ApoReview-Introduction to Apoptosis:Page I of 26 ApoReview Introduction to Apoptosis this review was composed by Andreas Gewies in 2003 INDEX 1.The development of the term apoptosis. 2.The significance of apoptosis. .2 3.Morphological features of apoptosis. .4 4.Molecular mechanisms of apoptosis signalling pathways. .5 二 5 4.4 Mitochondria as central regulators of intrinsic apoptosis pathways. .12 5.Regulatory mechanisms in apoptosis signalling .13 of apoptosis by IAPs.】 6.Disease as a consequence of dysregulated apoptosis.18 7.References. .22
ApoReview - Introduction to Apoptosis: Page 1 of 26 ApoReview Introduction to Apoptosis this review was composed by Andreas Gewies in 2003 _ INDEX 1. The development of the term apoptosis. 2 2. The significance of apoptosis. 2 3. Morphological features of apoptosis. 4 4. Molecular mechanisms of apoptosis signalling pathways. 5 4.1 Various death signals activate common signalling .5 4.2 Caspases are central initiators and executioners of apoptosis.7 4.3 Extrinsic apoptosis pathways of type I and type II . 10 4.4 Mitochondria as central regulators of intrinsic apoptosis pathways .12 5. Regulatory mechanisms in apoptosis signalling . 13 5.1 The Bcl-2 family .13 5.2 Regulation of apoptosis by IAPs.16 6. Disease as a consequence of dysregulated apoptosis. 18 7. References. 22
ApoReview-Introduction to Apoptosis:Page 2 of26 Introduction to Apoptosis 1. The development of the term apoptosis Already since the mid-nineteenth century,many observations have indicated that cell death plays a considerable role during physiological processes of multicellular organisms,particularly during embryogenesis and metamorphosis [Gluecksmann,1951;Lockshin,2001].The term programmed cell death was introduced in 1964,proposing that cell death during development is not of accidential nature but follows a sequence of controlled steps leading to locally and temporally defined self- destruction [Lockshin,1964]. Eventually,the term apoptosis had been coined in order to describe the morphological processes leading self-destruction and was first introduced na publication by and Currie [Kerr,1972].Apoprosis is of greek origin,having the meaning"falling off or dropping of in analogy to leaves falling off trees or petals dropping off flowers.This analogy emphasizes that the death of living matter is an integral and necessary part of the life cycle of organisms.The apoptotic mode of cell death is an active and defined process which plays an important role in the development of multicellular organisms and in the regulation and maintenance of the cell populations in tissues upon physiological and pathological conditions.It should be stressed that apoptosis is a well-defined and possibly the most frequent form of programmed cell death,but that other,non-apoptotic types of cell death also might be of biological significance [Leist,2001] 2- The significance of apoptosis The development and maintenance of multicellular biological systems depends on a sophisticated interplay between the cells forming the organism,it sometimes even seems to involve an altruistic behaviour of individual cells in favour of the organism as a whole.During development many cells are produced in excess which eventually undergo programmed cell death and thereby contribute to sculpturing many organs and tissues [Meier,2000]
ApoReview - Introduction to Apoptosis: Page 2 of 26 Introduction to Apoptosis 1. The development of the term apoptosis Already since the mid-nineteenth century, many observations have indicated that cell death plays a considerable role during physiological processes of multicellular organisms, particularly during embryogenesis and metamorphosis [Gluecksmann, 1951; Lockshin, 2001]. The term programmed cell death was introduced in 1964, proposing that cell death during development is not of accidential nature but follows a sequence of controlled steps leading to locally and temporally defined selfdestruction [Lockshin, 1964]. Eventually, the term apoptosis had been coined in order to describe the morphological processes leading to controlled cellular self-destruction and was first introduced in a publication by Kerr, Wyllie and Currie [Kerr, 1972]. Apoptosis is of greek origin, having the meaning "falling off or dropping off", in analogy to leaves falling off trees or petals dropping off flowers. This analogy emphasizes that the death of living matter is an integral and necessary part of the life cycle of organisms. The apoptotic mode of cell death is an active and defined process which plays an important role in the development of multicellular organisms and in the regulation and maintenance of the cell populations in tissues upon physiological and pathological conditions. It should be stressed that apoptosis is a well-defined and possibly the most frequent form of programmed cell death, but that other, non-apoptotic types of cell death also might be of biological significance [Leist, 2001]. 2. The significance of apoptosis The development and maintenance of multicellular biological systems depends on a sophisticated interplay between the cells forming the organism, it sometimes even seems to involve an altruistic behaviour of individual cells in favour of the organism as a whole. During development many cells are produced in excess which eventually undergo programmed cell death and thereby contribute to sculpturing many organs and tissues [Meier, 2000]
ApoReview-Introduction to Apoptosis:Page3of26 Fig.1 Examples of physiological cell death hhehnmnbeat9apo0ceeroaidsmeye8ng.gost Development and Morphogenesis: all neurons di) Homeostasis: tasis ishen Deletion of damaged and dangerous cells: sualy are sig g that is in co ental or cellula ell of the A particularly instructive example for the implication of programmed cell death in animal development is the formation of free and independent digits by massive cell death in the interdigital mesenchymal tissue [Zuzarte-Luis,2002].Other examples are the development of the brain,during which half of the neurons that are initially created will die in later stages when the adult brain is formed [Hutchins,199]and the development of the reproductive organs [Meier,2000].Also cells of an adult organism constantly undergo physiological cell death which must be balanced with proliferation in order to maintain homeostasis in terms of constant cell numbers.The majority of the developing lymphocytes die either during genetic rearrangement events in the formation of the antigen receptor,during negative selection or in the periphery,thereby tightly controlling the pool of highly efficient and functional but not self-reactive immune cells and at the same time keeping lymphocyte numbers relatively constant [Rathmell.2002] Taken together,apoptotic processes are of widespread biological significance.being involved ing development,differentiation,proliferation/homocostasis,regulation and function of the immune system and in the removal of defect and therefore harmful cells.Thus,dysfunction or dysregulation of the apoptotic program is implicated in a varicty of pathological conditions.Defects in apoptosis can result in cancer,autoimmune diseases and spreading of viral infections,while ncurodegenerative disorders,AIDS and ischaemic diseases are caused or enhanced by excessive apoptosis [Fadeel. 1999a
ApoReview - Introduction to Apoptosis: Page 3 of 26 Fig. 1 Examples of physiological cell death Development and Morphogenesis: - 131 of the 1,090 somatic cells die during C.elegans development - during limb formation separate digits evolve by death of interdigital mesenchymal tissue (a) - ablation of cells no longer needed such as the amphibian tadpole tail during metamorphosis (b) - demise of cells allows sculpturing of hollow structures (c) - formation of reproductive organs (d) (Müllerian duct Æ uterus, deleted in males;Wolffian duct Æ male organs, deleted in females) - massive cell death occurs during early development of the nervous system (> 50 percent of all neurons die) In the human body about 100,000 cells are produced every second by mitosis and a similar number die by apoptosis (Vaux and Korsmeyer, 1999, Cell) ! Homeostasis: - a paradigm for the involvement of apoptosis in homeostasis is the immune system: several millions of B and T cells are generated every day and the majority (> 95 percent) of those die during maturation (death by neglect, negative selection) or by AICD of peripheral immune cells) Deletion of damaged and dangerous cells: - Cells with severely damaged DNA that cannot be repaired appropriately usually are removed by apoptosis - Inappropriate mitogenic signalling that is in conflict with the environmental or cellular status of the cell usually results in cell cycle arrest or apoptosis - Autoreactive cells of the immune system are deleted by apoptosis - Elimination of infected cells (a) (b) (c) (d) Development and Morphogenesis: - 131 of the 1,090 somatic cells die during C.elegans development - during limb formation separate digits evolve by death of interdigital mesenchymal tissue (a) - ablation of cells no longer needed such as the amphibian tadpole tail during metamorphosis (b) - demise of cells allows sculpturing of hollow structures (c) - formation of reproductive organs (d) (Müllerian duct Æ uterus, deleted in males;Wolffian duct Æ male organs, deleted in females) - massive cell death occurs during early development of the nervous system (> 50 percent of all neurons die) In the human body about 100,000 cells are produced every second by mitosis and a similar number die by apoptosis (Vaux and Korsmeyer, 1999, Cell) ! Homeostasis: - a paradigm for the involvement of apoptosis in homeostasis is the immune system: several millions of B and T cells are generated every day and the majority (> 95 percent) of those die during maturation (death by neglect, negative selection) or by AICD of peripheral immune cells) Deletion of damaged and dangerous cells: - Cells with severely damaged DNA that cannot be repaired appropriately usually are removed by apoptosis - Inappropriate mitogenic signalling that is in conflict with the environmental or cellular status of the cell usually results in cell cycle arrest or apoptosis - Autoreactive cells of the immune system are deleted by apoptosis - Elimination of infected cells (a) (b) (c) (d) A particularly instructive example for the implication of programmed cell death in animal development is the formation of free and independent digits by massive cell death in the interdigital mesenchymal tissue [Zuzarte-Luis, 2002]. Other examples are the development of the brain, during which half of the neurons that are initially created will die in later stages when the adult brain is formed [Hutchins, 1998] and the development of the reproductive organs [Meier, 2000]. Also cells of an adult organism constantly undergo physiological cell death which must be balanced with proliferation in order to maintain homeostasis in terms of constant cell numbers. The majority of the developing lymphocytes die either during genetic rearrangement events in the formation of the antigen receptor, during negative selection or in the periphery, thereby tightly controlling the pool of highly efficient and functional but not self-reactive immune cells and at the same time keeping lymphocyte numbers relatively constant [Rathmell, 2002]. Taken together, apoptotic processes are of widespread biological significance, being involved in e.g. development, differentiation, proliferation/homoeostasis, regulation and function of the immune system and in the removal of defect and therefore harmful cells. Thus, dysfunction or dysregulation of the apoptotic program is implicated in a variety of pathological conditions. Defects in apoptosis can result in cancer, autoimmune diseases and spreading of viral infections, while neurodegenerative disorders, AIDS and ischaemic diseases are caused or enhanced by excessive apoptosis [Fadeel, 1999a]
ApoReview-Introduction to Apoptosis:Page 4 of26 Due to its importance in such various biological processes,programmed cell death is a widespread phenomenon,occuring in all kinds of metazoans [Tittel,2000]such as in mammals,insects [Richardson,2002]nematodes [Liu,199and cnidaria [Cikala,199].Moreover,programmed cell death also might play a role in plant biology [Solomon,1999],and apoptosis-like cell death mechanisms even have been observed and used as a model system in yeast [Frohlich.2000. Skulachev,2002].Fascinating insights into the origin and evolution of programmed cell death might possibly be given by the fact,that programmed cell death is also an integral part of the life cycle of other unicellular eukaryotes (such as the kinetoplastid parasite Trypanosoma brucei brucei,the ciliate Tetrahymena thermophila.and the slime mold Dictvostelium discoideum)and that even prokaryotes (such as Bacillus subrilis,Streptomyces and Myxobacteria)sometimes undergo regulated cell death [Ameisen,20021 3. Morphological features of apoptosis Apoptotic cells can be recognized by stereotypical morphological changes:the cell shrinks,shows deformation and looses contact to its neighbouring cells.Its chromatin condenses and marginates at the nuclear membrane,the plasma membrane is blebbing or budding.and finally the cell is fragmented into compact membrane-enclosed structures,called 'apoptotic bodies which contain cytosol,the condensed chromatin,and organelles(Fig.2).The apoptotic bodies are engulfed by macrophages and thus are removed from the tissue without causing an inflammatory response.Those morphological changes are a consequence of characteristic molecular and biochemical events occurring in an apoptotic cell,most notably the activation of proteolytic enzymes which eventually mediate the cleavage of DNA into oligonucleosomal fragments as well as the cleavage of a multitude of specific protein substrates which usually determine the integrity and shape of the cytoplasm or organelles [Saraste,2000].Apoptosis is in contrast to the necrotic mode of cell-death in which ease the cells suffer a major insult,resulting in a loss of membrane integrity.swelling and disrupture of the cells. During necrosis,the cellular contents are released uncontrolled into the cell's environment which results in damage of surrounding cells and a strong inflammatory response in the corresponding tissue [Leist.20011
ApoReview - Introduction to Apoptosis: Page 4 of 26 Due to its importance in such various biological processes, programmed cell death is a widespread phenomenon, occuring in all kinds of metazoans [Tittel, 2000] such as in mammals, insects [Richardson, 2002], nematodes [Liu, 1999], and cnidaria [Cikala, 1999]. Moreover, programmed cell death also might play a role in plant biology [Solomon, 1999], and apoptosis-like cell death mechanisms even have been observed and used as a model system in yeast [Frohlich, 2000; Skulachev, 2002]. Fascinating insights into the origin and evolution of programmed cell death might possibly be given by the fact, that programmed cell death is also an integral part of the life cycle of other unicellular eukaryotes (such as the kinetoplastid parasite Trypanosoma brucei brucei, the ciliate Tetrahymena thermophila, and the slime mold Dictyostelium discoideum) and that even prokaryotes (such as Bacillus subtilis, Streptomyces and Myxobacteria) sometimes undergo regulated cell death [Ameisen, 2002]. 3. Morphological features of apoptosis Apoptotic cells can be recognized by stereotypical morphological changes: the cell shrinks, shows deformation and looses contact to its neighbouring cells. Its chromatin condenses and marginates at the nuclear membrane, the plasma membrane is blebbing or budding, and finally the cell is fragmented into compact membrane-enclosed structures, called 'apoptotic bodies' which contain cytosol, the condensed chromatin, and organelles (Fig. 2). The apoptotic bodies are engulfed by macrophages and thus are removed from the tissue without causing an inflammatory response. Those morphological changes are a consequence of characteristic molecular and biochemical events occurring in an apoptotic cell, most notably the activation of proteolytic enzymes which eventually mediate the cleavage of DNA into oligonucleosomal fragments as well as the cleavage of a multitude of specific protein substrates which usually determine the integrity and shape of the cytoplasm or organelles [Saraste, 2000]. Apoptosis is in contrast to the necrotic mode of cell-death in which case the cells suffer a major insult, resulting in a loss of membrane integrity, swelling and disrupture of the cells. During necrosis, the cellular contents are released uncontrolled into the cell's environment which results in damage of surrounding cells and a strong inflammatory response in the corresponding tissue [Leist, 2001]
ApoReview-Introduction to Apoptosis:Page 5 of 26 "Budding" Necrosis otic shrinking,ch is dis 4. Molecular mechanisms of apoptosis signalling pathways This paragraph is meant to provide a general overview of basic apoptotic signalling pathways and of the molecular machinery responsible for the induction and execution of apoptosis.The most important signalling molecules and cellular structures will be discussed in conext of their function and of the mechanisms in which they are involved in the initiation,mediation,execution,and regulation of apoptosis.This chapter should give an impression of the sophisticated interplay between factors that promote or suppress apoptosis,resulting in a complicated regulatory network which determines the fate of an individual cell as part of its multicellular environment(Fig.6). 4.1 Various death signals activate common signalling pathways Apoptosis is a tightly regulated and at the same time highly efficient cell death program which requires the interplay of a multitude of factors.The components of the apoptotic signalling network
ApoReview - Introduction to Apoptosis: Page 5 of 26 Fig. 2 Hallmarks of the apoptotic and necrotic cell death process. Apoptosis includes cellular shrinking, chromatin condensation and margination at the nuclear periphery with the eventual formation of membrane-bound apoptotic bodies that contain organelles, cytosol and nuclear fragments and are phagocytosed without triggering inflammatory processes.The necrotic cell swells, becomes leaky and finally is disrupted and releases its contents into the surrounding tissue resulting in inflammation. Modified from [Van Cruchten, 2002]. 4. Molecular mechanisms of apoptosis signalling pathways This paragraph is meant to provide a general overview of basic apoptotic signalling pathways and of the molecular machinery responsible for the induction and execution of apoptosis. The most important signalling molecules and cellular structures will be discussed in context of their function and of the mechanisms in which they are involved in the initiation, mediation, execution, and regulation of apoptosis. This chapter should give an impression of the sophisticated interplay between factors that promote or suppress apoptosis, resulting in a complicated regulatory network which determines the fate of an individual cell as part of its multicellular environment (Fig. 6). 4.1 Various death signals activate common signalling pathways Apoptosis is a tightly regulated and at the same time highly efficient cell death program which requires the interplay of a multitude of factors. The components of the apoptotic signalling network