Pakistan Journal of Medical Sciences

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Volume 23

October - December 2007 (Part-II)

Number  6


 

Abstract
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Apoptosis at a glance: Death or life?

Mohammad Derakhshan1

ABSTRACT

Apoptosis or programmed cell death that is genetically regulated is a process for killing cells. It is essential for the normal function of organisms and therefore variety of diseases including autoimmunity and cancer result from any defect in this physiological process. Two pathways are responsible for signalling apoptosis: intrinsic or mitochondrial pathway and extrinsic or death receptor pathway. As a final result of this process, cell destruction activated by a family of cysteine proteases (caspases) takes place. This article summarizes current knowledge of apoptosis.

Key words: Apoptosis, Caspases, Mitochondria.

Pak J Med Sci    October - December 2007 (Part-II)    Vol. 23 No. 6    979-982


1. Mohammad Derakhshan, MD. PhD,
Associate Professor of Virology,
Department of Virology and Buali Research Institute,
Mashhad University of Medical Sciences (MUMS),
Mashhad – Iran.

Correspondence

Mohammad Derakhshan, MD. PhD
Email: derakhsham@mums.ac.ir
m.derakhshanmd@yahoo.com

* Received for Publication: February 20, 2007
* Revision Received: February 27, 2007
* Revision Accepted: October 16, 2007


INTRODUCTION

Apoptosis was first described by the Australian pathologist; John Kerr in 1965. He recognized a distinct form of cell death and named it "shrinkage necrosis". In 1972 the term apoptosis was introduced by John Kerr, Alastair Currie and Andrew Wyllie for what was now recognized as a morphologically typical, dynamically controlled form of cell death.1 The term apoptosis was suggested by James Cormac, professor of classical Greek at the University of Aberdeen and is derived from the Greek meaning "dropping off" and so signifies the dropping of leaves from the tree.2 Apoptosis or programmed cell suicide is a genetically regulated, active process that eliminates cells in both physiological and pathological processes. It is characterized by profound and distinct changes in cellular architecture leading to self destruction.3,4 It is a normal physiological response to specific suicide signals, or lack of survival signals. It has an essential role in shaping tissues during development, endocrine dependent atrophy and normal cell turnover in many tissues.5 It also limits the accumulation of harmful cells, such as self-reactive lymphocytes, virus-infected cells and tumour cells.6

Significant progress has been made in defining the mechanisms of apoptotic control underlying the pathophysiology of viral infections, autoimmune diseases, neurodegenerative disorders, immunologic deficiencies, and cancers. In fact apoptosis itself plays a key role in the development of the immune system, controlling the immune response; deleting immune cells recognizing self-antigens, and cytotoxic killing.

Defects in the regulation of apoptosis in the immune system may lead to autoimmune disease.7 In many virus-infected cells, virus replication will kill the cell, releasing virus particles. Since the cell is doomed anyway, it is in the host’s interest to destroy the infected cell sooner rather than later and thus prevent or minimize virus replication. In an immune individual this may be accomplished by the active immune response generating cytotoxic T cells or antibody dependent cell killing. However, apoptosis may be seen as an innate equivalent of this process that may well have predated the development of the more active immunological mechanisms in evolutionary terms.

Typically apoptotic cell death proceeds morphologically with several characteristic features such as chromatin margination and nuclear fragmentation. Several endonucleases such as Caspase-activated DNAse (CAD), lysosomal DNAse II have been found responsible for DNA fragmentation in apoptotic cells.8 Apoptotic cells shrink and finally give rise to the formation of apoptotic bodies, which are small membrane-bound blebs containing the cell’s contents.9,10 The apoptotic bodies are taken up by macrophages and degraded. This avoids the release of soluble cell contents that would otherwise lead to inflammation. The apoptotic process can therefore be divided into three morphological phases: phase one includes changes such as cell shrinkage and extensive chromatin condensation. Phase two includes formation of vacuoles inside the cells and cell fragmentation; phase three includes formation of apoptotic bodies.11

It is important to distinguish between necrosis and apoptosis; Necrosis is considered to be a passive event that is largely dependent on the type of the external injurious agent. After necrosis there are many changes in the cell structure. The most important changes are: clumping of the chromatin, swelling/rupture of mitochondria and lysis of the plasma membrane. Cell contents spill out and a general inflammatory response is triggered. In contrast, the outer membrane of the cell remains intact in apoptosis and no inflammatory reaction is provoked, leaving the neighboring cells and tissues unharmed. Moreover, the distinct morphological features in apoptosis, i.e. chromatin margination, nuclear fragmentation, cellular shrinking and formation of apoptotic bodies do not take place in necrosis.12 Intracellular ATP levels have been implicated as an important factor in the cell’s decision to die by apoptosis or necrosis; apoptosis is ATP-dependent but necrosis is associated with depletion of intracellular ATP indicating that this process does not require ATP.13-17 There is accumulating evidence that apoptosis and necrosis are related phenomena18 and in tumours, increased numbers of apoptotic cells are seen adjacent to necrotic areas.19

A family of cysteine proteases (called caspases), which are present in most cells are responsible for apoptosis. Several members of this family have been identified and these are termed caspase-1 to caspase-14.20 The first known protease of the caspase family is interleukin-1 b-converting enzyme (ICE, caspase-1).21 They are themselves activated by specific proteolytic cleavage and then cleave their substrates on the carboxyl side of aspartate residues. Activation of these caspases is the main step in cells undergoing apoptosis and occurs by sequential proteolytic events that cleave the single peptide precursor into large and small fragments.22 The crystal structures of mature caspase-1 and caspase-3 suggest that the active caspases are composed of tetramers consisting of two molecules of each subunit.23

There are two major pathways involved in programmed cell death: mitochondrial (or intrinsic) pathway and the death receptor (or extrinsic) pathway.24 These are illustrated in Figure-1. In the extrinsic pathway or Fas mediated apoptosis, the apoptotic signal is initiated by direct ligand-mediated trimerization of death receptors at the cell surface.25 There are many known death receptors and among them the most widely studied is CD95 (cluster of differentiation 95, Fas).26

Death receptors are a family of type I trans-membrane proteins, which belong to the tumor necrosis factor (TNF) family27 and are expressed in several cell types. In this pathway the apoptotic process is begun by the binding of ligand (Fas-L) or anti-Fas antibodies to CD95/Fas, which then allows it to bind to the death domain of cytoplasmic proteins FADD (Fas associating death domain). This leads to the activation of procaspase-8. Active caspase-8 will activate procaspases-3, -7 and -6. Eventually this leads to the proteolysis events that are characteristic of the destruction of the cell.27,28 In the intrinsic pathway, cytochrome c is released from the mitochondria. Also Apaf-1 (apoptotic protease activating factor-1) binds to dATP or ATP, oligomerizes and binds to cytochrome c. This complex activates procapase-9. Active caspase-9 binds to this complex and forms an apoptosome with a size about 700 KDa. Subsequently caspases-3, 7 and possibly 6 are activated by the apoptosome.29 The activation of caspases-3, -6 and -7, whether by the direct action of caspase-8 or the formation of a functional apoptosome, is the final common pathway in programmed cell death. Approximately 40 proteins are cleaved by caspases in cells undergoing apoptosis.30

The apoptotic process is regulated by the protein superfamily Bcl-2 (B-cell lymphoma 2), of which at least 15 family members have been identified in mammalian cells and several others in viruses.31 These proteins have a major role in preventing cell death mediated by most stimuli. In conclusion for the apoptotic process, it is clear that the health of multicellular organisms depends not only on the body’s ability to produce new cells but also on controlled cell death. Changes in cell survival contribute to the pathogenesis of disorders such as cancers, many viral infections, neuropathies and immunopathies. In other words, apoptosis permits the safe disposal of cells when they have fulfilled their intended biological function.

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10. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980;284(5756):555-6.

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12. Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994;73(8):2013-26.

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14. Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 1997; 57(10):1835-40.

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19. Arai E, Katayama I. Role of apoptosis in spontaneous regression of peripheral T-cell lymphoma arising in the skin or subcutis. Hum Pathol 1997;28(4):472-7.

20. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998;281(5381):1312-16.

21. Thornberry NA, Bull HG, Calaycay JR. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992;356(6372):768-74.

22. Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999;68:383-424.

23. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997;22(8):299-306.

24. Kaufmann SH, Hengartner MO. Programmed cell death: alive and well in the new millennium. Trends Cell Biol 2001;11(12):526-34.

25. McWhirter SM, Pullen SS, Holton JM. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proc Natl Acad Sci USA 1999;96(15):8408-13.

26. Wallach D, Varfolomeev EE, Malinin NL. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 1999;17:331-67.

27. Ekert PG, Vaux DL. Apoptosis and the immune system. Br Med Bull 1997;53(3):591-603.

28. Van LG, Saelens X, van GM. The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ 2002;9(10):1031-42.

29. Gottlieb RA. Role of mitochondria in apoptosis. Crit Rev Eukaryot Gene Expr 2000;10(3-4):231-9.

30. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997;22(8):299-306.

31. Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science 1998;281(5381):1322-6.


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