MECHANISM OF APOPTOSIS SUPPRESSION BY PHORBOL ESTER IN IL-6-STARVED MURINE PLASMACYTOMAS - ROLE OF PKC MODULATION AND CELL-CYCLE

We show here that the mode of cell death in IL-6-starved T1165 and T11 98 plasmacytoma cell lines is apoptosis, and that it can be suppressed by phorbol ester (PMA) treatment in a protein kinase C (PKC)-mediated process that involves alpha and/or delta isozymes. PMA-induced PKC ac tivation, but not the depletion that follows it, participates in the s uppression of apoptosis. Extended PKC activation is necessary but not sufficient for the apoptosis suppression. In addition, the cells must be in a ''competent'' state, which appears not to be determined by PKC . We observed two points of ''competence'' during the time between wit hdrawal of IL-6 and the start of massive cell death: one, immediately after withdrawal, and another, just before onset of apoptosis, at the time corresponding to maximal accumulation of cells in a G0/G1 black i mposed by IL-6 withdrawal, Treatment with PMA and other PKC activators resulted in a shift of the cell population to S phase, Lifting tile G 0/G1 block, We propose a model in which cells are rescued in a certain stage of the G1 phase of cell cycle. Death suppression occurs when a transient PMA-induced PKC activation occurs when a significant number of cells are in this part of G1. allowing them to pass the restriction point safely without initiating the cell death program.