1,25-Dihydroxyvitamin D(3) induction of the tissue-type plasminogen activator gene is mediated through its multihormone-responsive enhancer.
Tissue-type plasminogen activator (t-PA) is a positive modulator of the plasminogen-plasmin system, which is involved in bone remodeling. In the present study, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] was found to stimulate t-PA gene expression in ROS17/2.8 osteosarcoma cells. Transient transfection analysis and in vitro DNA binding studies identified two vitamin D-responsive elements (VDRE) in the human t-PA enhancer. The first VDRE (bp -7175 to -7146) comprised an inverted palindrome separated by 9 bp (IP9) overlapping a palindrome separated by 3 bp. The second VDRE (bp -7315 to -7302) is an IP2 element overlapping the previously identified retinoic acid-responsive element. 1,25(OH)(2)D(3) treatment of primary osteoblasts derived from t-PAlacZ transgenic mice containing 9 kb of 5' sequence of the human t-PA gene increased the number of lacZ-positive cells, fitting with the probability model of enhancer function.
Merchiers
P
P
Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O and N, Herestraat 49, B-3000, Leuven, Belgium.
Bulens
F
F
Stockmans
I
I
De Vriese
A
A
Convents
R
R
Bouillon
R
R
Collen
D
D
Belayew
A
A
Carmeliet
G
G
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002117:Calcitriol / Q000235:genetics / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010006:Osteoblasts; D012516:Osteosarcoma / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D020218:Response Elements; D012886:Skull / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
D010959:Tissue Plasminogen Activator; D002117:Calcitriol