What is Apoptosis, the Programmed Cell Death

The term apoptosis first appeared in the biomedical literature in 1972, to delineate a structurally-distinctive mode of cell death responsible for cell loss within living tissues. The cardinal morphological features are cell shrinkage, accompanied by transient but violent bubbling and blebbing from the surface, and culminating in separation of the cell into a cluster of membrane-bounded bodies. The organellar structure is usually preserved intact, but the nucleus undergoes a characteristic condensation of chromatin, initiated at sub lamellar foci and often extending to generate toroidal or cap-like, densely heterochromatic regions. Changes in several cell surface molecules also ensure that, in tissues, apoptotic cells are immediately recognized and phagocytosed by their neighbors. The result is that many cells can be deleted from tissues in a relatively short time with little to show for it in conventional microscopic sections.


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What is Apoptosis



 This remarkable process is responsible for cell death in development, normal tissue turnover, atrophy induced by endocrine and other stimuli, negative selection in the immune system, and a substantial proportion of T-cell killing. It also accounts for many cell deaths following exposure to cytotoxic compounds, hypoxia or viral infection. It is a major factor in the cell kinetics of tumors, both growing and regressing. Many cancer therapeutic agents exert their effects through the initiation of apoptosis, and even the process of carcinogenesis itself seems sometimes to depend upon a selective, critical failure of apoptosis that permits the survival of cells after mutagenic DNA damage. Apoptosis probably contributes to many chronic degenerative processes, including Alzheimer’s disease, Parkinson’s disease and heart failure. 

Key Elements of the Apoptotic Pathway 

Death receptors
Apoptosis has been found to be induced via the stimulation of several different cell surface receptors in association with caspase activation. For example, the CD95 (APO-1, Fas) receptor-ligand system is a critical mediator of several physiological and pathophysiological processes, including homeostasis of the peripheral lymphoid compartment and CTL-mediated target cell killing. Upon cross-linking by ligand or agonist antibody, the Fas receptor initiates a signal transduction cascade which leads to caspase-dependent programmed cell death. 

Membrane alterations
In the early stages of apoptosis, changes occur at the cell surface and plasma membrane. One of these plasma membrane alterations is the translocation of phosphatidylserine (PS) from the inner side of the plasma membrane to the outer layer, by which PS becomes exposed at the external surface of the cell. 

Protease cascade 
Signals leading to the activation of a family of intracellular cysteine proteases, the caspases, (Cysteinyl-aspartate-specific proteinases) play a pivotal role in the initiation and execution of apoptosis induced by various stimuli. At least 11 different members of caspases in mammalian cells have been identified. Among the best-characterized cas- pases is caspase-1 or ICE (Interleukin-1C- Converting Enzyme), which was originally identified as a cysteine protease responsible for the processing of interleukin 1C. 

Mitochondrial changes
Mitochondrial physiology is disrupted in cells undergoing either apoptosis or necrosis. During apoptosis mitochondrial permeability is altered and apoptosis-specific protease activators are released from mitochondria. Specifically, the discontinuity of the outer mitochondrial membrane results in the redistribution of cytochrome C to the cytosol followed by subsequent depolarization of the inner mitochondrial membrane. Cytochrome C (Apaf-2) release further promotes caspase activation by binding to Apaf-1 and therefore activating Apaf-3 (caspase 9). AIF (apoptosis-inducing factor), released in the cytoplasm, has proteolytic activity and is by itself sufficient to induce apoptosis. 

DNA fragmentation

The biochemical hallmark of apoptosis is the fragmentation of the genomic DNA, an irreversible event that commits the cell to die and occurs before changes in plasma membrane permeability (prelytic DNA fragmentation). In many systems, this DNA fragmentation has been shown to result from the activation of an endogenous Ca2+ and Mg2+-dependent nuclear endonuclease. This enzyme selectively cleaves DNA at sites located between nucleosomal units (linker DNA) generating mono- and oligonucleosomal DNA fragments. 






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