Protein kinase C δ stimulates apoptosis by initiating G1 phase cell cycle progression and S phase arrest

Overexpression of protein kinase C delta(PKC delta) stimulates apoptosis in a wide variety of cell types through a mechanism that is incompletely understood. PKC delta-deficient cells are impaired in their response to DNA damage-induced apoptosis, suggesting that PKC delta is required to mount an appropriate apoptotic response under conditions of stress. The mechanism through which it does so remains elusive. In addition to effects on cell survival, PKC delta elicits pleiotropic effects on cellular proliferation. We now provide the first evidence that the ability of PKC delta to stimulate apoptosis is intimately linked to its ability to stimulate G(1) phase cell cycle progression. Using an adenoviral-based expression system to express PKC alpha, -delta, and -epsilon in epithelial cells, we demonstrate that a modest increase in PKC delta activity selectively stimulates quiescent cells to initiate G1 phase cell cycle progression. Rather than completing the cell cycle, PKC delta-infected cells arrest in S phase, an event that triggers caspase-dependent apoptotic cell death. Apoptosis was preceded by the activation of cell cycle checkpoints, culminating in the phosphorylation of Chk-1 and p53. Strikingly, blockade of S phase entry using the phosphatidylinositol 3-kinase inhibitor LY294002 prevented checkpoint activation and apoptosis. In contrast, inhibitors of mitogen-activated protein kinase cascades failed to prevent apoptosis. These findings demonstrate that the biological effects of PKC delta can be extended to include positive regulation of G1 phase cell cycle progression. Importantly, they reveal the existence of a novel, cell cycle-dependent mechanism through which PKC delta stimulates cell death.