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PubMed2000

Cloning and characterization of human estrogen receptor beta promoter.

Estrogen receptors beta (ERbeta) belong to the nuclear receptor superfamily of ligand-dependent transcription factors that play critical roles in regulating genes involved in a wide array of biological processes. To investigate regulation of tissue-specific expression of ERbeta, we cloned and characterized a 2.1-kilobase 5'-flanking region of the human ERbeta gene. Two major transcription start sites were identified by primer extension and rapid amplification of 5'-cDNA end. The human ERbeta proximal promoter contains both TATA box and initiator element (Inr) and is GC-rich with a GC content of 65%. An Alu repeat sequence containing an ER-dependent transcription enhancer exists between -1416 and -1703. The full-length 5'-flanking sequence of ERbeta fused to a luciferase reporter exhibited functional promoter activity in ERbeta-positive TSUPr1 cell, but not in ERbeta-negative DU145 cells. In addition, DNase I protection assays of the proximal promoter showed unique protection patterns with nuclear extracts from TSUPr1 cells and ERbeta negative HeLa cells, suggesting presence of cell-specific trans-acting factors that mediate tissue/cell-specific ERbeta expression. Serial deletion analysis revealed that a 293-bp region encompassing the TATA box and Inr element possesses basal promoter activity.

Base Sequence↗
PubMedDate not supplied

Transcription, processing and nuclear transport of a B1 Alu RNA species complementary to an intron of the murine alpha-fetoprotein gene.

The Alu sequence family comprises the major dispersed repeat sequences of rodent and primate genomes, numbering greater than 300,000 copies in the human haploid genome. The function of these elements is unknown. The sequences can be transcribed by RNA polymerase III and represent a substantial fraction of total heterogeneous nuclear RNA. Alu sequences can be found both in the flanking regions and within the transcription units of several well-characterized genes. Here we show that some members of the mouse B1 Alu sequence family encode a small cytoplasmic RNA. The mouse B1 sequence is congruent to 130 nucleotides long and shows homology with the monomeric units of the dimeric 300-nucleotide primate sequence. By means of microinjection studies in the Xenopus laevis oocyte, we have elucidated a novel pathway leading to the appearance of a processed B1-type Alu RNA species in the cytoplasm. The abundance of this small Alu RNA differs between various mouse tissues, suggesting a role in tissue-specific gene expression.

Animals↗
PubMed2001

Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene.

Chromosome 13q14 deletions constitute the most common genetic abnormality in chronic lymphocytic leukemia (CLL). To identify the putative tumor suppressor gene targeted by 13q14 genomic loss, we completely sequenced and characterized a segment of 790 kb at 13q14 spanning the minimal region of loss in CLL. Transcribed sequences in the region were identified through database homology searches and exon-prediction analysis. Two-hundred kb at the centromeric end of the sequence contain five CpG islands, three previously identified genes LEU5/RFP2, LEU2, and LEU1, seven of seven EST clusters composed of >10 ESTs, and a large number of predicted exons. Homology searches against the mouse EST database have allowed us to identify a highly conserved alternative first exon of the LEU2 gene, giving rise to a novel transcript, ALT1 (GenBank accession no. AF380424), which originates within a G+C region in the vicinity of the D13S272 marker. Two novel 3' exons of LEU2 were also identified and are present in both LEU2 and ALT1 transcripts. However, we have not identified any mutations in leukemia cases, or alterations in expression of mRNAs in the region, that might directly implicate these mRNAs in the pathology of CLL. The centromeric end of the sequence, where all reported genes are located, contains twice the expected amount of ALU repeats, whereas the telomeric end is LINE1 rich and contains four LINE1 elements longer than 4 kb, including two full-length LINE1 sequences. This feature of the sequence may favor the occurrence of chromosomal rearrangements and may confer instability to the region, resulting in deletions that may inactivate an as yet unidentified tumor suppressor.

Alternative Splicing↗
PubMed1992

The 4.4-kilodalton proline-rich polypeptides of the rat ventral prostate are the proteolytic products of a 637-kilodalton protein displaying highly repetitive sequences and encoded in a single exon.

We have determined the complete sequence of the 637-kilodalton precursor for the proline-rich polypeptides (PRPs). This protein is encoded in one large exon of a single copy gene. The acidic precursor of 5761 residues comprises a signal peptide and three large domains displaying a high proline content (11-15%). The sequence of domain A (928 residues) is unique and contains several small clusters of acidic amino acids. Domain B (830 residues) exhibits seven tandem repeats, four of them displaying a strongly diverged sequence. In domain C (3914 residues) 39 units, of which only 8 are degenerate, occur in a tandem repeat. Their sequence of 100 amino acids shows a high structural similarity (76-92%) and contains all the PRP variants which are produced by specific proteolytic processing. The COOH-terminal part (35 residues) is basic. Two variant PRP-precursor alleles occur which slightly differ in the number of repeats in domain C. The high degree of sequence conservation within the repeat regions suggests that the gene presumably evolved by multiple amplification and dispersion of two internal segments. In the 5097-base pair genomic region 5' upstream from the translation start, several control elements for transcription are recognized. A potential binding site for the Sp1 factor (GGGCGG) separated by 47 nucleotides from an initiator motif, most probably elements of the promoter, is detected in the vicinity of the ATG codon. Several putative androgen response elements (TGTYCT) are found in the 5' adjacent region and far upstream two Alu type III repeats and two (CA)n repeats are located. These results provide the basis for a detailed study of the androgen-regulated and tissue-specific expression of the PRP-precursor gene.

Amino Acid Sequence↗
PubMed1994

Structural comparison of human and rat prostate-specific acid phosphatase genes and their promoters: identification of putative androgen response elements.

Structural comparison of human and rat prostate-specific acid phosphatase (hPAP and rPAP) genes indicate that the exon number is different between these species. The hPAP gene contains 10 exons, whereas the rPAP gene was 11 exons. However, exons 2-9 of the genes are identical in size. The 5' regions of the two genes show 71% identity in the most homologous region +1 to +340. The 5' untranslated regions of the human and rat genes are 50 and 49 nucleotides long, respectively. An Alu sequence is present upstream from the proximal promoter of the hPAP gene. Five putative androgen response elements altogether were localized in both the human and rat gene, one of which is conserved in location and sequence between the two genes. Two of these elements in both genes, the conserved one in the proximal promoter region and another one in intron 1, were shown to bind androgen receptor efficiently in vitro.

Acid Phosphatase↗
PubMed1997

Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation.

Promoter region CpG island methylation is associated with tumor suppressor gene silencing in neoplasia. GenBank sequence analyses revealed that a number of CpG islands are juxtaposed to multiple Alu repeats, which have been proposed as "de novo methylation centers." These islands also contain multiple Sp1 elements located upstream and downstream of transcription start, which have been shown to protect CpG islands from methylation. We mapped the methylation patterns of the E-cadherin (E-cad) and von Hippel-Lindau (VHL) tumor suppressor gene CpG island regions in normal and neoplastic cells. Although unmethylated in normal tissue, these islands were embedded between densely methylated flanking regions containing multiple Alu repeats. These methylated flanks were segregated from the unmethylated, island CpG sites by Sp1-rich boundary regions. Finally, in human fibroblasts overexpressing DNA methyltransferase, de novo methylation of the E-cad CpG island initially involved sequences at both ends of the island and the adjacent, flanking regions and progressed with time to encompass the entire CpG island region. Together, these data suggest that boundaries exist at both ends of a CpG island to maintain the unmethylated state in normal tissue and that these boundaries may be progressively overridden, eliciting the de novo methylation associated with tumor suppressor gene silencing in neoplasia.

Base Sequence↗
PubMed1986

Cancer: involvement of replicative origins?

The assumption is made that movable genetic elements related to cancer are replicons and/or replicative origins. Some evidence is provided that certain mobile Alu-origins may represent candidates for precursors of chromosomal insertions. They could incorporate and interact with "fixed" chromosomal origins converting them to "procaryotic" ones. In other words, cancer is considered the result of a short and compact "re-evolution" from eucaryotic to "procaryotic" replication units.

Animals↗
PubMed1996

Human uracil-DNA glycosylase gene: sequence organization, methylation pattern, and mapping to chromosome 12q23-q24.1.

The human uracil-DNA glycosylase gene (UNG) spans approximately 13.5 kb including the promoter. UNG comprises 6 exons and 5 introns and was assigned to chromosome 12q23-q24.1 by radiation hybrid mapping. UNG exhibits typical features of housekeeping genes, including a 5' CpG island of 1.2 kb and a very GC-rich TATA-less promoter containing a number of elements involved in constitutive expression and cell cycle regulation. A smaller CpG island is located just downstream of the gene. Within the 15-kb sequence we identified 16 Alu retroposons, 2 of which contain putative competent RNA polymerase III promoters, 3 copies of medium reiteration frequency repeats, and 1 copy of a mammalian-wide interspersed repetitive element, as well as a 300-bp TA-dinucleotide repeat. In vitro methylation of the UNG promoter strongly reduced promoter activity, but methylation may not be involved in regulation of UNG in vivo since a narrow region of the 5' CpG island comprising the putative transcription factor binding region appears to be invariably methylation-free.

Amino Acid Sequence↗
PubMed1995

Common promoter features in human and mouse liver type phosphofructokinase gene.

The liver-type phosphofructokinase is a key glycolytic enzyme encoded by genes residing on human and mouse chromosomes 21 and 10 respectively. Genomic DNA regions upstream of the initiator ATG spanning 2.6Kb and 3.4Kb of human and mouse liver-type phosphofructokinase gene were sequenced and analyzed. The proximal 0.4Kb region of both genes featured a CpG island containing 60%-73% GC residues. The first 120 nucleotides preceding the ATG are highly conserved displaying 73% of sequence similarity between human and mouse genes. While this region lacks TATA and CAAT boxes it contains four Sp1 binding sites and was capable of promoting a non regulated expression of the reporter gene chloramphenicol acetyl transferase, in transfection assays. Additional conserved elements were found further upstream at the 5'-region of both the human and mouse genes. They consisted of two Alu repeats and several sequence motifs known to serve as transcription factors binding sites.

Animals↗
PubMed1994

A comparison of GC content and the proportion of Alu/KpnI-repetitive sequences in a single dark- and light-band region from a human chromosome.

To obtain direct evidence for a molecular basis of differentiation between regular Giemsa dark (G)- and light (R)-band regions of human chromosomes, two regions of chromosome 11, q14-q22 (G-band) and q23-q25 (R-band), were microdissected. The DNA fragments were amplified by the linker-primer polymerase chain reaction and cloned into pUC19. Microclones from each library were then compared by colony hybridization with repetitive DNA sequences, by Southern blot hybridization of each microclone to total human genomic DNA and mouse-human hybrid cell DNA containing only human chromosome 11, and by sequencing of unique and Alu-repetitive clones. Among the G-band-derived microclones analyzed, 43.0% were single-copy (unique) sequences and 23.2% contained highly repetitive sequence elements; in the R-band-derived library, 54.2% were unique clones and 20.3% had highly repetitive elements. The G-band library was significantly richer in clones positive for KpnI sequences (4.1% in the G-band library vs 2.8% in the R-band library). No significant difference was found in the proportion of Alu repetitive clones present in the two libraries, but Class IV Alu sequence derivatives were more frequently observed in the R-library than in the G-library. Sequence analysis revealed no significant difference in GC content or in the ratio of CpG sequence to GpC dinucleotide between 30 microclones derived from G-bands and 29 microclones derived from R-bands.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Composition↗
PubMed1988

The promoter of Alzheimer's disease amyloid A4 precursor gene.

The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Repetitive DNA in and around translocation breakpoints of the Philadelphia chromosome.

This paper describes systematic sequence studies of repetitive DNA in and around translocation breakpoints on chromosomes 9 and 22, which are involved in the formation of the Philadelphia chromosome in acute leukemias. In addition to Alu repeats described in previous studies, the breakpoint regions appear to contain many other repetitive elements, including a member of a new repetitive family (MER34) reported in this paper. Identification of these repeats broadens current studies on the possible involvement of repetitive DNA in this intensely studied chromosomal translocation.

Base Sequence↗
PubMed2004

Identification and comparative analysis of components from the signal recognition particle in protozoa and fungi.

BACKGROUND: The signal recognition particle (SRP) is a ribonucleoprotein complex responsible for targeting proteins to the ER membrane. The SRP of metazoans is well characterized and composed of an RNA molecule and six polypeptides. The particle is organized into the S and Alu domains. The Alu domain has a translational arrest function and consists of the SRP9 and SRP14 proteins bound to the terminal regions of the SRP RNA. So far, our understanding of the SRP and its evolution in lower eukaryotes such as protozoa and yeasts has been limited. However, genome sequences of such organisms have recently become available, and we have now analyzed this information with respect to genes encoding SRP components. RESULTS: A number of SRP RNA and SRP protein genes were identified by an analysis of genomes of protozoa and fungi. The sequences and secondary structures of the Alu portion of the RNA were found to be highly variable. Furthermore, proteins SRP9/14 appeared to be absent in certain species. Comparative analysis of the SRP RNAs from different Saccharomyces species resulted in models which contain features shared between all SRP RNAs, but also a new secondary structure element in SRP RNA helix 5. Protein SRP21, previously thought to be present only in Saccharomyces, was shown to be a constituent of additional fungal genomes. Furthermore, SRP21 was found to be related to metazoan and plant SRP9, suggesting that the two proteins are functionally related. CONCLUSIONS: Analysis of a number of not previously annotated SRP components show that the SRP Alu domain is subject to a more rapid evolution than the other parts of the molecule. For instance, the RNA portion is highly variable and the protein SRP9 seems to have evolved into the SRP21 protein in fungi. In addition, we identified a secondary structure element in the Saccharomyces RNA that has been inserted close to the Alu region. Together, these results provide important clues as to the structure, function and evolution of SRP.

Amino Acid Sequence↗
PubMed1995

Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation.

The complete human BCR gene (152-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy. Because these two chromosomes are translocated with breakpoints within the BCR and ABL genes in Philadelphia chromosome-positive leukemias, knowledge of these sequences also might provide insight into the validity of various theories of chromosomal rearrangements. Comparison of these genes with their cDNA sequences reveal the positions of 23 BCR exons and putative alternative BCR first and second exons, as well as the common ABL exons 2-11, respectively. Additionally, these regions include the alternative ABL first exons 1b and 1a, a new gene 5' to the first ABL exon, and an open reading frame with homology to an EST within the BCR fourth intron. Further analysis reveals an Alu homology of 38.83 and 39.35% for the BCR and ABL genes, respectively, with other repeat elements present to a lesser extent. Four new Philadelphia chromosome translocation breakpoints from chronic myelogenous leukemia patients also were sequenced, and the positions of these and several other previously sequenced breakpoints now have been mapped precisely, although no consistent breakpoint features immediately were apparent. Comparative analysis of genomic sequences encompassing the murine homologues to the human ABL exons 1b and 1a, as well as regions encompassing the ABL exons 2 and 3, reveals that although there is a high degree of homology in their corresponding exons and promoter regions, these two vertebrate species show a striking lack of homology outside these regions.

Animals↗
PubMed1996

Transcripts from a novel human KRAB zinc finger gene contain spliced Alu and endogenous retroviral segments.

During the course of an investigation into the potential effects of endogenous retroviruses on adjacent gene expression, we isolated two cDNA clones containing a small sequence segment belonging to the human endogenous retrovirus family, HERV-H. Characterization of the clones revealed that they represent transcripts from a novel KRAB zinc finger gene termed ZNF177. The two cDNA clones differ at their 5' termini and in the presence of a 559-bp internal exon. The clone containing this internal exon has six imperfect zinc finger motifs followed by seven perfect copies of the C2H2 type but has a frame shift between the KRAB domain and the downstream zinc finger region. The smaller clone lacks the six imperfect motifs and has an intact ORF. The 5' putative untranslated regions of both cDNAs contain an 86-bp HERV-H env segment and a segment of an Alu repeat, both in the antisense orientation, that have been incorporated by splicing. RT-PCR experiments show evidence of alternative splicing but the majority of transcripts appear to contain the Alu and env segments. Genomic PCR and hybridization experiments suggest that a partial HERV-H element is integrated within the ZNF177 locus, which Southern analysis has shown to be a single-copy gene. Northern and RT-PCR analyses suggest that ZNF177 is transcribed at a low level in a variety of cell types.

Amino Acid Sequence↗
PubMed1996

SINE sequences detect DNA fingerprints in salmonid fishes.

DNA probes homologous to two previously described salmonid short interspersed nuclear elements (SINEs) detected DNA fingerprint patterns in 14 species of salmonid fishes. The probes showed more homology to some species than to others and little homology to three nonsalmonid fishes. The DNA fingerprint patterns derived from the SINE probes are individual-specific and inherited in a Mendelian manner. Probes derived from different regions of the same SINE detect only partially overlapping banding patterns, reflecting a more complex SINE structure than has been previously reported. Like the human Alu sequence, the SINEs found in salmonids could provide useful genetic markers and primer sites for PCR-based techniques. These elements may be more desirable for some applications than traditional DNA fingerprinting probes that detect tandemly repeated arrays.

Animals↗
PubMed1995

Repetitive DNA sequences located in the central region of the human mdr1 (multidrug resistance) gene may account for a gene fusion event during its evolution.

The mdr1 gene, first member of the human multidrug-resistance gene family, is a major gene involved in cellular resistance to several drugs used in anticancer chemotherapy. Its product, the drug-excreting P-glycoprotein, shows a bipartite structure formed by two similar adjacent halves. According to one hypothesis, the fusion of two related ancestral genes during evolution could have resulted in this structure. The DNA sequence analysis of the introns located in the region connecting the two halves of the human mdr1 gene revealed a highly conserved poly(CA).poly (TG) sequence in intron 15 and repeated sequences of the Alu family in introns 14 and 17. These repeated sequences most likely represent "molecular fossils" of ancient DNA elements which were involved in such a recombination event.

Base Sequence↗
PubMed1986

Primate evolution of the alpha-globin gene cluster and its Alu-like repeats.

The arrangement of alpha-globin genes in Old World and New World monkeys and a prosimian, galago, has been determined by restriction mapping. Recombinant DNAs containing galago and Old World monkey alpha-globin genes have been isolated and subjected to a partial sequence determination for comparison to alpha-globin genes in human, chimpanzee and non-primate mammals. The results of this extensive structural analysis are relevant to several topics concerning the evolution of primate alpha-globin genes and Alu family repeats. All orders of higher primates (i.e. Old and New World monkeys, chimpanzee and human) have the same arrangement of alpha-globin genes. In contrast, the arrangement and correction of galago alpha-globin genes differ from those of higher primates, but are similar to those of non-primate mammals. The 5' and 3'-flanking regions of the human alpha 1 gene are orthologous to the corresponding region in galago, identifying the human alpha 2 gene as the more recently duplicated gene. The human psi alpha 1 gene is found to be inactivated after divergence of the human and galago lineages but prior to the divergence of human and monkey. Orthologous Alu family members in human and monkey DNAs indicate that the dispersion of some Alu repeats occurred prior to the divergence of these lineages. However, the Alu-like repeats of prosimian and higher primates result from entirely independent events giving rise to different repeat elements inserted at distinct genomic positions.

Animals↗