere with signal transduction through the pathway. Simultaneous approaches in a number of different model systems act synergistically in solving pathways of gene functions. By using multiple models, the field takes advantage of the strengths of each system and circumvents its limitations. As one of the most powerful genetic animal systems, C. elegans will continue to reveal new mammalian signaling components. In addition, now that the C. elegans genome sequence has been completed, an increasing number of researchers are likely to discover homologs of human disease genes in the nematode and to analyze gene function in the worm model. Combined with the great potential of this animal in drug screens, it is simple to predict that C. elegans will worm its way deeper and deeper into cancer research.

Animals↗
PubMed2002

Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets.

Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The virus has a positive-sense RNA genome encoding a single polyprotein with the virion components located in the N-terminal portion. During biosynthesis of the polyprotein, an internal signal sequence between the core protein and the envelope protein E1 targets the nascent polypeptide to the endoplasmic reticulum (ER) membrane for translocation of E1 into the ER. Following membrane insertion, the signal sequence is cleaved from E1 by signal peptidase. Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. Core protein is then free for subsequent trafficking to lipid droplets. This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein.

Amino Acid Sequence↗
PubMed1991

A nuclear mutation reversing a biased transmission of yeast mitochondrial DNA.

The highly biased transmission of p- mitochondrial DNA that occurs in hypersuppressive matings between p- and p+ cells of the yeast Saccharomyces cerevisiae is thought to be a consequence of the replication advantage of the p- mtDNA. A nuclear gene, MGT1, that is required for this displacement of p+ mtDNA from zygotic clones has been identified through mutation. When one haploid parent carries the mgt1 allele, transmission of p- mtDNA is substantially reduced. When both haploid parents carry the mgt1 allele, p- mtDNA is essentially eliminated from the zygotic progeny. Thus in the absence of the MGT1 gene there is a switch in the transmission bias; p+ mtDNA rather than the hypersuppressive p- mtDNA is inherited by most zygotic clones. In contrast to its semi-dominant behavior in haploid matings, mgt1 behaves as a recessive allele in diploid matings since the p+ genome in MGT1/mgt1 diploids is efficiently displaced when mated with a MGT1/mgt1 hypersuppressive p- diploid strain. We find that p+ genomes can be comaintained along with hypersuppressive p- mtDNA for extended periods in clonal lines derived from MGT1 x mgt1 matings. However, as expected from the recessive nature of the mgt1 mutation, these p+ genomes are eventually eliminated. Our work indicates that MGT1 plays a crucial role in the competition for inheritance between hypersuppressive p- mtDNAs and the p+ mitochondrial genome. The MGT1 gene product may be a component of a mtDNA replication system that acts preferentially at the rep sequences found in hypersuppressive mtDNAs.

Cell Nucleus↗
PubMed2003

Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics.

The spinocerebellar ataxias (SCAs) are a class of hereditary neurodegenerative diseases, which are caused by the pathological expansion of unstable CAG triplet repeats found in a number of apparently unrelated genes. The proteins encoded by the SCA genes typically translate this expanded (CAG)n repeat into an expanded poly(Q) stretch. Several pathological features are common to all SCAs, irrespective of the gene harbouring the expansion. The specific contributions of the mutated genes are currently hard to assess, as the physiological role of most of the so-called ataxins is not known. By combining the results of profile-based sequence analysis with genome-wide functional data available for model organisms, we have derived detailed predictions of the physiological function of two SCA gene products. Ataxin-3, the protein mutated in Machado Joseph Disease (SCA3), belongs to a novel group of cysteine-proteases and is predicted to be active against ubiquitin chains or related substrates. The catalytic site of this enzyme class is similar to that found in UBP and UCH type ubiquitin proteases. For ataxin-7, the gene product of the SCA7 gene, we have identified an orthology relationship to the yeast open reading frame Ygl066c. Recently published evidence from genome-wide studies suggests that Ygl066c is a component of the SAGA histone acetyltransferase complex. By analogy, a similar role for the mammalian ataxin-7 can be expected. The functional predictions reported here are sufficiently precise to allow a direct experimental verification. Moreover, both findings have implications for the general pathogenesis of spinocerebellar ataxias by providing a direct connection of these diseases with ubiquitin metabolism and histone acetylation.

Acetylation↗
PubMed1988

In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020: construction and evaluation in rodents.

The herpes simplex virus (HSV) recombinant R7017 was constructed from HSV-1 (strain F) by deleting a portion of the thymidine kinase (tk) gene and by replacing the sequences representing the internal inverted repeats and adjacent genes in the L component with a fragment of the HSV-2 genome encoding the glycoproteins G, D, I, and a portion of E. In addition, the R7020 recombinant contains an HSV-1 DNA fragment encoding the tk gene fused to the alpha 4 gene promoter. The results of studies in mice, guinea pigs, and rabbits were as follows: Both recombinants remained unchanged after nine serial, intracerebral passages in mice; the recombinants could not be differentiated with respect to attenuation in mice injected intracerebrally, in vaginally infected guinea pigs, and in rabbits inoculated on the scarified cornea. Given intradermally or intramuscularly, the recombinants prevented severe infections by virulent challenge viruses, and R7020 established latent infections (at a low frequency) in all species tested, whereas latent R7017 virus was detected in rabbits only.

Animals↗