Mechanisms for selecting 5′ splice sites in mammalian pre-mRNA splicing

Horowitz, David S.; Krainer, Adrian R.

doi:10.1016/0168-9525(94)90233-x

Cited by 235 publications

(148 citation statements)

References 43 publications

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“…Exon sizes ranged from 74 bp to 1.4 kb and intron sizes from 0.13 to 2.4 kb ( Table I). All exon-intron borders were consistent with the reported consensus sequence for 5Ј-splice donor and 3Ј-splice acceptor junctions in mammalian genes (24,25). While exon 1 contains noncoding sequences, exon 2 is composed of a noncoding stretch of nucleotides, the initiation codon, and most of the leader peptide coding region.…”

Section: Resultssupporting

confidence: 61%

Expression of the 90K Immunostimulator Gene Is Controlled by a Promoter with Unique Features

Brakebusch

Jallal

Fusco

et al. 1997

Journal of Biological Chemistry

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90K is a secreted glycoprotein with tumor suppressive functions, which is up-regulated in various types of cancer and in AIDS. In order to understand the regulation of its expression, the mouse 90K gene was isolated and analyzed. The gene spans about 8.8-kilobase pairs and consists of 6 exons and was localized on chromosome 11, region E. RNase protection identified one major transcription start site (؉1) and three minor ones (؊3, ؉32, ؉34). The mouse 90K gene was found to have a TATAless promoter of unusual structure. The 2.3-kilobase pair 5 -flanking region exhibited strong promoter activity in NIH 3T3 cells; however, it contained neither a TATA-box nor a SP1 site and was not GC-rich. No known initiator motif was found around the transcription start site. 5 -and 3 -deletions defined a minimal promoter of 51 base pairs (؊66 3 ؊16), not including the start site, essential and sufficient for promoter activity. This minimal promoter showed increased activity after stimulation with interferon-␥ or poly(I⅐C), a substance mimicking viral infection. Essential for both inductions was the integrity of an interferon regulatory factor element within this sequence, a potential binding site for the anti-oncogenic transcription factor interferon regulatory factor-1.

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Section: Resultssupporting

confidence: 61%

Expression of the 90K Immunostimulator Gene Is Controlled by a Promoter with Unique Features

Brakebusch

Jallal

Fusco

et al. 1997

Journal of Biological Chemistry

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“…Brain-specific variants in splicing patterns could be achieved by differing levels or modifications of ubiquitously expressed splicing factors. For example, antagonism between the heterogeneons nuclear ribonudeoprotein (hnRNP) A1 and ASF͞SF2 proteins determines the selection of 5Ј splice site (14), and varying ratios of these proteins have been shown to affect neuron-specific splicing of clathrin exon EN (15). Moreover, posttranslational modifications such as phosphorylation influence the activity of general splicing factors including ASF͞SF2 (16,17).…”

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confidence: 99%

A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of Nova to regulate neuron-specific alternative splicing

Polydorides

Okano

Yang

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

222

189

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The Nova paraneoplastic antigens are neuron-specific RNA binding proteins that participate in the control of alternative splicing. We have used the yeast two-hybrid system to isolate Nova interacting proteins and identify an RNA binding protein that is closely related to the polypyrimidine tract-binding protein (PTB). The expression of this protein, brPTB, is enriched in the brain, where it is expressed in glia and neurons. brPTB interacts with Nova proteins in cell lines and colocalizes with Nova within neuronal nuclei. We previously found that Nova binds to a pyrimidine-rich RNA element present upstream of an alternatively spliced exon, E3A, in glycine receptor ␣2 (GlyR␣2) pre-mRNA, and this binding is implicated in Novadependent regulation of splicing. Cotransfection assays with a GlyR␣2 minigene demonstrate that brPTB antagonizes the action of Nova to increase utilization of GlyR␣2 E3A. brPTB binds to a 90-nt GlyR␣2 RNA adjacent to the Nova binding site, but with an affinity that is more than 10-fold lower than Nova. When a putative binding site for brPTB on the GlyR␣2 RNA is mutated, binding is abolished and the inhibitory effect on Nova-dependent exon selection disappears. These results suggest that brPTB is a tissuerestricted RNA binding protein that interacts with and inhibits the ability of Nova to activate exon selection in neurons.N eurons make extensive use of alternative splicing to regulate functional differences in proteins. A wide variety of neurotransmitter receptor activities are regulated by alternative splicing, including NR1 N-methyl-D-aspartate (NMDA) receptor subcellular localization (1) and interaction with neurofilaments (2), the physiology of the glutamate (3) and NMDA (4) receptors, and the ability of agrin to induce clustering of acetylcholine receptors (5). Moreover, several neurologic diseases such as spinal muscular atrophy, amyotrophic lateral sclerosis, and paraneoplastic opsoclonus-myoclonus ataxia (POMA) have been associated with defects in proteins involved in generating the splicing machinery or in the accurate splicing of target .Since the discovery of tissue-specific splicing of the calcitonin͞ calcitonin gene-related peptide (CGRP) transcript in neurons, there has been an extensive search for cis-acting RNA elements and trans-acting RNA binding proteins that mediate neuronspecific splicing. The first example of cis-acting regulatory elements in neuronal pre-mRNAs identified was in calcitonin͞ CGRP pre-mRNA (9), and a number of specific sequences have been identified that are responsible for calcitonin͞CGRP tissuespecific processing (10, 11). Subsequent work identified regulatory sequences near other neuron-specific exons such as the N1 exon of src (12) and a 24-nt exon of the ␥-aminobutyric acid type A receptor ␥2 subunit (13).The identification of trans-acting factors that regulate neuronal splicing has been a greater challenge. Two general mechanisms might account for the way such factors could mediate regulation of neuronal splicing. Brain-specific variants in splicing ...

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“…The first nucleotide of a donor splice sequence is generally 100% conserved (Horowitz and Krainer, 1994), hence the transition identified at this site is very likely to affect RNA splicing. One missense mutation was identified in 2 families (CCD and CRP), which results in an Asn to Ser change at amino acid 216 in the 7 th LRR.…”

Section: Resultsmentioning

confidence: 99%

Mutations in theCACNA1F andNYX genes in British CSNBX families

Zito¹,

Allen

Patel³

et al. 2003

Hum. Mutat.

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Communicated by Jean-Louis MandelX-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX.

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Mechanisms for selecting 5′ splice sites in mammalian pre-mRNA splicing

Cited by 235 publications

References 43 publications

Expression of the 90K Immunostimulator Gene Is Controlled by a Promoter with Unique Features

Expression of the 90K Immunostimulator Gene Is Controlled by a Promoter with Unique Features

A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of Nova to regulate neuron-specific alternative splicing

Mutations in theCACNA1F andNYX genes in British CSNBX families

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