Nageswara R. Madamanchi, Zhao Y. Hu, Fengzhi Li, Chris Horaist, Sung-Kwon Moon, Cam Patterson and Marschall S. Runge @,
Carolina Cardiovascular Biology Center, Dept. of Medicine, University
of North Carolina, Chapel Hill, NC
27599-7126 USA
@ Corresponding author. School of Medicine, University
of North Carolina, 3033 Old Clinic Building, CB#7005, Chapel Hill, NC 27599-7005,
USA. Tel.: +1-919-966-4468; fax: +1-919-966-5775;
email: mrunge@med.unc.edu
Activation of the human protease-activated receptor-1 (PAR-1) by
thrombin leads to myriad functions essential for maintaining vascular integrity.
Upregulation of PAR-1 expression is considered important in atherosclerosis,
angiogenesis and tumor metastasis. In vitro analysis of the human PAR-1
promoter function revealed a positive regulatory element between -4.2 and
-3.2 kb of the transcription start site. This element was examined in transgenic
mice containing either 4.1 or 2.9 kb of the 5' flanking sequence driving
a LacZ reporter gene. Only the 4.1 kb PAR-1 transgene was expressed in
vivo and only during embryonic development. The transgene expression was
observed only in developing arteries and not in veins. Further examination
of this putative regulatory sequence identified a novel noncoding RNA
(ncR-uPAR:noncoding RNA upstream of the PAR-1) gene at -3.4 kb.
The ncR-uPAR upregulated
PAR-1-core promoter-driven luciferase activity and mRNA expression
in vitro in a Pol II-dependent manner. This noncoding RNA appears to
act in trans, albeit locally at the adjacent PAR-1 promoter. These
data suggest that an untranslated RNA plays a role in PAR-1 gene expression
during embryonic growth.
1. Herstein PR, and Frenster JH, "Mated Models of Gene Regulation in Eukaryotes".
2. Frenster JH, "Ultrastructural Probes of Active
DNA Sites, and the RNA Activators of DNA".