Regulation of the human protein S gene promoter by liver enriched transcription factors

Hall, Adrian; Peake, I. R.; Winship, Peter R.

doi:10.1111/j.1365-2141.2006.06327.x

Cited by 13 publications

(13 citation statements)

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“…Two alleles are in linkage disequilibrium when the probability of two alleles in combination from the same chromosome in a study population is more than the probability in random subjects. Two polymorphisms in PROS1 , rs8178583 and rs7650230 have been reported to be in strong linkage disequilibrium . Out of 16 SNPs analysed in this study, we found linkage disequilibrium in 5 PROC SNPs and 10 PROS1 SNPs.…”

Section: Discussionmentioning

confidence: 99%

Analysis of PROC and PROS1 single nucleotide polymorphisms in a thrombophilia family

Zhong

Chen

et al. 2019

Clinical Respiratory J

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Objective The aim of this study was to assess the association of single nucleotide polymorphisms (SNPs) in protein C (PROC) and protein S (PROS1) genes with deep venous thrombosis (DVT) in a thrombophilia family. Methods DNA were extracted from blood of participants. Five PROC SNPs and 11 PROS1 SNPs were selected from the Hapmap and 1000 Genomes databases. The minor allele frequencies (MAFs) of SNPs in the thrombophilia family (Group I) and healthy controls (Group II) were detected. SNPs were analysed by Chi‐square, logistic regression and linkage disequilibrium patterns. Results MAFs for all 16 SNPs were greater than 0.05. Chi‐square analysis showed significant differences between Group I and Group II in the frequency of mutant alleles of rs1799808, rs5936, rs6123, rs12634349, rs6441600 and rs13062355 SNPs (P < .05). Logistic regression analysis found that mutant alleles of rs1799808, rs6441600 and rs13062355 SNPs may contribute to DVT in this family (OR > 1, L95 > 1). Linkage disequilibrium was found among 15 of the PROC and PROS SNPs. Conclusions Single nucleotide polymorphisms (SNPs) of PROC and PROS1 may be closely associated with DVT in this thrombophilia family. Mutant alleles of rs1799808, rs6441600 and rs13062355 SNPs may contribute to DVT, whereas mutant alleles of rs1799810, rs6123 and rs12634349 may protect individuals from DVT. With the exception of rs9681204, there was linkage disequilibrium between PROC and PROS1 SNPs. We found that 12 haplotypes were in linkage disequilibrium, but linkage disequilibrium was strong in only eight of these (frequency >5%).

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Section: Discussionmentioning

confidence: 99%

Analysis of PROC and PROS1 single nucleotide polymorphisms in a thrombophilia family

Zhong

Chen

et al. 2019

Clinical Respiratory J

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“…The mutation was identified in a patient who experienced persistent low free PS levels which is likely to be a result of a defective transcriptional initiation process. Two studies have reported that either nucleotides -173, -174 or -175 form the starting point for transcription initiation of PROS1 mRNA synthesis in the liver and the human hepatoma cell line, HepG2 (Ploos van Amstel et al, 1990, Hall et al, 2006. Although multiple transcriptional start sites (TSSs) have been described for PROS1, the -173/74/75 transcript appears to be a highly expressed form in the liver, the principle organ for PS expression (Soria and Bertina, 1997, de Wolf et al, 2005, Hall et al, 2006.…”

Section: Discussionmentioning

confidence: 99%

“…The PS coding region comprises 15 exons (detailed in red) and 14 introns and is flanked by the 5` and 3` untranslated regions (5`UTR and 3`UTR). Previously reported transcriptional binding domains located within the promoter region, Sp1, HNF1, HNF3 and HNF4 are shown (Tatewaki et al, 2003, de Wolf et al, 2006a, Hall et al, 2006. Downward arrows denote dominant initiation start sites for various mRNA transcripts derived from human liver samples and various cell lines (de Wolf et al, 2005) Chromosome 3 Clinically it is well documented that PS levels are influenced by hormonal status, particularly in users of COCs and in pregnant women, where oestrogen and progesterone (or progestin isoforms) are increased.…”

Section: Protein S Geneticsmentioning

confidence: 99%

Hormonal Regulation of the Anticoagulant Protein S.

Hughes

Staton

Watson

et al. 2005

Blood

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The anticoagulant Protein S (PS) is coded for by the PROS1 gene and serves as a co-factor to APC in the inactivation of FVa and FVIIIa. It is produced predominately by the liver. Low PS levels are associated with an increased thrombotic risk. Clinically it is well documented that circulating PS levels are reduced in response to heightened estrogen (E2) levels (oral contraceptive use, pregnancy, etc.). However, an explanation as to how this is occurring at the molecular level has not yet been elucidated. Two approaches have been utilized. Firstly, a liver carcinoma cell line, HepG2, was exposed to 5 and 10nM concentrations of testosterone (T) and E2 for 6, 12 and 24h at which point’s total RNA was extracted and quantitated using real-time PCR. Secondly, a reporter plasmid pQH5′[2]DsRed2 was constructed that has 948bp of the PROS1 promoter region (up to but not including the ATG start codon) fused to an enhanced green fluorescent protein (EGFP) reporter gene sequence. A second reporter gene, DsRed2, was incorporated into pQH5′[2]DsRed2, and is constitutively expressed by a cytomegalovirus (CMV) promoter. This provides a means of standardizing any change in expression of the EGFP reporter. pQH5′[2]DsRed2 was transiently transfected into a breast cell carcinoma line MCF7 [chosen for its high levels of oestrogen receptor alpha (ERα)] and subsequently exposed to 5 and 10nM concentrations of E2 and T for 24h. Expression levels were assessed using a COULTER EPICS flow cytometer. The HepG2 6, 12 and 24h PROS1 mRNA hormone response experiment showed an erratic response to E2. However there were consistently higher levels of PROS1 mRNA over time in response to T compared to the vehicle alone. Higher levels still were evident for the 10nM concentration. The transient transfection of pQH5′[2]DsRed2 into MCF7s followed by a 24h exposure of either T or E2 at 5 and 10nM concentrations, showed a significant change in response to both the 5 and 10nM concentrations of E2, but little response to either of the T concentrations These results suggest that E2 is exerting a direct effect on the promoter of PROS1, down regulating transcription, reflecting clinical observations. However, T may be affecting PROS1 mRNA stability via a yet undetermined mechanism. Therefore, hormonal regulation of PS may be occurring at several levels of the overall production process.

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“…We performed in silico analysis to specifically identify transcription factor binding elements that are unique to this fragment compared with other non-responsive control fragments (Ϫ313/Ϫ427 and Ϫ177/Ϫ313, respectively). This showed that the Ϫ1/Ϫ177 fragment contains binding elements for c-jun, c-fos, AP-1, HNF1␣, HNF3␤, and C/EBP␦ (22)(23)(24). No predicted SMAD binding sites were found.…”

Section: Tgf-␤ Is An Inhibitor Of Habp2 Expression In Primary Hepatocmentioning

confidence: 98%

Transforming Growth Factor-β (TGF-β) Inhibits the Expression of Factor VII-activating Protease (FSAP) in Hepatocytes

Leiting

Seidl

Martínez-Palacián

et al. 2016

Journal of Biological Chemistry

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Deletion of the Habp2 gene encoding Factor VII-activating protease (FSAP) increases liver fibrosis in mice. A single nucleotide polymorphism (G534E) in HABP2 leads to lower enzymatic activity and is associated with enhanced liver fibrosis in humans. Liver fibrosis is associated with a decrease in FSAP expression but, to date, nothing is known about how this might be regulated. Primary mouse hepatocytes or the hepatocyte cell line, AML12, were treated with different factors, and expression of FSAP was determined. Of the various regulatory factors tested, only transforming growth factor-β (TGF-β) demonstrated a concentration- and time-dependent inhibition of FSAP expression at the mRNA and protein level. The TGF-β-Type I receptor (ALK-5) antagonist SB431542 and Smad2 siRNA, but neither SIS3, which inhibits SMAD3, nor siRNA against Smad3 could block this effect. Various regions of the HABP2 promoter region were cloned into reporter constructs, and the promoter activity was determined. Accordingly, the promoter activity, which could phenocopy changes in Habp2 mRNA in response to TGF-β, was found to be located in the 177-bp region upstream of the transcription start site, and this region did not contain any SMAD binding sites. Mutation analysis of the promoter and chromatin immunoprecipitation assays were performed to identify an important role for the ATF3 binding element. Thus, TGF-β is the most likely mediator responsible for the decrease in FSAP expression in liver fibrosis.

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Regulation of the human protein S gene promoter by liver enriched transcription factors

Cited by 13 publications

References 43 publications

Analysis of PROC and PROS1 single nucleotide polymorphisms in a thrombophilia family

Analysis of PROC and PROS1 single nucleotide polymorphisms in a thrombophilia family

Hormonal Regulation of the Anticoagulant Protein S.

Transforming Growth Factor-β (TGF-β) Inhibits the Expression of Factor VII-activating Protease (FSAP) in Hepatocytes

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