Identification and Tissue Distribution of Human Cystathionine β-Synthase mRNA Isoforms

Bao, Liming; Vlček, Čestmı́r; Pačes, Václav; Kraus, Jan P.

doi:10.1006/abbi.1997.0486

Cited by 101 publications

(78 citation statements)

References 32 publications

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“…Our previous studies suggested an important role for variations in CBS gene expression as a determinant of the enhanced Ara-C sensitivities of DS myeloblasts and CBS-transfected leukemia cell line models (9, 12). A wide range of CBS gene expression has been described among assorted human tissues (6). Furthermore, multiple transcripts have been reported for CBS (6).…”

Section: Phosphorylation Of Sp1 Modulates Its Binding To the Cbs ϫ1bmentioning

confidence: 99%

“…A wide range of CBS gene expression has been described among assorted human tissues (6). Furthermore, multiple transcripts have been reported for CBS (6). Five distinct 5Ј-noncoding exons have been described, the most frequent termed Ϫ1a and Ϫ1b, each encoded by its own unique GC-rich TATA-less promoter (5).…”

Section: Phosphorylation Of Sp1 Modulates Its Binding To the Cbs ϫ1bmentioning

confidence: 99%

“…There are at least two GC-rich TATA-less promoters upstream of exons Ϫ1a and Ϫ1b, containing numerous putative transcription elements (Sp1 (specificity protein 1), AP1, AP2, etc.) (5,6). In our recent study of the CBS Ϫ1b minimal promoter (mapping between positions Ϫ3792 and Ϫ3667), we demonstrated important transactivating roles for Sp1, Sp3, NF-Y, and USF-1 (7).…”

mentioning

confidence: 92%

“…The human CBS gene encodes multiple mRNAs differing in their 5Ј-untranslated regions, resulting from the use of five alternative noncoding exons (designated Ϫ1a to Ϫ1e) and a constant exon 0. Transcripts containing exons Ϫ1a and Ϫ1b appear to be the most abundant and are found in an assortment of adult and fetal tissues (6). By contrast, use of exons Ϫ1c, Ϫ1d, and Ϫ1e appears to be rare.…”

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confidence: 99%

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Transcriptional Regulation of Cell-specific Expression of the Human Cystathionine β-Synthase Gene by Differential Binding of Sp1/Sp3 to the −1b Promoter

Matherly¹,

Taub²

2001

Journal of Biological Chemistry

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Cystathionine ␤-synthase (CBS) catalyzes the condensation of serine and homocysteine to form cystathionine, an intermediate step in the synthesis of cysteine. We previously characterized the CBS ؊1b minimal promoter (؊3792 to ؊3667) and found that Sp1/Sp3, nuclear factor Y, and USF-1 were involved in the regulation of basal promoter activity (Ge, Cystathionine ␤-synthase (CBS 1 ; EC 4.2.1.22), a pyridoxal 5Ј-phosphate-dependent enzyme involved in the transsulfuration pathway, catalyzes the condensation of L-serine and Lhomocysteine to form cystathionine, an intermediate step in the synthesis of cysteine. The human CBS gene product is a 63,000-Da polypeptide. The tetrameric protein is catalytically dependent on both heme and pyridoxal phosphate and is allosterically regulated by S-adenosylmethionine (1-4). The human CBS gene spans over 30 kilobases and consists of 23 exons ranging in size from 42 to 209 base pairs (5). The CBS polypeptide is encoded by exons 1-14 and 16. The human CBS gene encodes multiple mRNAs differing in their 5Ј-untranslated regions, resulting from the use of five alternative noncoding exons (designated Ϫ1a to Ϫ1e) and a constant exon 0. Transcripts containing exons Ϫ1a and Ϫ1b appear to be the most abundant and are found in an assortment of adult and fetal tissues (6). By contrast, use of exons Ϫ1c, Ϫ1d, and Ϫ1e appears to be rare. There are at least two GC-rich TATA-less promoters upstream of exons Ϫ1a and Ϫ1b, containing numerous putative transcription elements (Sp1 (specificity protein 1), AP1, AP2, etc.) (5, 6). In our recent study of the CBS Ϫ1b minimal promoter (mapping between positions Ϫ3792 and Ϫ3667), we demonstrated important transactivating roles for Sp1, Sp3, NF-Y, and USF-1 (7).YThe CBS gene has been localized to human chromosome 21 (e.g. 21q22.3), and its overexpression has been suggested to be linked to certain of the phenotypic features of Down syndrome (DS). Elevated CBS expression in DS results in low plasma homocysteine compared with non-DS individuals and has been suggested to contribute to decreased atherosclerosis in DS patients (8). In our own studies of CBS and DS, we also found striking increases (ϳ12-fold) in CBS transcripts in myeloblasts from DS children with AML compared with non-DS myeloblasts (9). Interestingly, this elevated CBS expression was associated with increased in vitro sensitivities to cytosine arabinoside (Ara-C) and generation of Ara-C triphosphate, likely due to downstream effects of CBS on endogenous folate and nucleotide pools (9 -12). This may explain, in part, the remarkably high event-free survival rates (70 -100%) and low relapse rates (Ͻ15%) of DS children with AML compared with non-DS children treated with Ara-C-based chemotherapy protocols. Increased CBS transcripts in DS over non-DS myeloblasts in-*

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Section: Phosphorylation Of Sp1 Modulates Its Binding To the Cbs ϫ1bmentioning

confidence: 99%

Section: Phosphorylation Of Sp1 Modulates Its Binding To the Cbs ϫ1bmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

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Transcriptional Regulation of Cell-specific Expression of the Human Cystathionine β-Synthase Gene by Differential Binding of Sp1/Sp3 to the −1b Promoter

Matherly¹,

Taub²

2001

Journal of Biological Chemistry

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“…Transcripts containing exons -1a or -1b appear to be the most abundant and are found in an assortment of adult and fetal tissues. However, usage of exons -1c, -1d, and -1e appears rare [14,15]. In this study, the detection region covers the CBS 5′ regulatory region upstream of the first exon-1a (−6 251 to −3 623, numbered from ATG), together with the entire 3′ UTR fragment ( Figure 1A).…”

Section: The Cbs 5′ Regulatory Variant −4673c>g Significantly Reducesmentioning

confidence: 73%

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

et al. 2012

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Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant −4673C>G (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.96, P = 0.011) and 40% (OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 × 10 −7 ) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS −4673C>G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.

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Cystathionine ?-synthase mutations in homocystinuria

et al. 1999

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Identification and Tissue Distribution of Human Cystathionine β-Synthase mRNA Isoforms

Cited by 101 publications

References 32 publications

Transcriptional Regulation of Cell-specific Expression of the Human Cystathionine β-Synthase Gene by Differential Binding of Sp1/Sp3 to the −1b Promoter

Transcriptional Regulation of Cell-specific Expression of the Human Cystathionine β-Synthase Gene by Differential Binding of Sp1/Sp3 to the −1b Promoter

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

Cystathionine ?-synthase mutations in homocystinuria

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