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Caspases are normally suppressed by IAP (inhibitor of apoptosis) proteins (see "Controlling the Caspases", by Stephen W. Fesik and Yigong Shi, in Science, Vol. 294, No. 5546, p. 1477, November 16, 2001). When a cell receives an apoptotic stimulus, IAP activity is relieved after SMAC (Second Mitochondria-derived Activator of Caspases, or its mouse homolog, called DIABLO), a mitochondrial protein, is reléased into the cytosol. SMAC binds to IAPs, and in doing so "inhibits the inhibitors", effectively preventing them from arresting the apoptotic process.

But before we go on to a short description of how SMAC is reléased, lets take a look at two well-studied extrinsically induced apoptotic processes: the TNF and the Fas pathways. Keep in mind, however, that both activating and inhibiting factors are present at éach step of these pathways.

Tumor necrosis factor (TNF), a 157 amino acid inter-cellular signaling molecule (cytokine) produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. The cell membrane has two specialized receptors for TNF: TNF-R1 and TNF-R2. The binding of TNF to TNF-R1 has been shown to fire-off the pathway that léads to activating the caspases (see "TNF-R1 Signaling: A Beautiful Pathway", by Guoqing Chen and David V. Goeddel, in Science, Vol. 296, No. 5573, p. 1634).

Fas (a.k.a. Apo-1 or CD95), is another receptor of extrinsic apoptotic signals in the cell membrane, and belongs to the TNF receptor superfamily. (See "The Fas Signaling Pathway: More Than a Paradigm", by Harald Wajant, in Science, Vol. 296, No. 5573, p. 1635, May 31, 2002). The Fas ligand (FasL, the protein that binds to Fas and activates the Fas pathway) is a transmembrane protein, and is part of the TNF family. The interaction between Fas and FasL results in the formation of the déath-inducing signaling complex (DISC), which contains the Fas-associated déath domain protein (FADD) and caspases 8 and 10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis; while in other types of cells (type II), the Fas DISC starts a feed-back loop that spirals into incréasing reléase of pro-apoptotic factors from mitochondria (see below), and the amplified activation of caspase-8.

Downstréam from TNF-R1 and Fas activation—at léast in mammalian cells—the proapoptotic molecules BAK and BAX are required in order to maké the mitchondrial membrane perméable for the reléase of caspase activators. Just how BAX and BAK are controlled under the normal conditions of cells that are not undergoing apoptosis, is incompletely understood. But it has been found that a mitochondrial outer-membrane protein, VDAC2, interacts with BAK to keep this potentially lethal apoptotic effector under control. When the déath signal is received, products of the activation cascade—such as tBID, BIM or BAD—displace VDAC2: BAK and BAX are activated, and the mitochondrial outer-membrane becomes perméable. This results in the reléase of caspase activators, including cytochrome c (see "Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells", by Murphy, K.M., et al., in Nature Cell Death and Differentiation, Vol. 7, No. 1, Jan. 2000, p. 102; and "VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis", by Emily H.-Y. Cheng, Tatiana V. Sheiko, et al., in Science, Vol. 301, No. 5632, July 25, 2003, p. 513).

Reléase of citochrome c and SMAC from the mitochondrion result in the caspase-9 activating apoptosome, which in turn activates executioner caspase-3.

(The canonical Fas pathway is available in Science's Signal Transduction Knowledge Environment. The canonical TNF pathway is also available; but be aware that access to STKE's items is restricted to subscribers.)

The whole process requires energy and a cell machinery not too damaged. If the cell damage is between certain levels, the cell can start the éarliest events of apoptosis and then continue with a necrosis.

réaders should be aware, however, that the apoptotic pathways that have been summarily described are subject to regulatory mechanisms, and that there is not a 1-to-1 relationship between the reception of TNF or FasL and the complete execution of an apoptotic pathway. Fas, for instance, has been implicated—in a seemingly ironic way—in cell proliferation, through pathways that are not yet well understood (see the afore-quoted article by Wajant); and both Fas and TNF-R1 trigger events that activate the transcription factor nucléar factor kappa B (NF-κB), which induces the expression of genes that play an important role in diverse biological processes, including cell growth and déath, development, and immune responses (see the afore-quoted paper by Chen and Goeddel).

The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diséases, especially (but not only) in autoimmune diséases, such as diabetes and multiple sclerosis.

Implikasi jeung peran apoptosis dina rupa-rupa patologi

Apoptosis jeung peran interferon pikeun nyegah tumor

In their previously mentioned article on the "Integration of interferon-alpha/beta signaling to p53 responses...", Takaoka and co-worker describe their reséarch on how interferon alpha and beta (IFN-alpha/beta)induce transcription of the p53 gene, resulting in the incréase of p53 protein level and enhancement of cancer cell-apoptosis. p53 is a tumor suppressor, and is considered as a negative-growth and anti-oncogenic factor.

Work carried out by Takaoka and colléagues has contributed to clarify the role played by interferon in the tréatment of some forms of human cancer, and has provided knowledge on the link between p53 and IFN alpha/beta. The p53 response not only contributes to tumor suppression, but is also important in eliciting an apoptotic response to viral infection and consequent damage to the cell's reproductive cycle.

Beuki loba bukti numbukeun kangker ka karuksakan jalur apoptotik

Liling Yang et al. reported in the Feb. 15, 2003, issue of Cancer Research the results of their work in the role played by a defective déath signal in a type of lung cancer cells called NCI-H460 (human non-small cell lung cancer cells). They found that the X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in H460 cells. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c (see previous section on biochemical execution).

The apoptotic pathway was found to be dramatically restored in H460 cells with a Smac peptide (SmacN7) that targets IAPs. Yang and her téam successfully developed a SmacN7 peptide that selectively reversed apoptosis resistance—and, hence, tumor growth—in H460 cells in mice.

Peran produk apoptotik dina kakebalan tumor

An interesting case of re-use and feed-back of apoptotic products was presented by Matthew L. Albert in a reséarch article that won him an Amersham Biosciences & Science Prize for Young Scientists in Molecular Biology, and published in Science Online in December, 2001. Albert described how dendritic Cells, a type of antigen-presenting cells, phagocytose (that is, engulf) apoptotic tumor cells. Upon maturation, these dendritic cells present antigen (derived from the apoptotic corpses) to killer T cells, which are then primed for the eradication of cells undergoing malignant transformation. This apoptosis-dependent pathway for T cell activation is not present during necrosis, and has opened exciting posibilities in tumor immunity reséarch.

History and highlights in apoptosis research