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At least 739 records · Page 41Linked to original sources
PubMed2004

Signal recognition particle Alu domain occupies a defined site at the ribosomal subunit interface upon signal sequence recognition.

The eukaryotic signal recognition particle (SRP) is essential for cotranslational targeting of proteins to the endoplasmic reticulum (ER). The SRP Alu domain is specifically required for delaying nascent chain elongation upon signal sequence recognition by SRP and was therefore proposed to interact directly with ribosomes. Using protein cross-linking, we provide experimental evidence that the Alu binding protein SRP14 is in close physical proximity of several ribosomal proteins in functional complexes. Cross-linking occurs even in the absence of a signal sequence in the nascent chain demonstrating that SRP can bind to all translating ribosomes and that close contacts between the Alu domain and the ribosome are independent of elongation arrest activity. Without a signal sequence, SRP14 cross-links predominantly to a protein of the large subunit. Upon signal sequence recognition, certain cross-linked products become detectable or more abundant revealing a change in the Alu domain-ribosome interface. At this stage, the Alu domain of SRP is located at the ribosomal subunit interface since SRP14 can be cross-linked to proteins from the large and small ribosomal subunits. Hence, these studies reveal differential modes of SRP-ribosome interactions mediated by the Alu domain.

Alu Elements↗
PubMed2002

Quantitative determination of tumor cell intravasation in a real-time polymerase chain reaction-based assay.

Tumor cells acquire the ability to enter blood vessels surrounding the primary tumor, endowing them with the capacity to disseminate and become established in distant sites, originating a metastasis. Determination of the intravasation ability of tumor cells is thus important, as it can be correlated with their potential malignancy. To analyze the intravasation phenotype of human tumor cells in vivo, we performed chick embryo chorioallantoic membrane (CAM) assays. Cells were inoculated on the CAM of 9-day-old chick embryos and the membrane at the opposite side of the egg was recovered after 48 h incubation. To measure intravasation ability, we calculated the amount of human DNA in each CAM sample by real-time PCR of Alu sequences and SYBR Green 1 fluorescence detection. This analysis showed a detection limit of 1 human cell per 10(5) total cells, and we were able to distinguish between tumor cells of distinct invasive capacity. This assay has several advantages over current methods to measure intravasation ability, including the elimination of post-PCR analysis, sensitivity and easy scale-up of sample numbers.

Adenocarcinoma↗
PubMed2002

Quantification of human Alu sequences by real-time PCR--an improved method to measure therapeutic efficacy of anti-metastatic drugs in human xenotransplants.

For measuring the efficacy of new anti-metastatic drugs in preclinical models, macroscopical analysis or classical histology of secondary organs are established methods. However, macroscopical evaluation does not take into consideration intra-organ metastasis. Histological analysis is often performed in few sections of the relevant organs, and this may be misleading, since equal distribution of tumor cells within an organ is unlikely. In addition, recent studies have demonstrated that anti-tumorigenic drugs are able to promote metastasis and to change the metastatic pattern. Therefore, extensive analysis of metastasis is mandatory for the evaluation of new compounds. A feasibility study was conducted to find out if the quantification of human Alu sequences could be applied as a surrogate marker for metastasis in xenografts. Alu PCR was performed by using the LightCycler system, which allows PCR reaction and subsequent quantification of the PCR products in less than 30 min. We found that i) the equivalent of one human tumor cell in 1 x 10(6) murine cells could be detected; ii) in tumor-carrying mice, Alu signal increased over time in secondary organs; iii) this increase was more prominent using highly metastatic tumor cells; iv) Alu signal intensity in DNA extracted from tissue slides correlated with the expression of histological tumor markers; v) in three different tumor models (colon, breast and lung), treatment with Taxol or 5-fluorouracil reduced the amount of Alu in different organs. In contrast, reduction of Alu by the matrix metalloproteinase inhibitor RO 28-2653 was not significant. Taken together, quantification of Alu sequences is a fast and accurate method to evaluate the therapeutic efficacy of anti-metastatic drugs in xenografts.

Alu Elements↗
PubMed1998

Characterization of a human genomic DNA fragment which rescues defective lipid-linked oligosaccharide synthesis in a mutant G258 cell line isolated from the FM3A mouse mammary carcinoma cell line.

The G258 mutant cell line, isolated from the FM3A mouse mammary carcinoma cell line, is temperature-sensitive for both cell growth and asparagine-linked glycosylation due to mutation at a single location. The biochemical defect in the G258 mutant resides in the formation of lipid-linked oligosaccharide, presumably in one of the steps of GDP-mannose-dependent mannosylation (Y. Nishikawa, J. Cell. Physiol. 119, 260-266, 1984; Y. Nishikawa, Biochim. Biophys. Acta 1091, 135-140, 1991). In the present study, we transfected human genomic DNA fragments into the G258 mutant by the radiation hybrid method and isolated transformants (KK-1, -3 and -4) which showed recovery from both temperature-sensitive cell growth and asparagine-linked glycosylation. These transformants contained a common Alu-containing human DNA fragment (1.3 kb) which will be used as a marker for isolating the gene that complements the defect of lipid-liked oligosaccharide synthesis in the G258 mutant.

Alu Elements↗
PubMed2003

The I allele of the angiotensin-converting enzyme gene is associated with an increased percentage of slow-twitch type I fibers in human skeletal muscle.

The insertion (I) allele of the human angiotensin-converting enzyme (ACE) gene is associated with lower serum and tissue ACE activity, and with greater endurance performance and enhanced mechanical efficiency of trained muscle. We tested the hypothesis that the ACE-I allele may be associated with increased slow-twitch fiber, which is more efficient than fast-twitch fiber in low-velocity contraction, by examining the association between the ACE genotype and skeletal muscle fiber (SMF) types in 41 untrained healthy young volunteer subjects (31 males, 10 females, age 24 +/- 3 years). Skeletal muscle samples were taken from the left vastus lateralis using the needle-biopsy method. Slow-twitch type I fibers and fast-twitch type IIa and IIb fibers were classified histochemically based on staining for myosin adenosine triphosphatase (ATPase) activity at different pH values. Amylase-periodic acid-Schiff staining was used to visualize capillaries around fibers. ACE-II subjects had significantly (p < 0.01) higher percentages of type I fibers (50.1 +/- 13.9%vs 30.5 +/- 13.3%) and lower percentages of type IIb fibers (16.2 +/- 6.6%vs 32.9 +/- 7.4%) than ACE-DD subjects. The linear trends for decreases in type I fibers and increases in type IIb fibers from ACE-II --> ID --> DD genotypes were significant as assessed by an analysis of variance. The ratio of type I:II fibers also differed according to the ACE genotype. A multivariate logistic regression analysis showed that the ACE-I allele had significant additive and recessive (codominant) effects on the increased type I fibers and the ratio of type I:II fibers. No specific pattern of capillarization was observed among the three ACE genotypes. In conclusion, the ACE-I allele was associated with increased type I SMF, which may be a mechanism for the association between the ACE genotype and endurance performance.

Adult↗
PubMed2003

Association of MHC dimorphic Alu insertions with HLA class I and MIC genes in Japanese HLA-B48 haplotypes.

A large proportion of Japanese with the HLA-B48 allele have a MICA gene deletion associated with a MICB null allele within the class I region of the Major Histocompatibility Complex (MHC). Here, we report for the first time a novel positive association between the presence of a polymorphic Alu insertion, AluyMICB, within the first intron of the MICB gene and the MICAdel/MICBnull/HLA-B48 haplotype for five of six well-characterized Japanese cell-lines. The AluyMICB insertion was found to be present at a frequency of 0.242 in 86 Japanese tissue donors and in four of the five individuals with the HLA-B48 allele. The AluyMICB insertion was also associated with at least three different MICB alleles, *0102, *0107N and *0105, and three different HLA-B alleles, B13, B48 and B57, respectively, in the seven Workshop cell-lines (the 4th Asia-Oceania Histocompatibility Workshop, and the 10th International Histocompatibility Workshop) and the six Japanese cell-lines that were selected for this study. Based on the analysis of associations between different polymorphic markers within the beta block, the MICB*0102 allele was inferred to be the ancestral form of the MICB*0105 and MICB*0107N alleles. The AluyMICB polymorphism can now be used to further investigate its relationship with other MICB alleles and consequently their origins. In addition, we have examined the absence and presence of three other polymorphic Alu markers distributed within the alpha block of the class I region of the HLA-B48/AluyMICB haplotype. We conclude that the extended HLA-B haplotypes are best defined by considering multiple genomic sites including the four polymorphic Alu insertions described in this study.

Alu Elements↗
PubMed1999

Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).

Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration.

Alu Elements↗
PubMed2005

Initial sequence of the chimpanzee genome and comparison with the human genome.

Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differences that have accumulated since the human and chimpanzee species diverged from our common ancestor, constituting approximately thirty-five million single-nucleotide changes, five million insertion/deletion events, and various chromosomal rearrangements. We use this catalogue to explore the magnitude and regional variation of mutational forces shaping these two genomes, and the strength of positive and negative selection acting on their genes. In particular, we find that the patterns of evolution in human and chimpanzee protein-coding genes are highly correlated and dominated by the fixation of neutral and slightly deleterious alleles. We also use the chimpanzee genome as an outgroup to investigate human population genetics and identify signatures of selective sweeps in recent human evolution.

Alleles↗
PubMed1992

A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias.

Some acute lymphocytic leukaemias, particularly those in young children, are associated with a t(4;11)(q21;q23) reciprocal translocation. We have cloned the translocation breakpoint on chromosome 11q23 and isolated corresponding RNA transcripts from this region. The translocation occurs within a cluster of Alu repetitive elements located within an intron of a gene that gives rise to 11.5 (kb) transcript spanning the translocation breakpoint. The 11.5 kb transcript encodes a protein that is highly homologous to the Drosophila trithorax gene, a developmental regulator. An analysis of a series of leukaemic patients carrying t(4;11) and t(9;11) translocations indicate that the majority of breakpoints in infant leukaemias lie within a 5 kb region.

Amino Acid Sequence↗
PubMed2004

Global patterns of human mitochondrial DNA and Y-chromosome structure are not influenced by higher migration rates of females versus males.

Global-scale patterns of human population structure may be influenced by the rate of migration among populations that is nearly eight times higher for females than for males. This difference is attributed mainly to the widespread practice of patrilocality, in which women move into their mates' residences after marriage. Here we directly test this hypothesis by comparing global patterns of DNA sequence variation on the Y chromosome and mitochondrial DNA (mtDNA) in the same panel of 389 individuals from ten populations (four from Africa and two each from Europe, Asia and Oceania). We introduce a new strategy to assay Y-chromosome variation that identifies a high density of single-nucleotide polymorphisms, allows complete sequencing of all individuals rather than relying on predetermined markers and provides direct sequence comparisons with mtDNA. We found the overall proportion of between-group variation (Phi(ST)) to be 0.334 for the Y chromosome and 0.382 for mtDNA. Genetic differentiation between populations was similar for the Y chromosome and mtDNA at all geographic scales that we tested. Although patrilocality may be important at the local scale, patterns of genetic structure on the continental and global scales are not shaped by the higher rate of migration among females than among males.

Alu Elements↗
PubMed2006

Editor meets silencer: crosstalk between RNA editing and RNA interference.

The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A-->I RNA editing) in double-stranded (ds)RNA substrates. A-->I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A-->I RNA editing crosstalks with RNA-interference pathways, which, like A-->I RNA editing, involve dsRNAs. A-->I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.

Adenosine↗
PubMed2003

Does race exist?

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Alu Elements↗
PubMedDate not supplied

Y chromosomal polymorphisms reveal founding lineages in the Finns and the Saami.

Y chromosomal polymorphisms were studied in 502 males from 16 Eurasian ethnic groups including the Finns, Saami (Inari Lake area and Skolt Saami), Karelians, Mari, Mokshas, Erzas, Hungarians (Budapest area and Csángós), Khanty, Mansi, Yakuts, Koryaks, Nivkhs, Mongolians, and Latvians. The samples were analysed for polymorphisms in the Y chromosome specific Alu insertion (YAP) and six microsatellites (DYS19, DYS389-I and II, DYS390, DYS392, DYS393). The populations were also screened for the recently described Tat polymorphism. The incidence of YAP+ type was highest in the Csángós and in other Hungarians (37.5% and 17.5%, respectively). In the Karelians and the Latvians it was present at approximately the same level as commonly found in other European populations, whilst absent in our further samples of Eurasian populations, including the Finns and the Saami. Aside from the Hungarians, the C allele of the Tat polymorphism was common in all the Finno-Ugric speaking populations (from 8.2% to 63.2%), with highest incidence in the Ob-Ugrian Khanty. The C allele was also found in the Latvians (29.4%). The haplotypes found associated with the Tat C allele showed consistently lower density than those associated with the T allele, indicating that the T allele is the original form. The computation of the age of the Tat C suggested that the mutation might be a relatively recent event giving a maximum likelihood estimate of 4440 years (95% confidence interval about 3140-6200 years). The distribution patterns of the 222 haplotypes found varied considerably among the populations. In the Finns a majority of the haplotypes could be assigned to two distinct groups, one of which harboured the C allele of the Tat polymorphism, indicating dichotomous primary source of genetic variation among Finnish males. The presence of a bottleneck or founding effect in the male lineages of some of the populations, namely in the Finns and the Saami, would appear to be one likely interpretation for these findings.

Alu Elements↗