Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand specific mechanisms involved in the regulation of insulin-like growth factor binding protein-1 (IGFBP-1), an important modulator of IGF bioactivity, we cloned the rat IGFBP-1 gene and sequenced a 1.5 kb Sph1-Sph1 fragment containing 1110 bases upstream from the translation start site. Computer analysis reveals the presence of ATA, CACCC, and CCAAT elements, and putative homeodomain, AP-1, insulin and glucocorticoid response elements in the 5' promoter. Primer extension and ribonuclease protection studies reveal a single cap site in RNA from rat hepatoma cells and both control and diabetic rat liver.
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PMID:Cloning of the rat insulin-like growth factor binding protein-1 gene and analysis of its 5' promoter region. 137 73

The expression of the beta isoenzyme for protein kinase C is regulated developmentally and in response to inducers of cell differentiation (such as phorbol esters and 1 alpha,25-dihydroxyvitamin D3). The 5' segment of the gene for protein kinase C beta was cloned from a human leukocyte genomic library in EMBL3 bacteriophage. This segment of the gene (greater than 54 kilobases in length) encompassed the coding sequence for the amino-terminal regulatory domain of the enzyme, the 5'-untranslated region, and the 5'-flanking region. Initiation of transcription was identified by S1 nuclease analysis and confirmed by RNase protection analysis at 197 base pairs 5' of the initiator ATG. Sequence analysis of the 5'-flanking region revealed it to be extremely G+C-rich (> 80%) with many features of a CpG island. Comparison of sequence with known cis-regulatory motifs disclosed a number of potential regulatory elements including an octamer binding motif at -76, Sp1-binding sites at -94 and -63, E boxes at -110, -26, and +18, an AP-1 site at -442, and an AP-2 site at -330. To demonstrate promoter activity, a 630-base pair fragment extending from -587 to +43 was subcloned in front of a promoterless luciferase gene. This fragment was able to drive the expression of luciferase in transient transfections of human hematopoietic cells. Deletion analysis demonstrated that a fragment -111 to +43 was necessary and sufficient for promoter activity; this fragment did not contain TATA or CAAT motifs. The promoter was stimulated 8-20-fold by phorbol esters accounting for the previously observed transcriptional activation of protein kinase C beta. This phorbol ester responsiveness was conferred by the basal promoter (-111 to +43) and was independent of the AP-1 site. These results define a novel mechanism of protein kinase C autoregulation at a transcriptional level.
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PMID:Cloning and characterization of the major promoter of the human protein kinase C beta gene. Regulation by phorbol esters. 140 Mar 96

We have cloned and characterized 5'-flanking sequences of the DNA methyltransferase (MeTase) gene. DNA MeTase gene transcription is initiated at a few discrete sites: 343 and 90 base pairs upstream of the translation initiation site as determined by RNase protection and primer extension assays. The promoter sequences that regulate expression of DNA MeTase, as defined by chloramphenicol acetyltransferase assays, reside between position -171 and the transcription start site. The promoter of DNA MeTase does not contain TATAA or CAAT boxes and is unusual because it does not contain the CG-rich elements characteristic of TATAA-less housekeeping genes. The 5'-flanking region of DNA MeTase contains AP-1, AP-2 and glucocorticoid response elements, suggesting possible regulation by cellular signal transduction pathways. The base composition of the DNA MeTase promoter is markedly different from that of other housekeeping genes. Whereas most housekeeping genes are characterized by CG-rich areas in their 5'-flanking regions, the TG dinucleotide is over-represented in DNA MeTase 5'-flanking sequences, including a perfect tandem repeat of T/G between positions -685 and -650. DNA methylation patterns play an important role in the developmental regulation of gene expression in vertebrates. DNA MeTase activity is probably regulated to maintain this pattern of methylation. We suggest that the DNA MeTase promoter represents a new class of housekeeping gene promoters that was designed to ensure high fidelity regulation of gene expression.
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PMID:The mouse DNA methyltransferase 5'-region. A unique housekeeping gene promoter. 155 80

Recent studies have revealed that the expression of P-glycoprotein/multidrug resistance genes is crucial for the development of resistance to a number of lipophilic cancer chemotherapeutic agents. To better understand the regulatory mechanisms of pgp gene expression, we isolated and characterized a DNA fragment containing the 5' portion of a Chinese hamster pgp gene. DNA sequence analysis revealed that this gene is pgp1, the hamster homologue of murine mdr3/mdr1a. This gene is expressed at a higher level in intestines than in kidney and liver, consistent with the expression pattern for the murine mdr3/mdr1a gene. The major transcription start site, determined by the S1 nuclease protection, RNase protection, and primer extension methods, lies 67 nucleotides upstream of the murine and human downstream transcription start site. A chimera containing 101 base pairs upstream from this start site and the chloramphenicol acetyltransferase (CAT) gene was able to direct CAT expression in transient transfection experiments. The AP-1 site, located at -48 base pairs, was crucial for the full pgp1 promoter activity, as demonstrated by site-directed mutagenesis of this site, enhancement of the CAT expression by cotransfection with the expression vectors encoding c-Jun/c-Fos genes, but sequestration with those containing retinoic acid receptor genes. The sequestration effect could be partially abolished when c-Jun/c-Fos genes were also included in cotransfection. An AP-1 or AP-1-like site is also present at the same location in both human and mouse mdr homologues. The involvement of AP-1 in the expression of mammalian pgp1-class genes is discussed.
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PMID:Analysis of the Chinese hamster P-glycoprotein/multidrug resistance gene pgp1 reveals that the AP-1 site is essential for full promoter activity. 166 Nov 34

To investigate the transcriptional regulation of human glutathione S-transferase pi (GST pi) gene expression, we fused the GST pi promoter, including 2203 bp of the 5'-flanking region, exon 1, and most of intron 1, to the chloramphenicol acetyltransferase (CAT)-encoding reporter gene (cat). When transfected into human cell lines, this GST-cat construct (-2203 GST-cat) supported high level cat gene expression. RNase-protection and primer-extension experiments showed that the normal GST pi transcriptional start point (tsp) is utilized, and furthermore, that intron 1 is faithfully removed by splicing from the majority of primary GST-cat transcripts. A series of constructs containing deletions in the GST pi sequences of the -2203 GST-cat vector were prepared to define potential regulatory regions. Transfection of these deletion plasmids revealed that a region between GST pi sequences -80 and -8 is absolutely required for cat expression. Furthermore, transfection of the -2203 GST-cat and deletion vectors into two human cell lines--one line which does not produce endogenous GST pi (HeLa cells) and one which produces high levels of endogenous GST pi (HS 578T cells)--failed to identify sequences that differentially influence the level of transcription in either cell line. A putative TRE (TPA responsive element or AP-1 recognition sequence) strategically situated upstream from the GST pi tsp (-69 to -63) was examined by TPA treatment of HeLa cells transfected with GST-cat DNA. Additionally, the potential interaction of fos and jun proteins with the GST pi promoter was examined by co-transfection of GST-cat constructs with jun and fos expression vectors in F9 cells. Both of these treatments, which are known to enhance transcription of several genes containing 5'-flanking TREs, failed to induce GST-cat expression. These data suggest that the putative TRE sequence in GST pi is unresponsive both to phorbol esters and to these particular transcriptional activating factors of the fos and jun family.
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PMID:Regulation of human glutathione S-transferase pi gene transcription: influence of 5'-flanking sequences and trans-activating factors which recognize AP-1-binding sites. 211 5

The JUN protooncogene encodes a protein that is functionally and biochemically identical to the transcription factor AP-1 (activator protein 1). To understand the structure and regulation of this important gene, a genomic clone of human JUN was isolated and its primary structure and transcription pattern were determined. Most surprisingly, the sequence of the genomic clone was found to be contiguous with the sequence of the JUN cDNA, suggesting that it lacks introns. RNase protection experiments confirm that JUN is an intronless gene that yields several transcripts due to 5' and 3' heterogeneities. Transfection experiments show that the cloned gene is functional, as it encodes a trans-acting factor that stimulates transcription of AP-1-dependent reporter gene. In situ hybridization was used to map JUN to chromosomal region 1p31-32. Interestingly, this region is frequently deleted in neuroblastomas, suggesting that elimination of AP-1 may play an important role in the pathogenesis of this disease.
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PMID:Structure and chromosomal localization of the functional intronless human JUN protooncogene. 319 15

The human gene encoding aquaporin-CD (AQP-CD) was isolated, and its structural organization was characterized. The gene appeared to exist as a single copy in the human genome and comprises four exons distributing over 5 kilobases. The size range of exons is 81-761 base pairs, and that for introns is approximately 3000 to approximately 250 base pairs. The exon-intron boundaries of human AQP-CD gene are identified at identical positions in other related genes, the human AQP-CHIP gene and the human major intrinsic protein gene. The major transcription initiation sites were identified to positions 93 and 94 base pairs upstream of the ATG initiation codon by primer extension and ribonuclease protection assay. The 5'-flanking region of the hAQP-CD gene was characterized by a TATA box, two GATA consensus sequences, an AP-1 site, an AP-2 site, three E-boxes, and a cyclic AMP-responsive element. These structural features will lead to a better understanding of the mechanisms of tissue-specific expression and the regulation by dehydration in AQP-CD gene and will also be of help in search for possible genetic disorders in human AQP-CD gene.
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PMID:Isolation of human aquaporin-CD gene. 752 28

Decay accelerating factor (DAF) is a complement regulatory protein that protects host tissue from complement-mediated damage by preventing the assembly and/or promoting the dissociation of C3 and C5 convertases. To identify and analyze the DNA sequence elements responsible for controlling DAF expression, the 5'-flanking region of the human DAF gene was cloned. Sequencing of 880 nucleotides upstream from the ATG codon revealed the absence of classic TATA or CAAT boxes. RNase protection and primer extension assays revealed a series of transcription start sites in a 10 nucleotide region located 86 nucleotides upstream from the ATG (the first of these start sites is numbered +1). Using HeLa, K562, EBV, and Molt 4 cells, DAF mRNA and protein were analyzed by Northern and Western blot. The DAF mRNA and protein levels roughly correlated, suggesting transcriptional control of gene expression. K562 and HeLa expressed high levels, EBV expressed intermediate levels, and Molt 4 expressed essentially no detectible DAF mRNA or protein. Regions of DAF 5'-flanking DNA were subcloned into plasmids containing the chloramphenicol acetyltransferase reporter gene and tested in transient transfection assays. The construct extending from -206 to +84 (-206/+84) had transcriptional activity in the DAF-positive HeLa, K562, and EBV lines, but no activity in the DAF-negative Molt 4 line. In the three DAF-positive lines, major enhancer activity was demonstrated between -206 and -77, and between -77 and -54 (containing cAMP responsive element and AP-1 binding site). Additional deletion of the region between -54 and -34 (containing an Sp1 binding site) reduces chloramphenicol acetyltransferase activity further but the low numerical values preclude statistical significance. The identification of transcription start sites and enhancer regions in the DAF gene will be important for studies of the mechanisms whereby cytokines and other factors may modulate DAF expression.
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PMID:Identification of 5'-flanking regions affecting the expression of the human decay accelerating factor gene and their role in tissue-specific expression. 767 27

APEX nuclease (Apex gene product) is a mammalian multifunctional DNA repair enzyme possibly involved in the repair of apurinic/apyrimidinic (AP) sites and single-strand DNA breaks with 3' termini blocked by nucleotide fragments and also in transcriptional regulation via redox activation of the AP-1 transcription factors. We cloned a 15-kb DNA fragment containing the Apex gene from a mouse leukocyte genomic library and determined a 4-kb stretch of its nucleotide sequence, including the complete sequence of the mouse Apex gene. The gene consists of 5 exons and 4 introns spanning 2.21 kb, and the boundaries between exons and introns follow the GT/AG rule. Two major and one minor transcription initiation sites were assigned to positions +1 and +24 and position +14, respectively, by a combination of ribonuclease protection, primer extension, and 5' RACE analyses. Position +1 is located 312 nucleotides upstream from the ATG initiation codon. The translation initiation and termination sites are located in exon II and exon V, respectively. The sequenced 5' flanking region (1.32 kb) lacks a typical TATA box, but contains a CAAT box and putative binding sites for several transcription factors, such as ATF, NF-IL6, Sp1, and AP2. The 0.8-kb region from position -410 (5' flanking region) to position +386 (intron II) contains a CpG island. The Apex gene locus was mapped to mouse chromosome 14C2-D1 using in situ hybridization.
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PMID:Cloning, sequence analysis, and chromosomal assignment of the mouse Apex gene. 778 87

Using deletion analysis and site-specific mutagenesis to map the 5' regulatory region of the DNA methyltransferase (MeTase) gene, we show that a 106-bp sequence (at -1744 to -1650) bearing three AP-1 sites is responsible for induction of DNA MeTase promoter activity. Using transient cotransfection chloramphenicol acetyl-transferase assays in P19 cells, we show that the DNA MeTase promoter is induced by c-Jun or Ha-Ras but not by a dominant negative mutant of Jun, delta 9. The activation of the DNA MeTase promoter by Jun is inhibited in a ligand dependent manner by the glucocorticoid receptor. Stable expression of Ha-Ras in P19 cells results in induction of transcription of the DNA MeTase mRNA as determined by nuclear run-on assays and the steady state levels of DNA MeTase mRNA as determined by an RNase protection assay. These experiments establish a potential molecular link between nodal cellular signaling pathways and the control of expression of the DNA MeTase gene. This provides us with a possible molecular explanation for the hyperactivation of DNA MeTase in many cancer cells and suggests that DNA MeTase is one possible downstream effector of Ras.
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PMID:Regulation of the DNA methyltransferase by the Ras-AP-1 signaling pathway. 782 90


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