Cell death occurs both pathologically and naturally. Pathologically, cells deprived of a blood supply may swell, rupture their membranes, and burst. Such cellular death, leading to tissue death, is known as necrosis. In certain cases, however, a different pattern is observed. Instead of swelling, the cells shrink. The membranes remain intact but become bubbled, and the nuclei condense. This process was named apoptosis (from a Greek term describing the shedding of leaves from a tree), and its discoverers were awarded the 2002 Nobel prize in Physiology or Medicine.
The machinery of cell death is set in motion by a family of enzymes called caspases, which are normally inactive within the cell but become activated during apoptosis. These enzymes have thus been called the "executioners" of the cell. Mitochondria may play an essential role in the activation of caspases and resulting apoptosis. This occurs when certain stimuli cause the outer and inner mitochondrial membranes to become permeable to proteins and other products that do not normally leak into the cell cytoplasm.
Apoptosis has been implicated in many disease processes, but it also occurs normally as part of programmed cell death—a process described previously in the section on lysosomes. Programmed cell death refers to the physiological process responsible for the remodeling of tissues during embryonic development and for tissue turnover in the adult body. As mentioned earlier, the epithelial cells lining the digestive tract are programmed to die 2 to 3 days after they are produced, and epidermal cells of the skin live only for about 2 weeks until they die and become completely cornified. Apoptosis is also important in the functioning of the immune system. A neutrophil (a type of white blood cell), for example, is programmed to die by apoptosis 24 hours after its creation in the bone marrow. A killer T lymphocyte (another type of white blood cell) destroys targeted cells by triggering their apoptosis.
Using mice with their gene for p53 knocked out, scientists have learned that p53 is needed for the apoptosis that occurs when a cell's DNA is damaged. The damaged DNA, if not repaired, activates p53, which in turn causes the cell to be destroyed. If the p53 gene has mutated to an ineffective form, however, the cell will not be destroyed by apoptosis as it should; rather, it will divide to produce daughter cells with damaged DNA. This may be one mechanism responsible for the development of a cancer.
There are three forms of skin cancer—squamous cell carcinoma, basal cell carcinoma, and melanoma, depending on the type of epidermal cell involved—all of which are promoted by the damaging effects of the ultraviolet portion of sunlight. Ultraviolet light promotes a characteristic type of DNA mutation in which either of two pyrimidines (cytosine or thymine) is affected. In squamous cell and basal cell carcinoma (but not melanoma), the cancer is believed to involve mutations that affect the p53 gene, among others. Whereas cells with normal p53 genes may die by apoptosis when their DNA is damaged, and are thus prevented from replicating themselves and perpetuating the damaged DNA, those damaged cells with a mutated p53 gene survive and divide to produce the cancer.
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