Programmed Cell Death

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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).

BOX 46-1 Key Terms

Programmed Cell Death: An active cellular process that culminates in cell death. This may occur in response to developmental or environmental cues or as a response to physiological damage detected by the cell’s internal surveillance networks.

Necrosis (Accidental Cell Death): Cell death that results from irreversible injury to the cell. Cell membranes swell and become permeable. Lytic enzymes destroy the cellular contents, which then leak out into the intercellular space, leading to the mounting of an inflammatory response.

Apoptosis: One type of programmed cell death that initially was characterized by a particular pattern of morphologic changes but now is defined by the action of molecular pathways involving cell surface receptors or mitochondria and resulting in the activation of specialized proteases. The name comes from the ancient Greek, referring to shedding of the petals from flowers or leaves from trees. Apoptosis is observed in all metazoans, including both plants and animals.

Apoptotic death occurs in two phases. During the latent phase, the cell looks morphologically normal but is actively making preparations for death. The execution phase is characterized by a series of dramatic structural and biochemical changes that culminate in the fragmentation of the cell into membrane-enclosed apoptotic bodies. Activities that cause cells to undergo apoptosis are said to be pro-apoptotic. Activities that protect cells from apoptosis are said to be anti-apoptotic.

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.

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.

Cells That Serve No Function

The elimination of obsolete cells whose function has been completed is most evident in organisms, such as insects and amphibians, that undergo metamorphosis during development. For example, programmed cell death initiated by a burst of thyroid hormone is responsible for resorption of the tadpole tail.

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).

During craniofacial development, the hard palate develops from two lateral precursors, each covered in a protective layer of epithelial cells. As the two halves grow together at the midline of the nasopharynx, they remain separated by this covering of epithelium until, in response to a developmental cue, the epithelial cells at the midline undergo programmed cell death. Then the two halves of the palate can fuse. Failure of the epithelial cells to die at the appropriate time can interfere with the fusion of the bone, causing cleft palate.

Populations of cells that are fully functional may become obsolete as a result of physiological changes in the status of an organism. For example, in male mammals, certain accessory glands of the reproductive system are regulated by the levels of circulating male hormone. If hormone levels fall below a critical threshold, these organs, including the prostate, virtually disappear in a very brief time as their constituent cells undergo massive apoptotic death. Should levels of circulating androgens rise again, the remaining prostatic stem cells proliferate and reconstruct the gland. A similar cycle of growth and involution is seen in the mammary gland of female mammals, which exhibits substantial differences in size and cellular composition in the lactating and nonlactating states. Interference with survival signaling by sex hormones is one important strategy that is commonly used in the treatment of breast and prostate cancer.

Programmed cell death is also used to eliminate certain populations of cells that never served any function to begin with. The Müllerian ducts develop into the female oviduct. In male embryos, progenitors of the Müllerian ducts develop, even though they have no function. Programmed cell death eliminates the constituent cells of these embryonic ducts.

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

Cells that harbor infectious agents, such as viruses, are harmful to the organism. Cytotoxic T lymphocytes eliminate virus-infected cells by causing them to undergo programmed cell death either by apoptosis or by a second related pathway.

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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