Apoptosis
Apoptosis is a controlled series of events in eukaryotic cells which leads to cell death. The process is also called programmed cell death or cell suicide. The term was coined in 1972 to distinguish this form of cell death from necrosis, which was associated with acute injury to cells. Apoptosis is a central part of normal development. Some of the events which occur in a cell undergoing apoptosis are the shrinkage of the cell, breakdown of their mitochondria (a specialized portion of the cell which functions in energy production), breakdown of DNA and protein, and the bubbling of the surface into "blebs". Ultimately specialized cells called macrophages engulf the cell. This latter process, called phagocytosis, differs from the phagocytosis seen in inflammatory responses.
Apoptotic death can be triggered by a wide variety of stimuli, and not all cells necessarily will die in response to the same stimuli. Damage to genetic material and the presence of hormones such as corticosteroids are two such stimuli. The triggers upset the previously-existing balance between positive signals required for continued cell growth (adhesion to surfaces for many cells, growth factors for neurons, interleukin-2 for lymphocytes) and incoming negative signals (increased levels of oxidants, DNA damage, binding of molecules which can stimulate apoptosis).
The triggers for apoptosis can be internal or external. Internally, many healthy cells display an association between two proteins, designated Bcl-2 and Apaf-1. Disruption of this association results in leakiness, and the formation of a complex called the apoptosome. Accumulation of apoptosomes causes protein degradation inside the cell and, ultimately, the cell's death. External triggers are the binding of a death activator (FasL or TNF) to its complimentary receptor on the cell's surface. Binding triggers the activation of protein degrading molecules inside the cell.
The orderly nature of apoptosis indicates that it is a normal part of normal cellular processes. Programmed cell death is required for fetal finger and tow formation, formation of proper connections between neurons in the brain and for the proper metamorphosis of a tadpole into a frog. Also, apoptosis is needed to destroy cells that represent a threat to the integrity of the organism. Examples include killing of virus-infected cells by cytotoxic T lymphocytes, removal of DNA damaged cells and induction of apoptosis in cancerous cells by radiation and chemical therapy.
Conversely, apoptotic malfunction has deleterious effects. Defects in the apoptotic machinery are associated with autoimmune diseases such as lupus erythematosus and rheumatoid arthritis. Several forms of cancer involve the inactivation of the apoptotic process, thus enabling the cancer cells to continue to proliferate. For example, the p53 gene, which has been strongly implicated in human and animal carcinogenesis, can also be a significant regulator of the process of apoptosis. A hallmark of acquired immunodeficiency syndrome is the decline in CD3+T cells, which produces an ineffective immune response to disease challenge. The CD4 + decline has been shown to be due to apoptosis.
Understanding apoptosis, and so an ability to manipulate it, could allow therapeutic intervention in major diseases such as cancer, heart disease, stroke, AIDS, autoimmunity and degenerative diseases. Also, improved acceptance of organ transplants could be facilitated. Cells in the anterior chamber of the eye and in the testes are hyper-producers of an apoptotic protein, which will result in death of cells of the body's immune system. If transplanted tissue could behave similarly, the body's rejection of the transplant might be lessened or eliminated.
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