Identification of a cis-acting sequence in the human plasminogen activator inhibitor type-1 gene that mediates transforming growth factor-beta1 responsiveness in endothelium in vivo.

The Journal of Biological Chemistry
G DongD A Dichek

Abstract

The mechanism of regulation of the plasminogen activator inhibitor type-1 (PAI-1) gene by transforming growth factor-beta1 (TGF-beta1) was studied in vitro and in vivo in endothelial cells. We constructed adenovirus vectors containing PAI-1 5'-flanking sequences driving expression of a beta-galactosidase (beta-gal) reporter gene. Cultured bovine endothelial cells were transduced with the vectors and treated with TGF-beta1. beta-Gal expression was up-regulated 10-20-fold by TGF-beta1 when vectors contained 799-base pair (bp) of 5'-flanking sequence, but only minimally (2-3-fold) from a vector containing only 82-bp of 5' PAI-1 flanking sequence. TGF-beta1 up-regulated beta-gal expression at the mRNA level, congruently with TGF-beta1 up-regulation of expression of the endogenous PAI-1 gene. The constructs were transduced into intact rat carotid endothelium, and TGF-beta1 was injected systemically. In vivo, TGF-beta1 up-regulated endothelium-specific expression of beta-gal 3-fold (p < 0.03) from a vector containing the 799-bp sequence, but did not alter expression from a vector containing the 82-bp sequence. The sequence between -799 and -82 mediates up-regulation of reporter gene expression by TGF-beta1 in endothelial cells in vit...Continue Reading

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Citations

Jul 8, 1999·Human Gene Therapy·M B DeYoungD A Dichek
May 15, 1998·Human Gene Therapy·D B SchneiderR L Geary
Oct 28, 1998·The Journal of Clinical Investigation·M M VéniantS G Young
Jun 6, 1998·Proceedings of the National Academy of Sciences of the United States of America·R J HajjarA Rosenzweig
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·A H SchulickD A Dichek
May 1, 1997·Expert Opinion on Investigational Drugs·P Charlton
Feb 17, 2000·Arteriosclerosis, Thrombosis, and Vascular Biology·D B SchneiderD A Dichek
Mar 25, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·Douglas E Vaughan
Aug 21, 2007·Clinical Journal of the American Society of Nephrology : CJASN·Manish P Ponda, Thomas H Hostetter
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Jun 24, 2000·Annals of the New York Academy of Sciences·H IshiiF Numano
Nov 18, 2000·Molecular Therapy : the Journal of the American Society of Gene Therapy·F D CamargoD A Dichek

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