Apoptosis
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Apoptosis
A. Cell proliferation and apoptosis
The number of cells in any tissue is mainly regulated by two processes—cell proliferation and physiological cell death, apoptosis. Both of these processes are regulated by stimulatory and inhibitory factors that act in solute form (growth factors and cytokines) or are presented in bound form on the surface of neighboring cells (see below). Apoptosis is genetically programmed cell death, which leads to “tidy” breakdown and disposal of cells .Morphologically, apoptosis is characterized by changes in the cell membrane (with the formation of small blebs known as “apoptotic bodies”), shrinking of the nucleus, chromatin condensation, and fragmentation of DNA. Macrophages and other phagocytic cells recognize apoptotic cells and remove them by phagocytosis without inflammatory phenomena developing. Cell necrosis (not shown) should be distinguished from apoptosis. In cell necrosis, cell death is usually due to physical or chemical damage. Necrosis leads to swelling and bursting of the damaged cells and often triggers an inflammatory response. The growth of tissue (or, more precisely, the number of cells) is actually regulated by apoptosis. In addition, apoptosis allows the elimination of unwanted or superfluous cells—e. g., during embryonic development or in the immune system. The contraction of the uterus after birth is also based on apoptosis. Diseased cells are also eliminated by apoptosis—e. g., tumor cells, virus-infected cells, and cells with irreparably damaged DNA. An everyday example of this is the peeling of the skin after sunburn. B. Regulation of apoptosis
Apoptosis can be triggered by a number of different signals that use various transmission pathways. Other signaling pathways prevent apoptosis. At the center of the apoptotic process lies a group of specialized cysteine-containing aspartate proteinases , known as caspases. These mutually activate one another, creating an enzyme cascade resembling the cascade involved in blood coagulation . Other enzymes in this group, known as effector caspases, cleave cell components after being activated—e. g., laminin in the nuclear membrane and snRP proteins — or activate special DNases which then fragment the nuclear DNA. An important triggerfor apoptosis is known as the Fas system. This is used by cytotoxic T cells, for example, which eliminate infected cells in this way (top left).Most of the body’s cells have Fas receptors (CD 95) on their plasma membrane. If a T cell is activated by contact with an MHC presenting a viral peptide , binding of its Fas ligands occurs on the target cell’s Fas receptors. Via the mediator protein FADD (“Fasassociated death domain”), this activates caspase- 8 inside the cell, setting in motion the apoptotic process. Another trigger is provided by tumor necrosis factor- α (TNF-α), which acts via a similar protein (TRADD) and supports the endogenous defense system against tumors by inducing apoptosis. Caspase-8 activates the effector caspases either directly, or indirectly by promoting the cytochrome c from mitochondria. Once in the cytoplasm, cytochrome c binds to and activates the protein Apaf-1 (not shown) and thus triggers the caspase cascade. Apoptotic signals can also come from the cell nucleus. If irreparable DNA damage is present, the p53 protein —the product of a tumor suppressor gene—promotes apoptosis and thus helps eliminate the defective cell. There are also inhibitory factors that oppose the signals that activate apoptosis. These include bcl-2 and related proteins. The genomes of several viruses include genes for this type of protein. The genes are expressed by the host cell and (to the benefit of the virus) prevent the host cell from being prematurely eliminated by apoptosis.
18.6.6. Mitochondria Play a Key Role in Apoptosis In the course of development or in cases of significant cell damage, individual cells within multicellular organisms undergo programmed cell death, or apoptosis. Mitochondria act as control centers regulating this process. Although the details have not yet been established, a pore called the mitochondrial permeability transition pore (mtPTP) forms in damaged mitochondria. This pore appears to consist of VDAC (the adenine nucleotide translocator) and several other mitochondrial proteins, including members of a family of proteins (Bcl family) that were initially discovered because of their role in cancer. One of the most potent activators of apoptosis is cytochrome c. Its presence in the cytosol activates a cascade of proteolytic enzymes called caspases. These cysteine proteases (Section 9.1.6) are conserved in evolution, being found in organisms ranging from hydra to human beings. Cytochrome c, in conjunction with other proteins, initiates the cascade by activating procaspase 9 to form caspase 9, which then activates other caspases. Activation of the caspase cascade does not lead to generalized protein destruction. Rather, the caspases have particular targets. For instance, the proteins that maintain cell structure are destroyed. Another example is the degradation of a protein that inhibits an enzyme that destroys DNA (caspase-activated DNAse, CAD), freeing CAD to cleave the genetic material. This cascade of proteolytic enzymes has been called "death by a thousand tiny cuts."
Programmed Cell Death At certain stages in the development of a multicellular organism, some cells must die. This wellregulated process is called is called apoptosis (programmed cell death), as suggested by Kerr in 1972. The importance of this biological phenomenon was first realized in studies of a tiny worm, the soil nematode C. elegans (see p. 304). If apoptosis does not occur, developmental failure of the organism or cancer may result. Apoptosis is regulated in the apoptosis pathway by many proteins, which either trigger or prevent apoptosis. Apoptosis can be triggered by a variety of stimuli that act either from outside the cell (extrinsic pathway) or from within the cell (intrinsic pathway). External stimuli may be irradiation, withdrawal of essential growth factors, or glucocorticoids. An intrinsic stimulus may be spontaneous damage to the DNA of the cell.
A. Importance of apoptosis Apoptosis occurs mainly during development. For example, the digits in the developing mammalian embryo are sculptured by apoptosis (1). The paws (hands in humans) start out as spadelike structures. The formation of digits requires that cells between them die (here shown as bright green dots on the left). More staggering is the amount of apoptosis in the developing vertebrate nervous system. Normally up to half of the nerve cells die soon after they have been formed. In the embryos of mice that lack an important gene regulating apoptosis (caspase 9, see below), neurons proliferate excessively and the brain protrudes above the face (2). (Illustration in 1 modified from Alberts et al., 2002; in 2 from Gilbert, 2003, according to Kaida et al., 1998.)
B. Cellular events in apoptosis The first visible signs of apoptosis are condensation of chromatin and shrinking of the cell. The cell membrane shrivels (membrane blebbing), and the cell begins to disintegrate (nuclear segmentation, DNA fragmentation). An apoptotic body of cell remnants forms, which eventually dissolves by a process called lysis. (Figure modified from Dr. A. J. Cann, Microbiology, Leicester University, displayed at Google Images, 22 March, 2005.)
C. Regulation of apoptosis Specialized cysteine-containing aspartate proteinases, called caspases, play a central role. They activate or inactivate each other in a defined sequence. Binding of a ligand, Fas, of a cytotoxic T cell (see section on immune system) to the Fas receptor (also called CD95) activates an intracellular adaptor protein, FADD (Fas-associated death domain). This binds to and activates procaspase 8 into active caspase 8. Caspase 8 causes release of cytochrome c in mitochondria (see p. 130) and activates several different effector caspases. Downstream of caspase 8, two pathways exist. In type I cells (in thymocytes and fibroblasts), caspase 8 directly activates caspase 3. In type II cells, such as hepatocytes, caspase 8 cleaves Bid, a member of the Bcl-2 family. The mouse and human genomes contain 13 caspase genes (1–12 and 14; see table in the appendix). Human caspases 3 and 6–10 are involved in apoptosis, the others in inflammation (Nagata, 2005). Caspase 8 also serves as a selective
signal transducer for nuclear factor KB (NFkB) during the early genetic response to an antigen (Su et al., 2005). Other regulators of apoptosis are members of the Bcl-2 family (the name Bcl is derived from B-cell lymphoma, a human malignant tumor originating from B-lymphocytes and caused by mutations in this gene). (Figure from Koolman & Rِhm, 2005.)
A. Cell proliferation and apoptosis
The number of cells in any tissue is mainly regulated by two processes—cell proliferation and physiological cell death, apoptosis. Both of these processes are regulated by stimulatory and inhibitory factors that act in solute form (growth factors and cytokines) or are presented in bound form on the surface of neighboring cells (see below). Apoptosis is genetically programmed cell death, which leads to “tidy” breakdown and disposal of cells .Morphologically, apoptosis is characterized by changes in the cell membrane (with the formation of small blebs known as “apoptotic bodies”), shrinking of the nucleus, chromatin condensation, and fragmentation of DNA. Macrophages and other phagocytic cells recognize apoptotic cells and remove them by phagocytosis without inflammatory phenomena developing. Cell necrosis (not shown) should be distinguished from apoptosis. In cell necrosis, cell death is usually due to physical or chemical damage. Necrosis leads to swelling and bursting of the damaged cells and often triggers an inflammatory response. The growth of tissue (or, more precisely, the number of cells) is actually regulated by apoptosis. In addition, apoptosis allows the elimination of unwanted or superfluous cells—e. g., during embryonic development or in the immune system. The contraction of the uterus after birth is also based on apoptosis. Diseased cells are also eliminated by apoptosis—e. g., tumor cells, virus-infected cells, and cells with irreparably damaged DNA. An everyday example of this is the peeling of the skin after sunburn. B. Regulation of apoptosis
Apoptosis can be triggered by a number of different signals that use various transmission pathways. Other signaling pathways prevent apoptosis. At the center of the apoptotic process lies a group of specialized cysteine-containing aspartate proteinases , known as caspases. These mutually activate one another, creating an enzyme cascade resembling the cascade involved in blood coagulation . Other enzymes in this group, known as effector caspases, cleave cell components after being activated—e. g., laminin in the nuclear membrane and snRP proteins — or activate special DNases which then fragment the nuclear DNA. An important triggerfor apoptosis is known as the Fas system. This is used by cytotoxic T cells, for example, which eliminate infected cells in this way (top left).Most of the body’s cells have Fas receptors (CD 95) on their plasma membrane. If a T cell is activated by contact with an MHC presenting a viral peptide , binding of its Fas ligands occurs on the target cell’s Fas receptors. Via the mediator protein FADD (“Fasassociated death domain”), this activates caspase- 8 inside the cell, setting in motion the apoptotic process. Another trigger is provided by tumor necrosis factor- α (TNF-α), which acts via a similar protein (TRADD) and supports the endogenous defense system against tumors by inducing apoptosis. Caspase-8 activates the effector caspases either directly, or indirectly by promoting the cytochrome c from mitochondria. Once in the cytoplasm, cytochrome c binds to and activates the protein Apaf-1 (not shown) and thus triggers the caspase cascade. Apoptotic signals can also come from the cell nucleus. If irreparable DNA damage is present, the p53 protein —the product of a tumor suppressor gene—promotes apoptosis and thus helps eliminate the defective cell. There are also inhibitory factors that oppose the signals that activate apoptosis. These include bcl-2 and related proteins. The genomes of several viruses include genes for this type of protein. The genes are expressed by the host cell and (to the benefit of the virus) prevent the host cell from being prematurely eliminated by apoptosis.
18.6.6. Mitochondria Play a Key Role in Apoptosis In the course of development or in cases of significant cell damage, individual cells within multicellular organisms undergo programmed cell death, or apoptosis. Mitochondria act as control centers regulating this process. Although the details have not yet been established, a pore called the mitochondrial permeability transition pore (mtPTP) forms in damaged mitochondria. This pore appears to consist of VDAC (the adenine nucleotide translocator) and several other mitochondrial proteins, including members of a family of proteins (Bcl family) that were initially discovered because of their role in cancer. One of the most potent activators of apoptosis is cytochrome c. Its presence in the cytosol activates a cascade of proteolytic enzymes called caspases. These cysteine proteases (Section 9.1.6) are conserved in evolution, being found in organisms ranging from hydra to human beings. Cytochrome c, in conjunction with other proteins, initiates the cascade by activating procaspase 9 to form caspase 9, which then activates other caspases. Activation of the caspase cascade does not lead to generalized protein destruction. Rather, the caspases have particular targets. For instance, the proteins that maintain cell structure are destroyed. Another example is the degradation of a protein that inhibits an enzyme that destroys DNA (caspase-activated DNAse, CAD), freeing CAD to cleave the genetic material. This cascade of proteolytic enzymes has been called "death by a thousand tiny cuts."
Programmed Cell Death At certain stages in the development of a multicellular organism, some cells must die. This wellregulated process is called is called apoptosis (programmed cell death), as suggested by Kerr in 1972. The importance of this biological phenomenon was first realized in studies of a tiny worm, the soil nematode C. elegans (see p. 304). If apoptosis does not occur, developmental failure of the organism or cancer may result. Apoptosis is regulated in the apoptosis pathway by many proteins, which either trigger or prevent apoptosis. Apoptosis can be triggered by a variety of stimuli that act either from outside the cell (extrinsic pathway) or from within the cell (intrinsic pathway). External stimuli may be irradiation, withdrawal of essential growth factors, or glucocorticoids. An intrinsic stimulus may be spontaneous damage to the DNA of the cell.
A. Importance of apoptosis Apoptosis occurs mainly during development. For example, the digits in the developing mammalian embryo are sculptured by apoptosis (1). The paws (hands in humans) start out as spadelike structures. The formation of digits requires that cells between them die (here shown as bright green dots on the left). More staggering is the amount of apoptosis in the developing vertebrate nervous system. Normally up to half of the nerve cells die soon after they have been formed. In the embryos of mice that lack an important gene regulating apoptosis (caspase 9, see below), neurons proliferate excessively and the brain protrudes above the face (2). (Illustration in 1 modified from Alberts et al., 2002; in 2 from Gilbert, 2003, according to Kaida et al., 1998.)
B. Cellular events in apoptosis The first visible signs of apoptosis are condensation of chromatin and shrinking of the cell. The cell membrane shrivels (membrane blebbing), and the cell begins to disintegrate (nuclear segmentation, DNA fragmentation). An apoptotic body of cell remnants forms, which eventually dissolves by a process called lysis. (Figure modified from Dr. A. J. Cann, Microbiology, Leicester University, displayed at Google Images, 22 March, 2005.)
C. Regulation of apoptosis Specialized cysteine-containing aspartate proteinases, called caspases, play a central role. They activate or inactivate each other in a defined sequence. Binding of a ligand, Fas, of a cytotoxic T cell (see section on immune system) to the Fas receptor (also called CD95) activates an intracellular adaptor protein, FADD (Fas-associated death domain). This binds to and activates procaspase 8 into active caspase 8. Caspase 8 causes release of cytochrome c in mitochondria (see p. 130) and activates several different effector caspases. Downstream of caspase 8, two pathways exist. In type I cells (in thymocytes and fibroblasts), caspase 8 directly activates caspase 3. In type II cells, such as hepatocytes, caspase 8 cleaves Bid, a member of the Bcl-2 family. The mouse and human genomes contain 13 caspase genes (1–12 and 14; see table in the appendix). Human caspases 3 and 6–10 are involved in apoptosis, the others in inflammation (Nagata, 2005). Caspase 8 also serves as a selective
signal transducer for nuclear factor KB (NFkB) during the early genetic response to an antigen (Su et al., 2005). Other regulators of apoptosis are members of the Bcl-2 family (the name Bcl is derived from B-cell lymphoma, a human malignant tumor originating from B-lymphocytes and caused by mutations in this gene). (Figure from Koolman & Rِhm, 2005.)
