During normal development, many cells are designated for programmed cell death, also known as apoptosis (see Chapter 21). Many abnormalities, including errors in mitosis, DNA damage, or an abnormal excess of cells not needed for development of a working organ, can trigger apoptosis. For some cells, apoptosis appears to be the default situation, and signals are required to ensure cell survival. Cells can receive instructions to live and instructions to die, and a complex regulatory system integrates these various kinds of information.

If cells do not die when they should and instead keep proliferating, a tumor may form. For example, chronic lymphoblastic leukemia (CLL) occurs because cells survive when they should not. The cells accumulate slowly, and most are not actively dividing, but they do not die. CLL cells have chromosomal translocations that activate a gene called BCL2, which we now know to be a critical blocker of apoptosis (see Figure 21-38). The resultant inappropriate overproduction of BCL2 protein prevents normal apoptosis and allows survival of these tumor cells. CLL tumors are therefore attributable to a failure of cell death. Another dozen or so proto-oncogenes that are normally involved in negatively regulating apoptosis have been found to be mutated to become oncogenes. Overproduction of their encoded proteins prevents apoptosis even when it is needed to stop cancer cells from growing.

Conversely, genes whose protein products stimulate apoptosis behave as tumor suppressors. An example is the PTEN gene discussed in Chapter 16. The phosphatase encoded by this gene dephosphorylates phosphatidylinositol 3,4,5-trisphosphate, a secondary messenger that functions in activation of AKT (see Figure 16-29). Cells lacking PTEN phosphatase have elevated levels of phosphatidylinositol 3,4,5-trisphosphate and active AKT, which promotes cell survival, growth, and proliferation and prevents apoptosis by several pathways. Thus PTEN acts as a pro-apoptotic tumor suppressor by decreasing the anti-apoptotic and proliferation-promoting effects of AKT.

The most common pro-apoptotic tumor-suppressor gene implicated in human cancers is p53. Among the genes activated by p53 are several encoding pro-apoptotic proteins such as BAX (see Figure 21-38). As we will discuss in Section 24.5, when cells suffer extensive DNA damage or numerous other stresses such as hypoxia, the p53-induced expression of pro-apoptotic proteins leads to their quick demise. While apoptosis may seem like a drastic response to DNA damage, it prevents proliferation of cells that are likely to accumulate multiple mutations. When p53 function is lost, apoptosis cannot be induced, and the accumulation of mutations required for cancer to develop and progress becomes more likely.