Characterization of the gene encoding a folate-binding protein expressed in human placenta. Identification of promoter activity in a G-rich SP1 site linked with the tandemly repeated GGAAG motif for the ets encoded GA-binding protein.

Sadasivan, Easwara; Cedeno, Marisol M.; Rothenberg, Sheldon P.

doi:10.1016/s0021-9258(17)37605-6

Cited by 55 publications

(2 citation statements)

References 38 publications

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“…The organization and sequence of the 3′ terminal exons of the R hFR gene are very similar to those of the β hFR gene (Page et al, 1993;Sadasivan et al, 1994), and the murine FBP1 (Brigle et al, 1992) and FBP2 (Brigle et al, 1994) genes. In each of these genes, the open reading frame is encoded by four 3′ exons that are homologous to putative exons 4 through 7 of the R hFR gene.…”

Section: Discussionmentioning

confidence: 87%

“…The stuttering of transcription initiation, a feature of TATA-less promoters (Lewin, 1990), from the P1 promoter suggests that these TATA boxes are not functional or, alternatively, that the P1 promoter region contains more than one promoter element. In contrast to the P1 and P4 promoters of the R hFR gene, the β hFR gene contains a single promoter (Sadasivan et al, 1994) that contains an array of three GA binding protein motifs immediately upstream from the transcriptional start site. Similar to the R hFR promoters, the β hFR promoter contains an Sp1 binding site and lacks canonical eukaryotic promoter elements.…”

Section: Discussionmentioning

confidence: 99%

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The Divergent 5‘ Termini of the α Human Folate Receptor (hFR) mRNAs Originate from Two Tissue-Specific Promoters and Alternative Splicing: Characterization of the α hFR Gene Structure

et al. 1997

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The human KB cell or alpha folate receptor (alpha hFR) is a membrane glycoprotein of 42 kDa that participates in the internalization of folates and antifolates. Seven independent alpha hFR cDNA isoforms have been reported that contain unique 5' termini but share a common open reading frame (ORF). To investigate the molecular basis of these heterogeneous 5' sequences, we determined the sequence of the alpha hFR gene from two clones isolated from a human lymphocyte lambda DASH genomic library. The gene is composed of seven exons that span 6.8 kb. The ORF is encoded by exons 4 through 7 while the reported 5' termini of the cDNA isoforms (including two novel cDNAs designated KB2 and KB4) are encoded by exons 1 through 4. Using RNase protection assays, we demonstrate that transcripts corresponding to the KB1 and KB4 cDNAs originate from promoters upstream from exon 1 and exon 4, designated P1 and P4, respectively, and that these mRNA isoforms are the most abundant transcripts expressed in KB cells and selected normal tissues (including kidney, lung, and cerebellum). We observed a heterogeneous start site within exon 1 from the P1 promoter while transcripts from the P4 promoter originate from a single site. In addition, we detected tissue specificity for the P1 and P4 promoter utilization. Transcripts originating from the P1 promoter are the most abundant transcripts expressed by human cerebellum and kidney. In contrast, transcripts from the P4 promoter are the most abundant transcripts expressed by human KB cells and lung. Total RNA from KB cells also protects a 66 bp fragment of an exon 3 riboprobe that is consistent with an alternatively spliced transcript. To examine the functional activity of the predicted P1 and P4 promoters, alpha hFR promoter-CAT chimeric plasmids were constructed using sequences flanking exon 1 and exon 4. We observed a 7.5- and 10-fold increase in CAT activity in HeLa cells transiently transfected with the P1 and P4 promoter constructs, respectively. These data demonstrate that a single gene encodes the divergent 5' termini of the alpha hFR cDNAs and that the alpha hFR transcripts are transcribed from two promoters that are activated in a tissue-specific manner.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

The Divergent 5‘ Termini of the α Human Folate Receptor (hFR) mRNAs Originate from Two Tissue-Specific Promoters and Alternative Splicing: Characterization of the α hFR Gene Structure

et al. 1997

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Folate pathway gene alterations in patients with neural tube defects

et al. 2000

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Periconceptional folate supplementation reduces the recurrence and occurrence risk of neural tube defects (NTD) by as much as 70%, yet the protective mechanism remains unknown. Inborn errors of folate and homocysteine metabolism may be involved in the aetiology of NTDs. Previous studies have demonstrated that both homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, and combined heterozygosity for the C677T and for another mutation in the same gene, the A1298C polymorphism, represent genetic risk factors for NTDs. In an attempt to identify additional folate related genes that contribute to NTD pathogenesis, we performed molecular genetic analysis of folate receptors (FRs). We identified 4 unrelated patients out of 50 with de novo insertions of pseudogene (PS)-specific mutations in exon 7 and 3'UTR of the FRalpha gene, arising by microconversion events. All of the substitutions affect the carboxy-terminal amino acid membrane tail, or the GPI anchor region of the nascent protein. Furthermore, among 150 control individuals, we also identified one infant with a gene conversion event within the FRalpha coding region. This study, though preliminary, provides the first genetic association between molecular variations of the FRalpha gene and NTDs and suggests that this gene can act as a risk factor for human NTD.

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Selective expression of folate receptor ? and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis

Nakashima-Matsushita

Homma

et al. 1999

Arthritis & Rheumatism

218

158

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Characterization of the gene encoding a folate-binding protein expressed in human placenta. Identification of promoter activity in a G-rich SP1 site linked with the tandemly repeated GGAAG motif for the ets encoded GA-binding protein.

Cited by 55 publications

References 38 publications

The Divergent 5‘ Termini of the α Human Folate Receptor (hFR) mRNAs Originate from Two Tissue-Specific Promoters and Alternative Splicing: Characterization of the α hFR Gene Structure

The Divergent 5‘ Termini of the α Human Folate Receptor (hFR) mRNAs Originate from Two Tissue-Specific Promoters and Alternative Splicing: Characterization of the α hFR Gene Structure

Folate pathway gene alterations in patients with neural tube defects

Selective expression of folate receptor ? and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis

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