The Involvement of the Cell Cycle in Apoptosis

Abstract

The term apoptosis was proposed in 1972 to describe dying cells that undergo characteristic morphological changes that were distinctly different from necrosis (Kerr et al., 1972; reviewed in Wyllie et al., 1980). In necrosis, cells swell leading to rupture of plasma and organelle membranes, release of hydrolytic enzymes, and loss of organized structure. In contrast, apoptosis was recognized as reduction in cell size and therefore it was originally termed “shrinkage necrosis.” It was believed that apoptosis was involved in tissue homeo-stasis so the new name was intended to emphasize the normal balance between cell replication (mitosis) and cell death (apoptosis). The earliest morphological change observed in a cell dying by apoptosis is chromatin condensation to the periphery of the nucleus, followed by nuclear and cytoplasmic blebbing, cell shrinkage, and eventual loss of membrane integrity. Biochemically, the earliest event observed is DNA digestion in the internucleosome spacer region. These events occur late in the pathway of cell death, but understanding what regulates them will lead to an understanding of the upstream events that directly cause cell death (Figure 1). One frequently cited requirement for apoptosis is new protein synthesis, although the identity of the critical protein(s) is unknown. These proteins are frequently thought of as lethal, but results discussed below will present an argument that they may be normal cell cycle regulatory proteins, and that their expression leads to passage of a cell to a phase of the cell cycle at which they can undergo apoptosis.