THE INDUCTION OF THE PLASMINOGEN-ACTIVATOR SYSTEM DURING PHORBOL ESTER (PMA)-INDUCED DIFFERENTIATION IN HL-60 LEUKEMIC-CELLS

HL-60 human promyelocytic leukemia cells can be induced to differentiate in the monocyte/macrophage direction by the tumour promoter, phorbol myristate acetate (PMA) . Earlier studies reported the induction of the plasminogen activator, urokinase (uPA) during this process. In this study the induction of uPA, its receptor, and its inhibitor, PAI-1 was studied. PMA rapidly down-regulates c-myc mRNA, and induces the transcription and translation of the uPA gene. Northern blots show several phases in the steady state level of uPA mRNA, which is then reflected in large fluctuations in the concentration of uPA antigen in the cell lysates during the first 12 h following PMA treatment. The message for uPA receptor is undetectable in the undifferentiated cells but rises linearly following induction and peaks at 24 h, while the receptor itself is present already in the leukemic stage and rises upon induction from 32 000 to 75 000 receptors/cell, PAI-1 transcription, as well as translation are late events, starting 4 h after PMA, and peaking at 24 h. Thus, all 3 essential components of the plasminogen activator system are induced during the first 12 h of differentiation. Concerning the function of the system, there is good evidence that uPA itself promotes differentiation in HL-60 cells (Nusrat A R, Chapman H A. J Clin Invest 1991; 87: 1091-1097), and uPA is thought to promote the various functions of both sedentary and migrating macrophages, The large fluctuations in the appearance of the enzyme, first described here, are likely to reflect sequential inductions by agents emerging during the process of differentiation, or to the opening of signal transduction pathways to agents already present in the cells, or in the medium.