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					APOPTOSIS Apoptosis, ( a combination of the Greek words apo, off, and ptosis, falling) or programmed cell death, is an orderly and genetically controlled form of cell death defined . by distinct morphological and biochemical features. Regulation of the homeostatic balance between cell proliferation and cell death is essential for development and . maintenance of multicellular organisms. It has become clear that the regulatory mechanisms controlling programmed cell death are as fundamenental, and as complex, as those regulating cell proliferation. Perturbation of the signaling cascades regulating apoptosis, whether by . extracellular triggers, acquired or germline genetic mutations, or viral mimicry of signaling molecules, can . result in a wide variety of human diseases.

Apoptosis vs. Necrosis
Apoptosis differs from necrosis in that no inflammatory changes occur. ''Accidental'' cell death occurs in response to a wide variety of harmful conditions and toxic substances, including: hyperthermia hypoxia ischemia metabolic poisons direct cellular trauma

A cell undergoing necrosis typically exhibits distinctive morphological and biochemical characteristics . changes include
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swelling of the cytoplasm and organelles (especially mitochondria) organelle dissolution rupture of the plasma membranes leakage of cellular contents into the extracellular space . Necrosis typically affects groups of contiguous cells, and an inflammatory reaction usually develops in the . adjacent viable tissue in response to the released cellular debris.

Apoptosis usually affects single cells or small groups of . cells in an asynchronous fashion. In a morphological sense, it differs from necrosis in that cellular shrinkage and . chromatin condensation occurs, followed by framentation of nuclear components within membrane-bound vesicles . which are cleared by phagocytosis without damage to . adjacent tissue. Apoptosis is characterized by several key phases: INITIATING PHASE DECISION PHASE EXECUTION PHASE CLEARING PHASE

INITIATING PHASE

The molecular pathway includes an initiating phase, which starts after signalling by internal triggers a. b.
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increases in intracellular Ca++ activation of protein kinases A and C increases in protein synthesis changes in gene regulation

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external triggers such as a. b. ligation to distinct receptors or ehdogenous mechanisms related to aging or to exogenous irreversible cellular or nuclear damage

DECISION PHASE . During this phase transduction occurs of the apoptotic signal to nuclear and cytoplasmatic target enzymes, which includes activation of endonucleases and enzymatic
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alterations of the cytoskeleton. There are numerous proteins and lipid-derived moieties which modulate the apoptotic . . . mechanism in positive or negative direction.

EXECUTION PHASE

The execution phase is started when the cell has arrived at a stage of no return. The nuclear DNA is cleaved in
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multiples of 180-200 base pairs, the plasma membrane integrity and the mitochondria remain initially intact, the cell . splits up into apoptotic bodies, small vesicles which enclose the nuclear and cellular remnants.
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CLEARING PHASE . The clearing phase is arrived, when the apoptotic bodies are phagocytosed by adjacent cells and macrophages. It is thought that the pharmacodynamics of anticancer drugs . consists of two distinct steps. The first step includes the . interaction with its cellular target; which is not lethal per se. . The commitment of the cell to undergo apoptosis forms the . second step. The efficacy of anticancer drugs is determined by the ability to selectively sensitize tumor cells to . apoptosis, which depends to a large extent from the expression of various oncogenes, such as bcl-2, p53, bax, ras, c-myc and others, and from endogenous factors.

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MITOCHONDRIA IN APOPTOSIS
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. Initiation Phase

APOPTOTIC INDUCERS

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Effector phase caspases ... ... A .

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Degradation phase

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Figure 8.1 The three phases of apoptosis: initiation, effector and degradation phases. cyt c, cytochrome c; AIF, apoptosi.s inducing factor; DFF, DNA fragmentation factor.

ABBREVIATIONS AIF, apoptosis-inducing factOT, ATM~ mitochondrial transmembrane potential; PT, permeability transition; ROS, reactive oxygen.species; z-VAD.frnk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyI ketone.

MOLECULAR REGULATION OF APOPTOSIS . Molecular regulation of apoptosis can be classified as follows I. the signaling pathways initiating apoptosis p53 tumor suppressor gene c-myc gene 2. the processing machinery executing the apoptosis process ICE family of proteases 3. 4. the molecules that inhibit apoptosis B62 family of genes
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Excessive apoptosis

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Ductopenia

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Regulated proifferationlapoptosis
Bile ducts Homeostasis

Inhibition of apoptosis

Hyperplasia/malignant transformation

Figure 2. Apoptosis in health and disease. The role of apoptosis in health and disease is schematically illustrated using interlobular bile ducts as a representative example. As shown in the middle line, under normal homeostatic conditions, there is a balance between apoptosis of senescent, damaged, and unwanted cells and the proliferation of new cholangiocytes (bile duct epithelial cells). However, excessive apoptosis that exceeds the proliferative response of the cholangiocytes because of immune-mediated processes, toxins, or infections would result in ductopenia (top lines). In contrast, hyperplasia of bile ducts and malignant transformation may be associated with inhibition of apoptotic processes (bottom lines).

Normal hepatocyte

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bcl-2, p53 mutation Failed apoptosis

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Figure 3. Apoptosis and carcinogenesis. The role of apoptosis in carcinogenesis is schematically illustrated using hepatocytes as a representative example. Usually, genotoxic events result in either DNA repair or, if the damage is beyond repair, deletion of the cell by apoptosis. These cellular mechanisms are thought to act as safeguards against malignant transformation. However, the presence of Bcl-2 expression or p53 mutations may inhibit apoptosis after the nonrepairable genotoxic event. The failure of apoptosis permits survival of the mutated cell. The cell may subsequently undergo further mutations leading to malignant transformation through a multistep process.

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