Comprehensive Physiology Wiley Online Library

Apoptosis

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Apoptotic Cell Death Shows Conserved Morphological and Biochemical Changes
1.1 Nuclear Condensation and Ladder Pattern of DNA Fragmentation
1.2 Cytoplasmic Shrinkage and Plasma Membrane Blebbing
1.3 Nuclear and Cytoplasmic Alterations
1.4 Phagocytosis
2 Cellular Mechanisms of Apoptosis Conserved During Evolution: Nematode as a Genetic Model
3 Genes Regulating Apoptosis
3.1 The ced‐9/bcl‐2 Gene Family
3.2 The ced‐3/caspase Gene Family
3.3 Death Domain‐Containing Proteins
3.4 Other Apoptosis Regulatory Genes
4 Extracellular Signaling of Apoptosis
4.1 Apoptosis Induction Is Cell Type‐Specific
4.2 The Mammalian Ovary Model
4.3 Fas‐Ligand/Fas Antigen and Apoptosis
5 Conclusion
Figure 1. Figure 1.

Diagrams illustrating sequences of structural changes during apoptosis and necrosis. Lower left: The nuclei of necrotic cells usually are associated with irregular chromatin clumping, and the plasma membrane dissolves following the loss of cell volume homeostasis. In addition, leakage of cellular contents to the environment leads to inflammatory reactions. Lower right: The nuclei of apoptotic cells are characterized by condensation and fragmentation of nuclear chromatin. Apoptotic cells also undergo volume shrinkage and become fragmented into membrane‐bound apoptotic bodies. These apoptotic bodies are phagocytosed by macrophages or neighboring cells before degradation within their lysosomes.

Figure 2. Figure 2.

Internucleosomal DNA fragmentation is a hallmark of apoptosis. Diagrams illustrate the superstructure of chromatin and sites cleaved during apoptosis (upper). In the lower panel, an autoradiogram shows the “ladder‐like” oligonucleosomal genomic DNA from ovarian cells undergoing apoptosis (A). Generation of “ladderlike” DNA fragments in apoptotic cells is the result of activation of endonucleases which cleave DNA at internucleosomal sites. In contrast, DNA from healthy cells shows no sign of fragmentation (H). Fragments of DNA are extracted from cells and labeled at 3′ ends with ddATP using terminal transferase, followed by fractionation in agarose gels and autoradiographic analysis.

Figure 3. Figure 3.

Cellular regulators of apoptosis during Caenorbabditis elegans embryogenesis. Based on genetic analyses, genes designated as ced‐1 to ced‐10 have been shown to function at different points of the apoptotic pathway. These genes are indispensable for the normal procession of apoptosis during early development, and they can be categorized into three different groups: survival factors, apoptotic factors, and phagocytosis mediators.

Figure 4. Figure 4.

hypothetical model for the regulation of functions of Bcl‐2–related proteins. The antiapoptosis function of Bcl‐2 could be mediated through interactions with other homologous proteins in the same family. A balance of the multiple pro‐apoptotic and anti‐apoptotic Bcl‐2‐proteins may determine a cell's susceptibility to apoptosis.

Figure 5. Figure 5.

Mechanism of action of ced‐3/caspases in apoptosis. The ced‐3/caspases promote apoptosis through degradation of specific cytoplasmic and nuclear components important for the maintenance of cellular homeostasis, and the multiple caspases present in different tissues may promote apoptosis in a collaborative or redundant manner. In a healthy cell, these enzymes are kept inactive by undefined mechanims, and the regulation of activities of these proteases may represent an important checkpoint for cellular control of apoptosis. These proteases may be kept inactive due to the lack of posttranscriptional modifications, and they become death promotors only after being activated. Alternatively, the function of these proteases may be blocked by endogenous inhibitors, for example, FLIP 302, and proteins functionally similar to specific viral inhibitors for ICE‐like proteases (for example, baculovirus p35 and cowpox virus CrmA). They become active when the inhibitor is removed.

Figure 6. Figure 6.

Regulatory cascade mediating the apoptosis‐promoting action of death domain–containing proteins. The death domain–containing receptors Fas antigen and tumor necrosis factor receptor 1 (TNF‐R1) may promote apoptosis by interacting with intracellular death domain–containing effectors including TRADD, MORT1/FADD, and RIP, followed by activation of caspases. Furthermore, studies on Drosophila have shown that the action of intracellular death domain–containing effectors, such as reaper, could be suppressed by specific inhibitors of apoptosis proteins (IAPs), suggesting that a balance between death domain–containing proteins and IAPs may serve as another checkpoint for the regulation of apoptosis.

Figure 7. Figure 7.

Multifactorial regulation of apoptosis in ovarian follicles. Based on studies on rat ovarian follicles, gonadotropins are the major survival factors which suppress ovarian cell apoptosis through the activation of cyclic adenosine monophosphate (cAMP)–dependent pathways. In addition, the apoptosis‐suppressing action of gonadotropins is augmented by multiple local factors, including interleukin‐1, estrogens, and insulin‐like growth factor‐1 (IGF‐1), which in turn promote cell survival by activating the cyclic guanosine monophosphate (cGMP)‐dependent pathway, nuclear estrogen receptor, and tyrosine phosphorylation, respectively.



Figure 1.

Diagrams illustrating sequences of structural changes during apoptosis and necrosis. Lower left: The nuclei of necrotic cells usually are associated with irregular chromatin clumping, and the plasma membrane dissolves following the loss of cell volume homeostasis. In addition, leakage of cellular contents to the environment leads to inflammatory reactions. Lower right: The nuclei of apoptotic cells are characterized by condensation and fragmentation of nuclear chromatin. Apoptotic cells also undergo volume shrinkage and become fragmented into membrane‐bound apoptotic bodies. These apoptotic bodies are phagocytosed by macrophages or neighboring cells before degradation within their lysosomes.



Figure 2.

Internucleosomal DNA fragmentation is a hallmark of apoptosis. Diagrams illustrate the superstructure of chromatin and sites cleaved during apoptosis (upper). In the lower panel, an autoradiogram shows the “ladder‐like” oligonucleosomal genomic DNA from ovarian cells undergoing apoptosis (A). Generation of “ladderlike” DNA fragments in apoptotic cells is the result of activation of endonucleases which cleave DNA at internucleosomal sites. In contrast, DNA from healthy cells shows no sign of fragmentation (H). Fragments of DNA are extracted from cells and labeled at 3′ ends with ddATP using terminal transferase, followed by fractionation in agarose gels and autoradiographic analysis.



Figure 3.

Cellular regulators of apoptosis during Caenorbabditis elegans embryogenesis. Based on genetic analyses, genes designated as ced‐1 to ced‐10 have been shown to function at different points of the apoptotic pathway. These genes are indispensable for the normal procession of apoptosis during early development, and they can be categorized into three different groups: survival factors, apoptotic factors, and phagocytosis mediators.



Figure 4.

hypothetical model for the regulation of functions of Bcl‐2–related proteins. The antiapoptosis function of Bcl‐2 could be mediated through interactions with other homologous proteins in the same family. A balance of the multiple pro‐apoptotic and anti‐apoptotic Bcl‐2‐proteins may determine a cell's susceptibility to apoptosis.



Figure 5.

Mechanism of action of ced‐3/caspases in apoptosis. The ced‐3/caspases promote apoptosis through degradation of specific cytoplasmic and nuclear components important for the maintenance of cellular homeostasis, and the multiple caspases present in different tissues may promote apoptosis in a collaborative or redundant manner. In a healthy cell, these enzymes are kept inactive by undefined mechanims, and the regulation of activities of these proteases may represent an important checkpoint for cellular control of apoptosis. These proteases may be kept inactive due to the lack of posttranscriptional modifications, and they become death promotors only after being activated. Alternatively, the function of these proteases may be blocked by endogenous inhibitors, for example, FLIP 302, and proteins functionally similar to specific viral inhibitors for ICE‐like proteases (for example, baculovirus p35 and cowpox virus CrmA). They become active when the inhibitor is removed.



Figure 6.

Regulatory cascade mediating the apoptosis‐promoting action of death domain–containing proteins. The death domain–containing receptors Fas antigen and tumor necrosis factor receptor 1 (TNF‐R1) may promote apoptosis by interacting with intracellular death domain–containing effectors including TRADD, MORT1/FADD, and RIP, followed by activation of caspases. Furthermore, studies on Drosophila have shown that the action of intracellular death domain–containing effectors, such as reaper, could be suppressed by specific inhibitors of apoptosis proteins (IAPs), suggesting that a balance between death domain–containing proteins and IAPs may serve as another checkpoint for the regulation of apoptosis.



Figure 7.

Multifactorial regulation of apoptosis in ovarian follicles. Based on studies on rat ovarian follicles, gonadotropins are the major survival factors which suppress ovarian cell apoptosis through the activation of cyclic adenosine monophosphate (cAMP)–dependent pathways. In addition, the apoptosis‐suppressing action of gonadotropins is augmented by multiple local factors, including interleukin‐1, estrogens, and insulin‐like growth factor‐1 (IGF‐1), which in turn promote cell survival by activating the cyclic guanosine monophosphate (cGMP)‐dependent pathway, nuclear estrogen receptor, and tyrosine phosphorylation, respectively.

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Sheau Yu Hsu, Aaron J. W. Hsueh. Apoptosis. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 559-588. First published in print 1998. doi: 10.1002/cphy.cp070120