Title
Stimulation of tissue-type plasminogen activator expression by retinoic acid in human endothelial cells requires retinoic acid receptor β2 induction
Author
Lansink, M.
Kooistra, T.
Gaubius Laboratory, Leiden, Netherlands Gaubius Laboratory TNO-PG, P.O. Box 2215, 2301 CE Leiden, Netherlands TNO Preventie en Gezondheid
Publication year
1996
Abstract
We previously showed the involvement of retinoic acid receptor α (RARα) in the induction of tissue-type plasminogen activator (t-PA) synthesis by RA in human umbilical vein endothelial cells (HUVECs). However, the rather slow onset of this induction of t-PA synthesis suggested an indirect role of RARα. Here, we show that the protein synthesis inhibitor, cycloheximide completely blocks the induction of t-PA by RA, which points to the need of an intermediary protein in t-PA stimulation. This intermediary protein is likely to be RARβ2 on the basis of the following findings: (1) the induction of RARβ by RA exactly precedes that of t-PA; (2) HUVECs with elevated RARβ mRNA levels show an undelayed t-PA induction on stimulation with RA, and this response can be almost completely inhibited with an RAR antagonist; and (3) an antisense oligodeoxynucleotide against the translation initiation site of RARβ2 mRNA greatly reduces the t-PA induction by RA. Thus, induction of t-PA by RA in HUVECs involves a 2-step mechanism requiring induction of RARβ2 via RARα, followed by induction of t-PA synthesis via RARβ2. Each of these steps is shown to have a different activation profile with RA and 9-cis RA. Chemicals/CAS: Benzoates; Chromans; Cycloheximide, 66-81-9; DNA, Complementary; Oligonucleotides, Antisense; Protein Synthesis Inhibitors; Receptors, Retinoic Acid; retinoic acid receptor alpha; retinoic acid receptor beta; Ro 41-5253, 144092-31-9; Tissue Plasminogen Activator, EC 3.4.21.68; Tretinoin, 302-79-4
Subject
Biology
Antisense oligodeoxynucleotide
Cycloheximide
Tetinoic acid receptor
Alternative rna splicing
Antibody response
Cell stimulation
competitive inhibition
Endothelium cell
Enzyme active site
Fibrinolysis
Gene induction
Human cell
Protein degradation
Base Sequence
Benzoates
Cells, Cultured
Chromans
Cycloheximide
DNA, Complementary
Endothelium, Vascular
Gene Expression Regulation
Humans
Molecular Sequence Data
Oligonucleotides, Antisense
Protein Synthesis Inhibitors
Receptors, Retinoic Acid
Tissue Plasminogen Activator
Tretinoin
Umbilical Veins
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http://resolver.tudelft.nl/uuid:caf5aab6-7a5d-4b3d-9579-d36dffd4c160
TNO identifier
233401
ISSN
0006-4971
Source
Blood, 88 (2), 531-541
Document type
article