CHAPTER 46 Programmed Cell Death
The Necessity for Cell Death in Multicellular Organisms
The ability to undergo programmed cell death (Box 46-1) is a built-in latent capacity in virtually all cells of multicellular organisms. Cell death is important for embryonic development, maintenance of tissue homeostasis, establishment of immune self-tolerance, killing by immune effector cells, and regulation of cell viability by hormones and growth factors. It has been proposed that most metazoan cells will die if they fail to receive survival signals from other cells. Abnormalities of the cell death program contribute to a number of diseases, including cancer, Alzheimer’s disease, and acquired immune deficiency syndrome (AIDS).
Programmed Cell Death versus Accidental Cell Death: Apoptosis versus Necrosis
Although cells die in many ways, it is useful to focus on the two poles of this spectrum: apoptosis and necrosis. Apoptosis is the most commonly described pathway for programmed cell death, which is cellular suicide resulting from activation of a dedicated intracellular program (Fig. 46-1). Often, these cells appear completely healthy prior to committing suicide. At the other end of the spectrum is necrosis, also called accidental cell death, which occurs when cells receive a structural or chemical insult that kills them outright (Fig. 46-2). Examples of such insults include extremes of temperature and physical trauma. The cell itself can also initiate necrosis in response to certain stimuli, particularly when induction of apoptosis is inhibited. In contrast to the orderly biochemical pathways of apoptosis, which involve the action of enzyme cascades and the consumption of ATP, necrosis typically involves a collapse of normal cell physiology as a result of ATP depletion.
Necrosis corresponds to what most of us naively imagine cell death would be like. Owing to lack of cellular homeostasis, water rushes into the dying cell, causing it to swell greatly so that the plasma and organelle membranes burst. As a result, the cell undergoes a generalized process of autodigestion and dissolution, culminating in the spilling of the cytoplasmic contents out into the surroundings (Fig. 46-2). This, in turn, produces local inflammation as phagocytic cells are activated, flock to the site, and ingest the debris (see Chapter 22). Because agents that damage cells act over areas that are large in comparison to the size of a single cell, necrosis often involves large groups of neighboring cells.
In contrast to necrosis, apoptotic cells shrink rather than swelling, as part of a reproducible pattern of structural alterations of both the nucleus and cytoplasm (Fig. 46-1). Apoptosis is a two-stage process. On receipt of the pro-apoptotic signal that triggers the pathway to death, cells enter a latent phase of apoptosis (Fig. 46-3). Although committed to a pathway that leads to their inevitable demise at some later time, cells in the latent phase look as healthy as their neighbors. The duration of the latent phase of apoptosis is extremely variable, ranging from a few hours to several days. The reason for this variability is not known.
Ultimately, the cells enter the execution phase of apoptosis, lasting about an hour, during which they undergo dramatic morphologic and physiological changes. These include (1) loss of microvilli and intercellular junctions (Fig. 46-4); (2) shrinkage of the cytoplasm; (3) dramatic changes in cytoplasmic motility with activation of violent blebbing (Fig. 46-5); (4) loss of plasma membrane asymmetry, with the distribution of phosphatidylserine being randomized so that it appears in the outer membrane leaflet; (5) hypercondensation of the chromatin and its collapse against the nuclear periphery; and (6) the “explosive” fragmentation of the cell into membrane-enclosed apoptotic bodies that contain remnants of the nucleus, mitochondria, and other organelles. The plasma membrane retains its integrity throughout the entire process. All of these changes are instigated by the action of a specific set of death-inducing proteases, discussed at length later.
In tissues, apoptotic bodies are rapidly phagocytosed by surrounding cells that recognize the phosphatidylserine and other markers exposed on their surface (Fig. 46-6). Apoptosis can thus be considered to be the disassembly of the cell into “bite-sized” vesicles. Because these vesicles remain membrane bound, the cellular contents are not released into the environment. It is important to note that surface markers on apoptotic bodies cause cells that ingest them to secrete anti-inflammatory cytokines. As a result, apoptotic death does not lead to an inflammatory response.
Nonapoptotic Programmed Cell Death
The terms apoptosis and programmed cell death are sometimes viewed as synonymous. However, in a number of well-documented systems, cells undergo programmed cell death without the dramatic structural changes that classically define apoptosis. Thus, all apoptosis is programmed cell death, but the converse is not necessarily true.
When the adult tobacco hawkmoth emerges from its cocoon, its intersegmental muscles undergo programmed cell death that differs in several ways from apoptosis as described earlier. The chromatin does not condense; DNA is not digested; and cytoplasm does not “boil.” Instead, a polyubiquitin gene is induced and plays an important role in intracellular protein degradation (see Chapter 23). Thus, although these muscle cells unquestionably undergo programmed cell death, they apparently do not use the apoptosis pathway.
Classes of Cells That Undergo Programmed Cell Death
At least six distinct classes of cells undergo programmed cell death (examples are given in Fig. 46-7).
Developmentally Defective Cells
During molecular maturation of T-lymphocyte antigen receptors (see Figs. 27-8 and 28-8), immature T cells in the thymus (known as thymocytes) rearrange the genes encoding the receptor a and b chains. Many newly created receptors bind to foreign antigens, but others interact with self-antigens. Cells with receptors recognizing self-antigens are potentially harmful and are eliminated through apoptosis in a process known as negative selection (Fig. 46-8). The drug cyclosporin A, which inhibits apoptosis in thymocytes, can cause autoimmune disease.
To function properly, the T-cell receptor must recognize major histocompatibility complex (MHC) glycoproteins on other cells during antigen presentation (see Fig. 27-8). T lymphocytes whose T-cell receptors cannot interact with the spectrum of MHC glycoproteins expressed in a given individual are ineffective in the immune response. These cells die by apoptosis in a process known as positive selection (Fig. 46-8). Overall, defects in T-cell receptor assembly are extremely common, and up to 95% of immature T cells die by apoptosis without leaving the thymus.
Similar positive and negative selection steps occur during the maturation of B lymphocytes (see Fig. 28-8), which is accomplished by a combination of gene rearrangements and facilitated mutagenesis. B lymphocytes expressing antibodies directed against self-antigens or producing antibodies whose affinity for antigen is below a critical threshold are eliminated through apoptosis.
Excess Cells
The use of programmed cell death for quality control during development is not limited to the immune system but is also extremely important during brain development. Embryonic ganglia often have many more neurons than are required to enervate their target muscles. Production of excess cells is part of a Darwinian strategy to ensure that a sufficient number of axons reach their targets. Excess neurons that fail to make appropriate connections have no function and are eliminated by programmed cell death. Up to 80% of neurons in certain developing ganglia die in this way. Because of the importance of apoptosis during its development, the brain is often seriously affected in mice that are engineered to lack components of the apoptotic pathway.
Cells That Serve No Function
Mammals also use programmed cell death to eliminate obsolete tissues during development. For example, in humans, the digits of hands and feet are connected by a tissue webbing during embryogenesis. Cells in this webbing serve no purpose in the adult and are eliminated by programmed cell death (Fig. 46-7).
Cells Whose Cell Cycle Is Perturbed
Chapters 40 to 43 describe how biochemical circuits called checkpoints regulate the cell cycle. If DNA is damaged, checkpoint activation blocks cell-cycle progression while repair processes operate. An important downstream effector of checkpoints, the p53 transcription factor, induces the expression of genes encoding proteins that arrest the cell cycle as well as genes encoding proteins that induce cell death. It is generally thought that if the damage cannot be repaired quickly, the pro-death factors win out, and the outcome is apoptosis. Types of DNA damage that commonly trigger cell death are double-strand breaks induced by ionizing radiation and DNA breaks or other damage induced by chemotherapeutic agents.
A second important cell-cycle checkpoint regulates the transition from the G1 phase to the S phase. Passage of the restriction point (see Fig. 41-7) represents the commitment of the cell to undergo another cycle of DNA replication and division. Restriction point control centers on the regulation of the E2F family of transcription factors. However, E2F not only regulates genes that promote cell-cycle progression; it also induces the expression of genes that promote apoptosis. It is now thought that if E2F is activated too strongly, as, for example, where restriction point control has broken down (see Fig. 41-10), its function as a death inducer takes over, and the cells undergo apoptosis. Cells that die in response to inappropriate signals to proliferate include those that are infected by certain viruses or overexpress genes involved in cell proliferation (such as c-myc and c-fos [Fig. 46-14]). This ability to recognize an inappropriate stimulus to proliferate and respond to it by undergoing apoptosis may be an important defense against cancer.
Virus-Infected Cells
At least part of the loss of mature CD4+ T helper cells (see Fig. 28-8) in people who are infected with HIV-1 results from programmed cell death. When exposed to agents that normally stimulate cell proliferation, these cells instead undergo apoptosis. Paradoxically, it ap-pears that many of these dying cells are not themselves infected with HIV.
Genetic Analysis of Programmed Cell Death
Several key components that are involved in the apoptotic execution of mammalian cells were first identified by a genetic analysis of the nematode worm Caenorhabditis elegans. Because C. elegans is optically clear, it is possible to see every cell in a developing worm by using differential interference contrast optics (see Fig. 6-2). This enabled investigators to develop a complete fate map for C. elegans that traces the lineage of each cell in an adult worm back to the fertilized egg. These studies led to the surprising discovery that programmed cell death is one of the most common fates for newborn C. elegans cells. Of the 1090 somatic cells that are produced during embryogenesis of the C. elegans hermaphrodite, 131 undergo programmed cell death at reproducible locations and times.
Mutations in at least 14 C. elegans genes affect programmed cell death (Fig. 46-9
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