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 differentia te in the monocyte/macrophage direction by the tumour promoter, phorbo l myristate acetate (PMA) . Earlier studies reported the induction of the plasminogen activator, urokinase (uPA) during this process. In thi s study the induction of uPA, its receptor, and its inhibitor, PAI-1 w as studied. PMA rapidly down-regulates c-myc mRNA, and induces the tra nscription and translation of the uPA gene. Northern blots show severa l phases in the steady state level of uPA mRNA, which is then reflecte d in large fluctuations in the concentration of uPA antigen in the cel l lysates during the first 12 h following PMA treatment. The message f or uPA receptor is undetectable in the undifferentiated cells but rise s linearly following induction and peaks at 24 h, while the receptor i tself is present already in the leukemic stage and rises upon inductio n from 32 000 to 75 000 receptors/cell, PAI-1 transcription, as well a s translation are late events, starting 4 h after PMA, and peaking at 24 h. Thus, all 3 essential components of the plasminogen activator sy stem are induced during the first 12 h of differentiation. Concerning the function of the system, there is good evidence that uPA itself pro motes 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 fluc tuations in the appearance of the enzyme, first described here, are li kely to reflect sequential inductions by agents emerging during the pr ocess of differentiation, or to the opening of signal transduction pat hways to agents already present in the cells, or in the medium.