Apoptosis is cell-initiated cell death. It performs tissue sculpturing during the development of the nervous system, digit formation, and other developmental programs by selective cell destruction. Apoptosis also removes cells that have sustained irreparable DNA damage, acts as a noninflammatory defense against viral infection, and prevents cell masses from becoming too large. The process of apoptotic cellular breakdown includes DNA fragmentation by a Mg2+-dependent endonuclease, chromatin condensation, compaction of cell organelles, blebbing of the cell membrane, cell shrinkage, and, in the end, partitioning of the cell into small membrane-bound packages that are absorbed by other cells. Members of the Bcl-2 family of transmembrane proteins inhibit other members of the Bcl-2 family of proteins, such as BAD (Bcl-2-associated death protein), BAX (Bcl-2-associated X protein), BIK (Bcl-2-interacting killer protein), and BAK (Bcl-2-antagonist/killer protein 1), from initiating apoptosis (Figure 16.4). The key feature of apoptosis is the activation of several cell death proteases (caspases) by a proteolytic cascade. Under normal conditions, the caspases are almost totally inactive proenzymes. However, the extracellular and intracellular signals that trigger the cell death processes cause inactive caspases (procaspases) to aggregate. This clustering increases the likelihood that the low level of intrinsic proteolytic activity of inactive caspases will activate some caspase molecules, which, in turn, initiate a full-blown caspase proteolytic cascade. Caspases, which cleave after an aspartic acid residue in target proteins, are activated by the removal of a portion of the proenzyme. Once activated, caspases attack specific cellular proteins and structures, which releases factors that activate other proteases, nucleases, and additional destructive enzymes.
When mutations or genomic alterations cause increased levels of apoptosis-inhibiting Bcl-2 proteins, apoptosis is blocked, and cell survival is prolonged. When BCL2 gene mutations of this type occur in combination with oncogenic mutations, the likelihood of cancer is increased, because potential cancer cells are not destroyed by apoptosis. Overproduction of Bcl-2 proteins has been associated with chronic lymphocytic leukemia (CLL) and cancers of the lymph nodes, prostate, lungs, breast, nose, and throat.
The protein p53 plays an important role in the induction of apoptosis (Figure 16.5). When DNA damage is extensive, wild-type p53, among other functions, represses the transcription of the BCL2 gene and increases the expression of the BAX gene. Both of these actions initiate apoptosis. On the other hand, mutations of the TP53 gene that do not invoke apoptosis in response to DNA damage allow cells to proliferate, accumulate oncogene mutations, and become cancerous. In addition to its role as an inducer of apoptosis, p53 is involved in the control of G1/S and G2/M transitions. In these instances, p53 halts the cell division cycle to allow damaged DNA to be repaired. Approximately 50% of all cancers have a mutated TP53 gene, which makes it the most commonly observed mutated oncogene. Metaphorically, p53 is the cellular equivalent of the Roman hero Horatius, who single-handedly held a small bridge against the onslaught of a large number of enemy soldiers!
DNA damage p53
Repression of transcription of the BCL2 gene
Increased transcription of the BAX gene
BAX concentration is increased damage, p53, and apoptosis. When DNA is damaged, a signal is sent to p53, which, among other actions, represses and stimulates transcription of the BCL2 and BAX genes, respectively. Each of these activities facilitates apoptosis.
Figure 16.5 Association of DNA
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