Regulation of Prion Protein Expression by Noncoding Regions of the Prnp Gene

Haigh, Cathryn L.; Wright, Josephine; Brown, David R.

doi:10.1016/j.jmb.2007.02.086

Cited by 17 publications

(23 citation statements)

References 41 publications

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“…The specific functions of exons I and II in the 5'UTR are also unknown. Differential splicing of exon II has not yet been observed, however cattle have a particular alternative splicing at exon I which creates either a 5'UTR with an additional 115 bases (exon Ib) [44] or a 5'UTR without exon I [40]. Again, their role is unidentified but one could speculate that the different mRNA are recognised in different regulatory pathways and in that way protein expression could be regulated at various cellular levels.…”

Section: Prp Genomics In Sheep Goats Cattle and Deermentioning

confidence: 99%

PrPgenetics in ruminant transmissible spongiform encephalopathies

2008

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-Scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) are prion diseases in ruminants with considerable impact on animal health and welfare. They can also pose a risk to human health and control is therefore an important issue. Prion protein (PrP) genetics may be used to control and eventually eradicate animal prion diseases. The PrP gene in sheep and other representatives of the order Artiodactyles has many polymorphisms of which several are crucial determinants of susceptibility to prion diseases, also known as transmissible spongiform encephalopathies (TSE). This review will present the current understanding of PrP genetics in ruminants highlighting similarity and difference between the species in the context of TSE.

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Section: Prp Genomics In Sheep Goats Cattle and Deermentioning

confidence: 99%

PrPgenetics in ruminant transmissible spongiform encephalopathies

2008

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“…Regulatory sequences have been mapped to a region ϳ90 base pairs upstream of the rat and bovine genes that appears to depend for activity on elements in intron 1 (9,10) and exon 1 (11). This upstream region is rich in consensus binding sites for SP1 that are highly conserved between species (12).…”

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confidence: 99%

Identification of Adjacent Binding Sites for the YY1 and E4BP4 Transcription Factors in the Ovine PrP (Prion) Gene Promoter

Burgess

Shen

Ferguson

et al. 2009

Journal of Biological Chemistry

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The PrP gene encodes the cellular isoform of the prion protein (PrP c ) which has been shown to be crucial to the development of transmissible spongiform encephalopathies (TSEs). PrP knock-out mice, which do not express endogenous PrP c , exhibit resistance to TSE disease. The regulation of PrP gene expression represents, therefore, a crucial factor in the development of TSEs. Two sequence motifs in the PrP promoter (positions ؊287 to ؊263 from transcriptional start) were previously reported as being highly conserved, and it was suggested that they represent binding sites for as yet unidentified transcription factors. To test this hypothesis, binding of nuclear proteins was analyzed by electrophoretic mobility shift assays using ovine or murine cells and tissues with radiolabeled DNA probes containing the conserved motif sequences. Specific binding was observed to both motifs, and polymorphic variants of these motifs exhibited differential binding. Two proteins bound to these motifs were identified as the Yin Yang 1 (YY1) (motif 1) and E4BP4 (motif 2) transcription factors. Functional promoter analysis of four different promoter variants revealed that motif 1 (YY1) was associated with inhibitory activity in the context of the PrP promoter, whereas motif 2 (E4BP4) was linked to a slight enhancing activity. This represents the first demonstration of binding of nuclear factors to two highly conserved DNA sequence motifs within mammalian PrP promoters. The action of these factors on the PrP promoter is haplotype-specific, leading us to propose that the prion protein expression pattern and, with it, the distribution of TSE infectivity may be associated with PrP promoter genotype.The ovine PrP gene (PRNP in human, prn-p in mice) encodes the prion protein (PrP C ), 4 which is a crucial component of prion diseases, also known as transmissible spongiform encephalopathies (TSEs). This group of diseases include scrapie in sheep, bovine spongiform encephalopathy in cattle, and Creutzfeldt-Jakob disease in humans (1). The hallmark of TSEs is the aggregation of a pathological isoform PrP Sc of the cellular PrP C protein (2). PrP C is highly expressed in neurons of the brain and also found in many other tissues, especially the lymphoreticular system. Prn-p knock-out mice, which do not express endogenous PrP C , exhibit resistance to TSE disease (3). Transgenic mice with differing copy numbers of the prn-p gene show a clear relationship between expression level and disease progression, characterized by changes in incubation periods (4). It is assumed that the TSE agent can only replicate in cells expressing PrP C , so that up-or down-regulation of the PrP promoter can have consequences for the distribution of the agent in the host and, therefore, the risk of transmission; for example, from consumption of specific animal parts or blood transfusion in humans (5).Beside its key role in disease, the physiological function of PrP C remains elusive with signal transduction, synaptic transmission, neuroprotection, and immunoregulation...

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“…In cattle, the PRNP gene is on chromosome 13 in the position Q17 BTA, being a single copy gene with about 2,5 kilobases (kb) containing three exons, the exon encoding the last ORF (open reading frame). The first intron is described for supporting the action of the promoter region and exon 1 contrast can be associated with suppressive activity than the promoter region (Haigh et al 2007). …”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the Prion Protein Gene of cattle breeds from Brazil

et al. 2016

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One of the alterations that occur in the PRNP gene in bovines is the insertion/deletion (indel) of base sequences in specific regions, such as indels of 12-base pairs (bp) in intron 1 and of 23- bp in the promoter region. The deletion allele of 23 bp is associated with susceptibility to bovine spongiform encephalopathy (BSE) as well as the presence of the deletion allele of 12 bp. In the present study, the variability of nucleotides in the promoter region and intron 1 of the PRNP gene was genotyped for the Angus, Canchim, Nellore and Simmental bovine breeds to identify the genotype profiles of resistance and/or susceptibility to BSE in each animal. Genomic DNA was extracted for amplification of the target regions of the PRNP gene using polymerase chain reaction (PCR) and specific primers. The PCR products were submitted to electrophoresis in agarose gel 3% and sequencing for genotyping. With the exception of the Angus breed, most breeds exhibited a higher frequency of deletion alleles for 12 bp and 23 bp in comparison to their respective insertion alleles for both regions. These results represent an important contribution to understanding the formation process of the Brazilian herd in relation to bovine PRNP gene polymorphisms.

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Regulation of Prion Protein Expression by Noncoding Regions of the Prnp Gene

Cited by 17 publications

References 41 publications

PrPgenetics in ruminant transmissible spongiform encephalopathies

PrPgenetics in ruminant transmissible spongiform encephalopathies

Identification of Adjacent Binding Sites for the YY1 and E4BP4 Transcription Factors in the Ovine PrP (Prion) Gene Promoter

Polymorphisms in the Prion Protein Gene of cattle breeds from Brazil

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