p53-Dependent Signal Transduction Induced by Stress.

While recent advances in elucidating the enzyme/substrate relationship of phosphorylation cascades have demonstrated several distinct pathways in membrane-cytoplasm signaling, the molecular dissection of p53 and the products of other proto-oncogenes have greatly promoted the studies of nuclear signaling and expanded the checkpoint concept to mammalian cells. The growing list of p53-activating factors ranges from genotoxic agents to non-genotoxic stresses. The diverse involvement of p53 and its close linkage to other nuclear and extranuclear signaling networks force us to reconsider the concept of cellular stress response. A signaling network emerges from crosstalks between different types of stress in the same signaling pathway and crosstalks between different pathways in response to the same stress. We review the present knowledge on cellular stress signaling with emphasis on the crosstalks between different pathways and the molecules which mediate these crosstalks and offer our concept of signaling checkpoints. The importance of stress signaling checkpoints in cancer evolution and cancer therapy is also discussed.