MAGNITUDE OF PROTEIN-TYROSINE PHOSPHORYLATION-LINKED SIGNALS DETERMINES GROWTH VERSUS DEATH OF THYMIC T-LYMPHOCYTES

Using concanavalin A (Con A) as a multireceptor-reactive agonist, we s tudied the relationship between the growth or death of thymic T lympho cytes and the agonist concentration-dependent magnitude of the intrace llulary delivered signal. Both immature and mature thymic T lymphocyte s were subjected to a high concentration of Con A-mediated signal for apoptotic cell death. In this model, a number of cellular proteins inc luding mitogen activated protein kinases were phosphorylated at tyrosi ne depending on the concentration of Con A, This effect was followed b y corresponding increase in serine 73 phosphorylation of c-jun and tra nscription of c-fos. DNA fragmentation and cell membrane disruption de veloped concomitantly after stimulation with high concentrations of Co n A. The addition of inhibitors of protein kinases which completely in hibited the growth of cells stimulated with low concentrations of Con A only partially prevented death, and even promoted DNA fragmentation of cells stimulated with high concentrations of Con A. The dissociated sensitivities of Con A-mediated cell growth and cell death to the inh ibitors were, however, shown to be due to the different efficiency of inhibition of high and low levels of intracellularly delivered signals . The results indicate that the magnitude of signaling could be the pr incipal element that determines the growth versus death of thymic T ly mphocytes.