The biochemistry of cell death by apoptosis

Abstract

In higher organisms homeostatic control of cell number is thought to be the result of the dynamic balance between cell proliferation and cell death. While the process of proliferation has received a great deal of attention over the past 20 years, much less emphasis has been placed on the biochemical events that occur before and during cell death. In higher organisms cell death can be classified into one of three different categories: necrosis, which occurs as a result of massive tissue damage; terminal differentiation of specialized tissues such as the skin, intestine, and red blood cells; and apoptosis, which is a process of active cellular selfdestruction that requires the expression of a number of genes. The latter process was originally recognized and described by Wyllie who coined the term to describe the sequence of events that lead to cell death in a variety of different systems (Kerr et al., Br. J . Cancer, 26, 239-257, 1972), specifically to distinguish this form of cell death from necrosis. Apoptosis is induced in the terminally differentiated cells of hormone-dependent tissues, such as the prostate and mammary gland in the absence of the appropriate trophic hormones, resulting in the regression of the tissue. In other tissues apoptosis can be induced by positive modulators, such as Mullerian duct inhibiting substance (MIS) in the Mullerian ducts, tumor necrosis factor (TNF) in adipocytes, and a variety of cell lines and glucocorticoids in lymphocytes and thymocytes. It can also be induced in cells that retain their proliferative potential (such as hepatocytes) to maintain homeostasis of cell numbers in organs such as the liver. In both proliferating and nonproliferating systems, apoptosis requires specific gene transcription and protein synthesis in the affected cell prior to death, although the biochemical sequence of events may vary slightly from one tissue to another.