Apoptosis can also be inhibited by signals from other cells and the surrounding environment via so-called survival factors. These include growth factors, hormones such as estrogen and androgens, neutral amino acids, zinc, and interactions with extracellular matrix proteins. Several cellular and viral proteins act as caspase inhibitors; for instance, nerve cells contain neuronal apoptosis inhibitory protein (NAIP) to protect them from premature apoptosis. However, the most important regulatory function in apoptosis is ascribed to internal signals from the Bcl-2 family of proteins. Members of this family consist of antiapoptotic and proapoptotic members that determine the life or death of a cell. These proteins interact with each other to suppress or propagate their own activity by acting on the downstream activation of various executional steps of apoptosis. They also act independently on mitochondria to regulate the release of cytochrome c, the most potent apoptosis-inducing agent.
Other Forms of Programmed Cell Death
Several forms of programmed cell death were recently identified that differ from apoptosis or necrosis.
There are several identified different forms of programmed cell death that do not fit into the classical apoptosis or necrosis scheme. They include the following.
FIGURE 3.18 • Schematic diagram of changes occurring in necrosis and apoptosis. This diagram shows the major steps in necrosis and apoptosis. In necrosis (left side), breakdown of the cell membrane results in an influx of water and extracellular ions, causing the organelles to undergo irreversible changes. Lysosomal enzymes are released into the extracellular space, causing damage to neighboring tissue and an intense inflammatory response. In apoptosis (right side), the cell shows characteristic morphologic and biochemical features such as DNA fragmentation, decrease in cell volume, membrane blebbing without loss of membrane integrity, and formation of apoptotic bodies, causing cell breakage. Apoptotic bodies are later removed by phagocytotic cells without inflammatory reactions.
 Autophagy is a regulated cellular process that enables cells to turn over their contents by lysosomal degradation of their own components. It starts when an intracellular membrane (often part of sER cistern) wraps around an or-ganelle or portion of cytoplasm, forming a closed double membrane–bound vacuole. This vacuole, called an
FIGURE 3.19 • Electron micrographs of apoptotic cells. a. This electron micrograph shows an early stage of apoptosis in a lymphocyte. The nucleus is already fragmented, and the irreversible process of DNA fragmentation is turned on. Note the regions containing condensed heterochromatin adjacent to the nuclear envelope. 5,200. b. Further fragmentation of DNA. The heterochromatin in one of the nuclear fragments (left) begins to bud outward through the envelope, initiating a new round of nuclear fragmentation. Note the reorganization of the cytoplasm and budding of the cytoplasm to produce apoptotic bodies. 5,200. c. Apoptotic bodies containing fragments of the nucleus, organelles, and cytoplasm. These bodies will eventually be phagocytosed by cells from the mononuclear phagocytotic system. 5,200. (Courtesy of Dr. Scott H. Kaufmann, Mayo Clinic.) d. This photomicrograph taken with light microscopy of intestinal epithelium from the human colon shows apoptotic bodies (AB) within a single layer of absorptive cells. BM, basement membrane. 750.
autophagosome, initially devoid of any lysosomal enzymes, fuses with lysosomes and initiates digestion. For a detailed description of three pathways utilized in autophagy, see pages 43 to 44.