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Transcriptional regulation of the human thromboxane synthase gene expression.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Transcriptional regulation of the human thromboxane synthase gene expression./
Author:	Lee, Kuan-Der.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 1996,
Description:	160 p.
Notes:	Source: Dissertations Abstracts International, Volume: 58-06, Section: B.
Contained By:	Dissertations Abstracts International58-06B.
Subject:	Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9639840
ISBN:	9780591055023

Transcriptional regulation of the human thromboxane synthase gene expression.
Lee, Kuan-Der.

Transcriptional regulation of the human thromboxane synthase gene expression. - Ann Arbor : ProQuest Dissertations & Theses, 1996 - 160 p.

Source: Dissertations Abstracts International, Volume: 58-06, Section: B.

Thesis (Ph.D.)--University of Maryland, Baltimore, 1996.

This item must not be sold to any third party vendors.

Thromboxane synthase (TS) catalyzes the conversion of prostaglandin H$\\sb2$ into thromboxane A$\\sb2$ (TxA$\\sb2),$ which is a potent mediator of platelet aggregation and vasoconstriction. A deficiency of platelet TS or mutations in the TxA$\\sb2$ receptor gene have been shown to result in bleeding disorders, while an elevated level of TxA$\\sb2$ may be associated with cardiovascular and renal diseases. Several post-transcriptional events have been demonstrated to curtail the level of TS in vivo, presumably for preventing over-production of the autacoid. At present, little is known about the transcriptional regulation of TS gene expression. To address this, a genomic DNA containing the human TS promoter was cloned and characterized. 5$\\sp\\prime$-RACE (rapid amplification of cDNA ends) and ribonuclease (RNase) A/T1 protection assays revealed multiple transcription initiation sites. Deletion analysis indicated that TS transcription is mainly TATA-independent. A proximal positive regulatory sequence (PPRS, $-$90 to $-$25 bp) and several distal repressive elements, including a silencer, were also identified in the promoter. The PPRS worked in an orientation-independent but position-dependent manner, and could be further divided into two independent elements, PPRS$\\sb1$ ($-$90 to $-$50 bp) and PPRS$\\sb2$ ($-$50 to $-$25 bp). While similar amounts of nuclear factor(s) from different cell types may interact with PPRS$\\sb2,$ those interacting with PPRS$\\sb1$ exhibit cell specificity. Internal sequence deletion and oligonucleotide competition established that a binding sequence for NF-E2 in PPRS$\\sb1$ ($-$60 tgctgattcat $-$50) was important for enhancing TS promoter activity in HL-60 cells. The presence of NF-E2 mRNA in HL-60 cells was demonstrated by RT-PCR amplification of the cDNA and Northern analysis. A 9-fold trans-activation of luciferase (luc) reporter gene expression was detected when NF-E2 cDNA was co-expressed with a TS promoter/luc construct. Despite that NF-E2 and the cis-elements could alter the level of TS transcription, they were not sufficient for restricting cell-specific TS expression. Analysis of the methylation status of the TS promoter in several human cell lines revealed cell-specific patterns of methylation that might correlate with TS expression. Taken together, these results suggest that the expression of human TS gene is modulated by multiple factors including cis-elements, trans-activator(s), and possibly genomic methylation.

ISBN: 9780591055023Subjects--Topical Terms:

530508
Genetics.
Subjects--Index Terms:

methylation

Transcriptional regulation of the human thromboxane synthase gene expression.
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100 1 $a Lee, Kuan-Der. $3 3680620
245 1 0 $a Transcriptional regulation of the human thromboxane synthase gene expression.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 1996
300 $a 160 p.
500 $a Source: Dissertations Abstracts International, Volume: 58-06, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Shen, Rong-Fong.
502 $a Thesis (Ph.D.)--University of Maryland, Baltimore, 1996.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a Thromboxane synthase (TS) catalyzes the conversion of prostaglandin H$\\sb2$ into thromboxane A$\\sb2$ (TxA$\\sb2),$ which is a potent mediator of platelet aggregation and vasoconstriction. A deficiency of platelet TS or mutations in the TxA$\\sb2$ receptor gene have been shown to result in bleeding disorders, while an elevated level of TxA$\\sb2$ may be associated with cardiovascular and renal diseases. Several post-transcriptional events have been demonstrated to curtail the level of TS in vivo, presumably for preventing over-production of the autacoid. At present, little is known about the transcriptional regulation of TS gene expression. To address this, a genomic DNA containing the human TS promoter was cloned and characterized. 5$\\sp\\prime$-RACE (rapid amplification of cDNA ends) and ribonuclease (RNase) A/T1 protection assays revealed multiple transcription initiation sites. Deletion analysis indicated that TS transcription is mainly TATA-independent. A proximal positive regulatory sequence (PPRS, $-$90 to $-$25 bp) and several distal repressive elements, including a silencer, were also identified in the promoter. The PPRS worked in an orientation-independent but position-dependent manner, and could be further divided into two independent elements, PPRS$\\sb1$ ($-$90 to $-$50 bp) and PPRS$\\sb2$ ($-$50 to $-$25 bp). While similar amounts of nuclear factor(s) from different cell types may interact with PPRS$\\sb2,$ those interacting with PPRS$\\sb1$ exhibit cell specificity. Internal sequence deletion and oligonucleotide competition established that a binding sequence for NF-E2 in PPRS$\\sb1$ ($-$60 tgctgattcat $-$50) was important for enhancing TS promoter activity in HL-60 cells. The presence of NF-E2 mRNA in HL-60 cells was demonstrated by RT-PCR amplification of the cDNA and Northern analysis. A 9-fold trans-activation of luciferase (luc) reporter gene expression was detected when NF-E2 cDNA was co-expressed with a TS promoter/luc construct. Despite that NF-E2 and the cis-elements could alter the level of TS transcription, they were not sufficient for restricting cell-specific TS expression. Analysis of the methylation status of the TS promoter in several human cell lines revealed cell-specific patterns of methylation that might correlate with TS expression. Taken together, these results suggest that the expression of human TS gene is modulated by multiple factors including cis-elements, trans-activator(s), and possibly genomic methylation.
590 $a School code: 0373.
650 4 $a Genetics. $3 530508
650 4 $a Molecular biology. $3 517296
650 4 $a Cellular biology. $3 3172791
653 $a methylation
690 $a 0369
690 $a 0307
690 $a 0379
710 2 $a University of Maryland, Baltimore. $3 1029166
773 0 $t Dissertations Abstracts International $g 58-06B.
790 $a 0373
791 $a Ph.D.
792 $a 1996
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9639840