PLATELET-DERIVED GROWTH-FACTOR INDUCES APOPTOSIS IN GROWTH-ARRESTED MURINE FIBROBLASTS

The platelet-derived growth factor (PDGF) is a potent mitogen for muri ne fibroblasts. PDGF-stimulated cells express a set of immediate-early -response genes but require additional (progression) factors in serum to progress through the cell cycle. Serum-deprived cells are reversibl y arrested in G(0) phase and fail to fully traverse the G(1) phase of the cell cycle when stimulated by PDGF alone. We now report that serum -deprived normal rat kidney fibroblast (NRK) cells stimulated by eithe r PDGF AA or PDGF BB homodimers undergo apoptotic cell death. Furtherm ore, we show that epidermal growth factor also induces apoptotic cell death in serum-deprived NRK cells, epidermal growth factor enhances th e rate of apoptosis in PDGF-treated cells, and a progression factor (i nsulin) but not endogenously expressed Bcl-2 fully protects NRK cells from PDGF-stimulated apoptosis. The results indicate that PDGF induces apoptosis in growth-arrested NRK cells and that the inability of NRK cells to transit the G(1)/S checkpoint is the critical determinant in establishing the genetic program(s) to direct the PDGF signal to apopt osis. The results suggest that polypeptide growth factors in vivo may signal cell fate positively or negatively in settings that limit the p otential of cells to completely transit the cell cycle.