View source for The Fas-mediated apoptosis pathway

&mdash;by [[Christoph Champ]]; 8-Mar-2004; ''Biochemistry, Winter 2004''

<blockquote><small>ABSTRACT</small>: Apoptosis, or cell suicide, is a complex and fascinating mechanism by which cells in multicellular organisms maintain healthy tissue as well as tissue morphogenesis. Since the term came into use (in 1972), this mechanism has been the subject of intense research. The promise of a possible therapeutic cure to cancer could be one of the secrets this complex mechanism will reveal in the near future.</blockquote>

=== Introduction ===

Programmed cell death (PCD), an evolutionarily conserved mechanism, is a natural process by which cells in apparently all multicellular organisms develop and maintain their health.<ref name=Steller>Steller H (1995). ''Science'', '''267''':1456-1462.</ref> In adult mammalian cells, PCD is important for removing damaged or infected cells (as in viral infection). It is thought to also be a mechanism for controlling the build up of mutations, as if they are allowed to be passed on to daughter cells they can lead to unregulated growth yielding cancerous tissue.<ref name=Perry>Perry DK (1999). Ceramide and apoptosis. ''Biochem Soc Trans'', '''27(4)''':399-404.</ref>

One of the most important and well-studied forms of PCD is apoptosis; also known as cell suicide. The word, apoptosis, is derived from a Greek word meaning "falling off" (as in leaves falling off trees) and was proposed for use in PCD by Kerr, Wyllie, and Currie in 1972.<ref name=Wyllie>Wyllie AH (1980). ''Nature'', '''284''':555-556.</ref> Under their definition, apoptosis referred to the "peculiar morphology of physiologically occurring cell death" and they argued that it was related to mitosis—for regulating cells—in opposite, yet corresponding ways.<ref name=Kerr>Kerr JFR, ''et al.'' (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. ''Br J Cancer'', '''26''':239-257.</ref>

Apoptosis can also be described as a process by which cells commit suicide through an intrinsic mechanism program.<ref name=Steller>Steller H (1995). ''Science'', '''267''':1456-1462.</ref> This process is characterized by morphological cellular changes and associated biochemical properties.<ref name=Wyllie>Wyllie AH (1980). ''Nature'', '''284''':555-556.</ref><ref name=Zakeri>Zakeri Z, ''et al.'' (1995). Cell death: programmed, apoptosis, necrosis, or other? ''Cell Death and Differentiation'', '''2''':87-96.</ref> The morphological changes in apoptosis include the distinct "blebbing" of the plasma membrane. The next phase is reduction of cytoplasmic volume (along with nuclear condensation) by cleavage of lamins and actin filaments. As the cells continue to shrink, they fragment into the characteristic apoptotic bodies, thereby allowing phagocytosis to occur by macrophages.<ref name=Steller>Steller H (1995). ''Science'', '''267''':1456-1462.</ref><ref name=Wyllie>Wyllie AH (1980). ''Nature'', '''284''':555-556.</ref> Caspases, a family of proteins, are some of the first molecules to be activated in apoptosis (discussed later). It is important that caspases are only activated during apoptosis because they breakdown or cleave key cellular substrates (e.g. structural proteins and DNA repair enzymes) used in normal cell function. It is these biochemical changes that cause the morphological changes observed.<ref name=Perry>Perry DK (1999). Ceramide and apoptosis. ''Biochem Soc Trans'', '''27(4)''':399-404.</ref>

Apoptosis is distinguished from necrosis in that it does not cause the dying cell to lyse or leak the cytoplasmic material (containing apoptotic agents) into neighboring cells, thereby minimizing and inflammatory response from the released proteases.<ref name=Steller>Steller H (1995). ''Science'', '''267''':1456-1462.</ref><ref name=Wyllie>Wyllie AH (1980). ''Nature'', '''284''':555-556.</ref> Apoptosis is also the primary mechanism by which tissue morphogenesis occurs (i.e. separating the tissue linking the digits on hands, or thymus maturation).<ref name=Steller>Steller H (1995). ''Science'', '''267''':1456-1462.</ref><ref name=Thompson>Thompson CB (1995). ''Science'', '''267''':1456-1462.</ref> It is also important that apoptosis is not inhibited or it may lead to diseases through viral infection or cancer.<ref name=Thompson>Thompson CB (1995). ''Science'', '''267''':1456-1462.</ref> Apoptosis is, however, highly regulated as discussed below.

=== Mechanisms ===

There are two major mechanisms of PCD in mammals: Death-receptor mediated and mitochondria mediated. The mitochondrial pathway can be further divided into death receptor dependent and death receptor independent. In both cases, cytochrome c is released from the intermembrane space of mitochondria. However, the "dependent" pathway requires activation from a death signal. This paper will focus on the death-receptor mediated pathway. There are various death receptors and their associated ligands. The list includes: TNF-R1, Fas, DR-3, DR-4, and DR-5. With all of these receptors, binding of their associated ligands allows for the recruitment of downstream activators or signalers. The end result is cell death. This paper will focus on the Fas-mediated pathway.<ref name=Fesik>Fesik SW (2000). Insights into programmed cell death through structural biology. ''Cell'', 103''':273-282.</ref>

The death-inducing signaling complex: The Fas-mediated pathway of apoptosis has received much attention primarily because this pathway proceed rapidly through cell death and has various homologues; such as tumor necrosis factor-R1 (TNF-R1).<ref name=Adrain>Adrain C, Martin SJ (2001). The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. ''TRENDS in Biochemical Sciences'', '''26''':390-397.</ref> The Fas receptor is a transmembrane death receptor and its associated ligand is FasL. Fas has an adaptor protein that attaches to the intracellular side of the receptor. Fas-associated death domain (FADD) is its name and it links pro-caspase-8 to Fas after activation from FasL. The Fas, FADD, and pro-caspase-8 complex is called a death-inducing signaling complex (DISC).<ref name=Fesik>Fesik SW (2000). Insights into programmed cell death through structural biology. ''Cell'', 103''':273-282.</ref>

The caspase cascade: Caspases (cysteine aspartic acid-specific proteases) are part of a family of cysteine proteases. There are around 14 known mammalian caspases and a subset of these are involved in apoptosis and will be considered here. This subset can be divided into initiator (upstream) and effector (downstream) caspases. The initiator caspases include caspase-8, which is the result of proteolytic processing and autoactivation of pro-caspase-8.<ref name=Salvesen>Salvesen GS, Dixit VM (1999). Caspase activation: The induced-proximity model. ''Proc Natl Acad Sci USA'', '''96''':10964-10967.</ref> Caspase-8, which has been released from DISC, is now free to act upon the effector caspases, primarily caspases-1, -3, and -7. These effectors, also known as "executioners", are part of the caspase cascade. The caspase cascade is the central part of this apoptotic process and leads to proteolysis of targeted proteins. This proteolysis is responsible for destroying cellular structures and causes the apoptotic phenotype as described earlier.<ref name=Adrain>Adrain C, Martin SJ (2001). The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. ''TRENDS in Biochemical Sciences'', '''26''':390-397.</ref>

Regulation of Fas-mediated apoptosis: In order to prevent the partially active initiator caspases from inducing apoptosis without the proper signals, healthy cells have produced caspase inhibitors. These inhibitors are endogenous and act on not only the initiators but also the effectors or executioners. Inhibition occurs at the three main points of Fas-mediated apoptosis: The initial signalling on the DISC, at the caspase cascade, and prior to proteolysis.<ref name=Fesik>Fesik SW (2000). Insights into programmed cell death through structural biology. ''Cell'', 103''':273-282.</ref><ref name=Adrain>Adrain C, Martin SJ (2001). The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. ''TRENDS in Biochemical Sciences'', '''26''':390-397.</ref><ref name=Salvesen>Salvesen GS, Dixit VM (1999). Caspase activation: The induced-proximity model. ''Proc Natl Acad Sci USA'', '''96''':10964-10967.</ref>

The caspase cascade is inhibited by the presence of the inhibitor of apoptosis family (IAPs). Members of this family (i.e. XIAP in mammals) bind to caspases-3 and -7, thereby inhibiting their function.<ref name=Salvesen>Salvesen GS, Dixit VM (1999). Caspase activation: The induced-proximity model. ''Proc Natl Acad Sci USA'', '''96''':10964-10967.</ref>

Other regulators act after the caspase cascade but prior to proteolysis. Inhibition at this step is achieved by members of the Bcl-2 family of proteins. Members of this family involved in antiapoptotic activity include Bcl-2 and Bcl-XL. These act by inhibiting the release of cytochrome c from the mitochondria (pathway not discussed here). However, this step in the pathway can also be promoted by the Bax and Bak proteins. Both pro- and antiapoptotic proteins interact with one another and even regulate each other’s effect on the pathway. The precise mechanism of these actors needs further study and there is even conflicting evidence as to their role in this process.<ref name=Salvesen>Salvesen GS, Dixit VM (1999). Caspase activation: The induced-proximity model. ''Proc Natl Acad Sci USA'', '''96''':10964-10967.</ref>

Regulation gone wrong: Of course, since apoptosis is a powerful mechanism, when its regulation goes wrong there can be dire consequences. If harmful genomic mutations build up and those cells are not removed, disease can result. The same is true of virally infected cells. However, the majority of attention given to apoptosis has been is possible role in cancer.<ref name=Steller>Steller H (1995). ''Science'', '''267''':1456-1462.</ref><ref name=Fesik>Fesik SW (2000). Insights into programmed cell death through structural biology. ''Cell'', 103''':273-282.</ref><ref name=Adrain>Adrain C, Martin SJ (2001). The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. ''TRENDS in Biochemical Sciences'', '''26''':390-397.</ref><ref name=Salvesen>Salvesen GS, Dixit VM (1999). Caspase activation: The induced-proximity model. ''Proc Natl Acad Sci USA'', '''96''':10964-10967.</ref>

=== Discussion ===

Although there is much to be learned about the mechanisms of apoptosis, one thing is clear: It is a fundamental characteristic of healthy tissue. Failure of cell death (by mutation, infection, or otherwise) can, ironically, lead to the death of the organism. There is promise for future therapeutic control of cancer itself if we can fully understand the mechanisms of apoptosis.

== References ==
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