Retinoic acid potentiates phorbol ester-mediated induction of urokinase and plasminogen activator inhibitor type 2 in human myeloid leukemic cell lines.
We investigated the interactive regulation of the plasminogen activators (PAs) and their inhibitors (PAIs) by all-trans-retinoic acid (RA) in the presence and absence of the phorbol ester, phorbol myristate acetate (PMA), in four developmentally distinct human myeloid leukemic cell lines. Treatment of HL-60, K562, THP-1, and U937 cells with PMA resulted in an induction of urokinase-type PA (u-PA), the u-PA receptor (u-PAR), and PAI types 1 and 2 (PAI-1 and PAI-2). The addition of RA alone failed to alter gene expression or antigen production of PAI-1, PAI-2, or u-PAR. However, RA potentiated PMA-mediated induction of PAI-2 mRNA in HL-60 and U937 cells and PAI-2 antigen in all four cell lines. The effect of PMA on u-PA mRNA was also potentiated by RA in HL-60 and U937 cells. A similar, but transient, effect was seen on u-PA antigen levels. Run-on transcription analysis confirmed that these effects were due at least in part to changes in gene template activity. Furthermore, RA did not potentiate the effects of PMA on either u-PAR or PAI-1. In fact, in U937 cells, RA inhibited PMA-induced PAI-1 antigen secretion by approximately 60%. It would seem that interactive regulation of these genes allows for greater diversity of control, which may, in turn, be required for localized control of plasminogen-dependent extracellular proteolysis generated by monocytes/macrophage during cell migration and tissue remodeling.
Schuster
W A
WA
Hematology Division, University Hospital, Lausanne, Switzerland.
Medcalf
R L
RL
Kruithof
E K
EK
D004357:Drug Synergism; D004790:Enzyme Induction; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000378:metabolism*; D010960:Plasminogen Activators / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D013698:Templates, Genetic; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
C524898:PLAUR protein, human; D017396:Plasminogen Activator Inhibitor 2; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014212:Tretinoin; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate