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Stem Cells, Vol. 17, No. 5, 306-313, September 1999
© 1999 AlphaMed Press

Special Feature

Apoptosis

Lyonel G. Israels, Esther D. Israels

University of Manitoba, Manitoba Cancer Treatment and Research Foundation, Manitoba, Canada

Dr. Lyonel G. Israels, Department of Medicine, University of Manitoba, 100 Olivia Street, Winnipeg, Canada R3E 0V9.


   Abstract
Top
 Abstract
Introduction
 Gene Regulation of Apoptosis
 Cytotoxic Regulation of...
 Removal of Apoptotic Bodies
 Clinical Correlates
 References
 
Mechanisms in Hematology is a book with an accompanying interactive CD-ROM designed to assemble basic concepts that underlie clinical understanding and progress. It is presented as a concise text with a series of diagrams that distill diffuse information into a compact form. The interactive CD, in particular, brings many of the processes "to life" as details of the more complex pathways are conveyed in clear visual images. The text begins with the basic molecular biology that underlies hematological and oncological physiology/pathology—cell signaling, adhesion molecules, and apoptosis. This is followed by sections, among others, on hematopoiesis, iron, B12, and folate metabolism, neutrophil function, immunoproteins, chemotherapy, and coagulation. With the permission of the authors and publisher, Stem Cells has reproduced the section on apoptosis, which we think our readers will enjoy.

This is the way the world ends
Not with a bang but a whimper.

"The Hollow Men"—T. S. Eliot


   Introduction
Top
 Abstract
 Introduction
Gene Regulation of Apoptosis
 Cytotoxic Regulation of...
 Removal of Apoptotic Bodies
 Clinical Correlates
 References
 
Cells die by two primary processes: A) necrosis, in which the release of intracellular proteases and lysozymes induce an inflammatory response, or B) apoptosis, where the cell remnants quietly disappear as they are phagocytosed by surrounding cells.

Cell death by necrosis usually follows major pathological acute injury such as hypoxia, hyperthermia, viral invasion, exposure to various exogenous toxins, or attack by complement. Necrosis is characterized by early mitochondrial swelling and failure, dysfunction of the plasma membrane with loss of homeostasis, cell swelling, and rupture. The loss of cell membrane integrity with release of cell contents, including proteases and lysozymes, induces an inflammatory response with cytokine release by the surrounding macrophages as they mop up the damaged cells and begin the process of repair.

The major physiological mechanism of cell removal is apoptosis—a Greek descriptive term for falling leaves or petals. Apoptosis describes the process by which cells are "silently" removed under normal conditions when they reach the end of their life span, are damaged, or superfluous. It is a general tissue phenomenon necessary for development and homeostasis: elimination of redundant cells during embryogenesis, cell atrophy upon endocrine withdrawal or loss of essential growth factors or cytokines, tissue remodelling and repair, and removal of cells that have sustained genotoxic damage. Externally induced apoptosis occurs in thymocytes exposed to corticosteroids and in immune-mediated tumor-cell kill. Cells characterized by a normally short life span, such as neutrophils, undergo apoptosis as an intrinsic pre-programmed suicidal event. Examples of apoptotic cell removal are: A) erythroid precursors upon withdrawal of erythropoietin; B) removal of neutrophils outside the inflammatory response; C) clonal selection of lymphocytes in the thymus, and D) cell kill by anti-neoplastic chemotherapeutic agents. Normal apoptotic cell removal and cell replacement in tissue remodeling is estimated at some 1 x 1011 cells per day—equivalent to the turnover of an adult's total body weight every 18 to 24 months.

Morphologically, in cells undergoing apoptosis there is ruffling, blebbing, and condensation of the plasma and nuclear membranes, and, subsequently, aggregation of nuclear chromatin. Mitochondria and ribosomes retain their gross structure and at least partial function. There is disruption of the cytoskeletal architecture; the cell shrinks and then fragments into a cluster of membrane-enclosed "apoptotic bodies" that are rapidly ingested by adjacent macrophages or other neighboring phagocytic cells. As these apoptotic bodies induce no significant cytokine release by the phagocytic cell, the process progresses without concomitant induction of an inflammatory response (Fig. 1Go).



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  		Figure 1. Pathways to apoptosis.

 
The hallmark of the end stage of apoptosis is endonuclease cleavage of DNA in the internucleosomal linker regions, yielding 180 base-pair fragments. Separation of these fragments by agarose gel electrophoresis reveals the characteristic DNA ladder pattern of apoptosis; this is in contrast to the smudge pattern seen with cell necrosis that confirms the presence of fully degraded DNA. Apoptosis is an active energy-dependent process requiring RNA and protein synthesis. It can be inhibited either by actinomycin D blockade of RNA synthesis or by cyclohexamide interference with protein synthesis—an indication that these cells both activate and participate metabolically in their own death.

The process may be set in motion by: A) genes responding to DNA damage; B) death signals received at the cell membrane (Fas ligand), or C) proteolytic enzymes entering directly into the cell (granzymes). The final events, evidenced by the changes in cell structure and disassembly, are the work of specific proteases (caspases).


   Gene Regulation of Apoptosis
Top
 Abstract
 Introduction
 Gene Regulation of Apoptosis
Cytotoxic Regulation of...
 Removal of Apoptotic Bodies
 Clinical Correlates
 References
 
Regulation of apoptosis is highly conserved, with many of the same gene control processes present in species from nematodes to humans. Although the death signal may be regulated by gene expression, the process can be set in motion by diverse stimuli such as genotoxic damage (e.g., chemotherapy, radiation), or deprivation of cytokines (e.g., erythropoietin). DNA single- or double-strand breaks or nucleotide deprivation activates a cascade beginning with the DNA-binding transcription factor p53 whose targets induce either growth arrest or entry of the cell into the apoptotic pathway.

The Role of p53
Cell injury resulting in genotoxic events activates p53, a transcription regulator gene. The p53 protein product is a regulator of DNA transcription; it binds directly to DNA, recognizes DNA damage (single- or double-strand breaks), and mediates at least two important cellular events: it can induce cell cycle arrest in G1 or it can promote apoptosis. If cellular damage is "considered" reparable, p53-induced cell cycle arrest allows time for DNA repair. With more extensive damage, to prevent the cell with an impaired DNA sequence from proliferating as a defective or malignant clone, p53 moves the cell into the apoptotic pathway.

p53 protein, normally, is present in the cytosol in low concentration. It is negatively regulated by another transcription factor, MDM2 (murine double minute 2), which downregulates p53 transcription, and binds to p53 protein, decreasing its activity and accelerating its degradation. In the event of DNA damage, p53 gene induction is accompanied by increased synthesis and phosphorylation of p53. Phosphorylation has profound consequences—it renders the protein more active and reduces its binding and inactivation by MDM2, thereby doubling its half-life (T/2). As a result, p53 protein activity may increase a hundredfold.

p53 promotes cell cycle arrest in late G1 at a restriction point guarded by the retinoblastoma (Rb) protein. Phosphorylation of Rb permits the cell to pass through this cell-cycle transition point—the cell now irreversibly committed to exit G1 and proceed unhindered into S phase. p53 exerts control of the cell cycle through upregulation of p21, an inhibitor of the cyclin-dependent kinases (CDKs) responsible for moving the cell through G1. The cyclinD/CDK4 complex normally promotes phosphorylation of Rb. Hypophosphorylated Rb binds E2F, a transcription factor required for passage through the G1 restriction point; upon Rb phosphorylation E2F is released, translocates to the nucleus, and induces transcription of a number of proteins, prompting the cell to move into S phase (Fig. 2Go). (The Rb family of proteins, referred to as "pocket proteins," associates with and blocks the activity of a number of transcription factors, specifically, members of the E2F family; phosphorylation of these pocket proteins in late G1 is associated with loss of their growth-suppressive activities). Cell injury results in increased expression of p53 followed by p53-regulated induction of p21, and consequently, by the inhibition of cyclinD/CDK4 phosphorylation of Rb. Maintenance of Rb in its active hypophosphorylated state holds the cell in G1, allowing time for repair. In the event that DNA damage is more severe and non-reparable, p53 performs its alternate role of moving the cell into apoptosis through the Bax/Bcl-2 pathway.



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  		Figure 2. The p53-Rb axis in the regulation of the cell cycle.

 
Bcl-2/Bax
A major downstream regulation of the apoptotic death signal resides with the bcl-2/bax gene family. Sixteen members of this family have been recognized: some (including Bcl-2 and Bcl-XL) are apoptosis-inhibitory proteins, others (such as Bax, Bad, and Bid) are promoters of apoptosis. Areas of commonality of structure allow these proteins to homo- and hetero-dimerize. A high expression of the Bax group promotes apoptosis; a high expression of the Bcl-2 group inhibits apoptosis—p53 probably functions by regulating the ratios of the Bax/Bax, Bax/Bcl-2, and Bcl-2/Bcl-2 groups.

Mitochondria are double-walled organelles; the Bcl-2 group of proteins resides on the outer mitochondrial membrane oriented toward the cytosol—they govern ion transport and protect against breaches in the membrane. The Bax proteins reside in the cytosol; upon receipt of the apoptotic signal, Bax proteins migrate and bind to the mitochondrial membrane "permeability transition pore," inducing loss of selective ion permeability. As a result of the membrane changes, there is release into the cytosol of the contents of the intermembrane space, including cytochrome c and apoptosis-inducing factor (AIF): AIF moves directly to the nucleus, where it produces chromatin condensation and nuclear fragmentation, while cytosolic cytochrome c sets in motion the terminal events of apoptosis. Cytochrome c is the only known activator of the cytoplasmic protein Apaf-1 (apoptotic protease activating factor -1); cytochrome c binding to Apaf-1 is necessary for the subsequent activation of procaspase-9. Caspase-9 activates downstream caspases, including procaspase-3, responsible for the cytological changes characteristic of apoptosis (Fig. 3Go).



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  		Figure 3. The role of mitochrondria in apoptosis.

 
The Caspases
As cytochrome c is released into the cytoplasm, it fires the enzyme system responsible for the terminal steps in apoptosis—the caspases. The caspases are cysteine proteases (with cysteine in their active center); the constitutively expressed zymogens (inactive precursors) are present in the cytosol. Thirteen caspases have been identified; ICE (interleukin 1ß converting enzyme), a protease first described as a promoter of inflammation, has been identified as a member of this family and renamed procaspase-1. Caspases activate other procaspases in a sequential cascade (reminiscent of the complement or the coagulation sequence); they are also activated by self-cleavage. Caspases are classified as either "initiators" (caspase 2, 8, 9, 10), or "effectors" (caspase 3, 6, 7) of proteolysis—the effector caspases activated downstream of the initiator caspases. Proteolysis by caspases is restricted and limited: peptide cleavage occurs only after specific aspartic acid residues (thus c-asp-ases), producing disassembly of the protein—not general proteolysis. Caspase activity results in: cleavage of cytoskeletal proteins, disruption of the nuclear membrane, disruption of cell-cell contact, and the freeing of the DNA nuclease (CAD, caspase-activated deoxyribonuclease) from its associated protein inhibitor (ICAD) to allow DNA fragmentation. The restricted proteolysis results not in cellular lysis but in membrane-bound sealed apoptotic bodies. These irreversible proteolytic events are responsible for the morphological changes characteristic of apoptotic cells and the DNA agarose gel ladder pattern that is the signature of apoptosis. The caspases may, in addition, act on mitochondrial membranes with further release of cytochrome c and of some intramitochondrial procaspases. A family of caspase inhibitors, IAPs (inhibitors of apoptosis), selectively inhibit effector caspases, blocking the apoptotic process; they are overexpressed in many malignant cells. The IAP family also inhibits apoptosis through non-caspase mechanisms: by modulation of transcription factors and by involvement in cell-cycle control.


   Cytotoxic Regulation of Apoptosis
Top
 Abstract
 Introduction
 Gene Regulation of Apoptosis
 Cytotoxic Regulation of...
Removal of Apoptotic Bodies
 Clinical Correlates
 References
 
The Granzyme System
This secretory apoptotic pathway is operative in removing pathogen-infected cells and tumor cells. Perforins and granzymes are proteins contained within the cytoplasmic secretory granules of cytotoxic lymphocytes (CTLs) and natural killer (NK) cells. Upon CTL receptor-mediated binding to a target cell, perforins are secreted and inserted into the membrane of the target cell, where they assemble into a circular membrane-spanning pore similar to the membrane attack complex (MAC) of complement; (this resemblance includes immunological cross-reactivity between perforin and MAC). The perforin pore induces a rapid increase in cytosolic calcium. The co-secreted serine protease granzyme B enters the target cell within a secretory vesicle by receptor-mediated endocytosis. The internalized perforin protein frees granzyme B from its vesicle. Granzyme B now rapidly triggers procaspase activation with subsequent DNA fragmentation and apoptosis. A second secretory-granule protease granzyme A also acts synergistically with perforin in the apoptotic process—apparently, through a caspase-independent pathway.

Fas—Fas Ligand
The alternative non-secretory mechanism of apoptosis is through activation of "death receptors" expressed on the cell membrane. Fas (CD95), a cell-surface receptor and a member of the tumor necrosis factor receptor (TNF-R) family, is a transducer of the apoptotic signal; it is expressed in a wide range of cell types: lymphoid cells, hepatocytes, some tumor cells, as well as in lung and myocardium. Fas ligand (FasL) is a member of the TNF family; its expression is more restricted: it is found on cytotoxic T cells and natural killer cells. FasL, by binding to and cross-linking the Fas receptor, sets the apoptotic process in motion (Fig. 4Go). This mechanism plays a significant role in: removal of activated T cells at the end of an immune response, deletion of virus-infected target cells, killing of tumor cells, and destruction of cells in numerous pathological states.



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  		Figure 4. Fas ligand and TNF-mediated apoptosis.

 
Fas ligand and tumor necrosis factor (TNF) produce apoptosis in an analogous fashion—FasL through the Fas receptor protein, and TNF by binding to the TNF receptor (TNFR-1). Upon binding of their respective ligands, the receptors assemble into trimeric complexes. The cytoplasmic tail of each receptor contains a so-called death domain (DD) that interacts with a cytoplasmic protein: the cytoplasmic portions of the Fas trimer interacts with FADD (Fas associating protein with a death domain), and the cytoplasmic tails of TNFR-1 with TRADD (TNFR-associated death domain protein) and RIP (receptor-interacting protein). These latter proteins, also containing DD, have a direct pathway to apoptosis through recruitment and activation of procaspase-8. Activated caspase-8 subsequently activates downstream effector caspases.


   Removal of Apoptotic Bodies
Top
 Abstract
 Introduction
 Gene Regulation of Apoptosis
 Cytotoxic Regulation of...
 Removal of Apoptotic Bodies
Clinical Correlates
 References
 
Phospholipid (PL) asymmetry in the lipid bilayer is a feature of the cell membrane. The phospholipids are distributed asymmetrically, with phosphatidylserine (PS) and phosphatidylethanolamine (PE)—the anionic PLs—confined to the inner bilayer, and phosphatidylcholine (PC) to the outer bilayer. In normal cells, this asymmetry is actively maintained by an ATP-dependent translocase. During apoptosis, either failure of the ATP translocase or activation of another enzyme system (scramblase) results in PS relocation to the surface bilayer. Relocation of PS to the outer leaflet of the apoptotic body provides a signal for phagocytic uptake by macrophages and neighboring "non-professional" phagocytic cells.


   Clinical Correlates
Top
 Abstract
 Introduction
 Gene Regulation of Apoptosis
 Cytotoxic Regulation of...
 Removal of Apoptotic Bodies
 Clinical Correlates
References
 
Apoptosis in the Hematopoietic System
Both hematopoietic cell production and elimination are regulated by apoptosis. The maintenance of the erythropoietic stem cells (BFU-Es and CFU-Es) is dependent upon the presence of erythropoietin (EPO); withdrawal of EPO results in apoptosis of these red cell precursors.

Endogenously-mediated apoptosis is exemplified by the neutrophil. Following development and maturation in the marrow, this cell is resident in the blood stream for approximately 12 h. Some disappear into the lung and gastrointestinal tract and are lost from mucosal surfaces. Many enter the tissue spaces where, within one to two days in the absence of an inflammatory focus, they spontaneously undergo apoptosis and are taken up by macrophages.

Lymphocyte death, in contrast, is mediated by exogenous events. Those thymocytes in which gene rearrangement fails to code and express the T-cell receptor are particularly sensitive to glucocorticoid activation of their apoptotic pathway. Autoreactive thymocytes, because they pose a threat of autoimmune disease, are removed by CTLs. The apoptotic event is initiated through: A) the secretory perforin/granzyme system and B) the non-secretory Fas/Fas ligand system. Both of these mechanisms are operative in CTL removal of non-functional or self-reactive T and B cells, as well as tumor cells and virus-infected cells. Binding of the Fas ligand or entry of granzyme B triggers procaspase activation.

Apoptosis and Malignant Disease
An inappropriate increase in cell number is one of the hallmarks of malignant cell transformation. It may be due to either increased proliferation or decreased cell death. Decreased apoptosis may result from an absent or mutated form of the tumor suppressor gene p53 or Rb (present in 50% and 40% of human tumors, respectively), from increased expression of Bcl-2, or a decrease in Bax. Deregulation and overexpression of Bcl-2 occurs with the translocation of the bcl-2 gene from chromosome 18 into the Ig locus on chromosome 14. This translocation is associated with low-grade follicular non-Hodgkin's lymphoma—a disease characterized not by a rapidly proliferating tumor cell population but by the gradual accretion of slow-growing lymphoma cells. (The bcl-2 gene was first identified in this B-cell lymphoma.) Overproduction of Bcl-2 protein is also associated with drug resistance in non-Hodgkin's lymphomas and chronic lymphocytic leukemia (CLL). In addition, a low apoptotic rate with accumulation of lymphoid cells in CLL has been attributed to the weak expression of Fas receptor on the cell membrane. Many chemotherapeutic and cytotoxic agents used in the treatment of malignant disease function by activating apoptosis—some by direct procaspase activation, others by DNA damage and p53 upregulation. Inhibitors of apoptosis (IAPs) that upregulate Bcl-2 or inhibit caspases may play a role in tumor growth and drug resistance.

Kindreds have been identified with mutations in the Fas-encoding gene resulting in a dysfunctional Fas/FasL system. The region of the gene most frequently mutated is the death domain in the cytoplasmic tail of Fas. These defects in functional Fas give rise to a non-malignant accumulation of T lymphocytes with lymphadenopathy, splenomegaly, hepatomegaly, and associated autoimmune hemolytic anemia and thrombocytopenia—designated as "autoimmune lymphoproliferative syndrome" (ALPS).

Apoptosis and Infectious Disease
An imperative in the evolutionary process of survival for viruses and some obligate bacterial pathogens is the preservation of the host cell. It is to be expected then that these organisms will inhibit apoptosis. Examples of this interference or abrogation of the apoptotic process include organisms that: A) encode a protein similar to Bcl-2 (adenovirus); B) promote expression of Bcl-2 (Epstein-Barr virus); C) encode a protease inhibitor that inactivates procaspases 1 and 8 (cowpox), and D) interfere with mitochondrial cytochrome c release into the cytosol (chlamydia).

Diseases Mediated by Increased Apoptosis
Disappearance of cells by apoptosis is central to a number of diseases as illustrated by: A) AIDS, which is characterized by depletion of CD4+ T cells; these cells may die in the absence of intracellular infecion by virus. Both virus and the viral protein gp120 have a high affinity for CD4 antigen; binding of virus or its gp120 protein to CD4 helper cells, without the simultaneous engagement of the MHC class II complex, triggers apoptosis. B) The disappearance of neurons in Alzheimer's disease, motor neuron disease, and Parkinson's disease. C) The death of cells in proximity to an area of acute infarction in the brain or in the heart. Tissue damage in myocardial infarction or in stroke extends beyond the infarcted area of initial cellular destruction as adjacent cells undergo apoptosis. It is postulated that therapeutic use of inhibitors of apoptosis (Bcl-2 or caspase inhibitors) might confine and reduce the amount of tissue loss in proximity to the infarct. D) The overexpression of Fas in hepatocytes infected with hepatitis C renders these cells vulnerable to destruction by cytotoxic T lymphocytes. E) Hashimoto's thyroiditis: thyroid cells in this disease express both Fas and Fas ligand—as a result, they may destroy one another under the stimulus of IL-1, which induces an increase in Fas expression. F) Tumor cells that constitutively express FasL on their membrane or secrete FasL, may escape cytotoxic T-cell destruction; FasL activates the T-cell Fas pathway, destroying T cells that have infiltrated the tumor, thus eliminating these anti-tumor cytotoxic lymphocytes.


   Acknowledgments
 
Adapted and reproduced from Mechanisms in Hematology courtesy of Core Health Services, Inc., Concord, Ontario, Canada.


   References
Top
 Abstract
 Introduction
 Gene Regulation of Apoptosis
 Cytotoxic Regulation of...
 Removal of Apoptotic Bodies
 Clinical Correlates
 References
 

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