Figure 18–12 Three ways that extracellular survival factors can inhibit apoptosis. (A) Some survival factors suppress apoptosis by stimulating the transcription of genes that encode antiapoptotic Bcl2 family proteins such as Bcl2 itself or BclXL. (B) Many others activate the serine/threonine protein kinase Akt, which, among many other targets, phosphorylates and inactivates the pro-apoptotic Bh3-only protein Bad (see Figure 15–53). When not phosphorylated, Bad promotes apoptosis by binding to and inhibiting Bcl2; once phosphorylated, Bad dissociates, freeing Bcl2 to suppress apoptosis. Akt also suppresses apoptosis by phosphorylating and inactivating transcription regulatory proteins that stimulate the transcription of genes encoding proteins that promote apoptosis (not shown). (C) In Drosophila, some survival factors inhibit apoptosis by stimulating the phosphorylation of the anti-IAp protein hid. When not phosphorylated, hid promotes cell death by inhibiting IAps. Once phosphorylated, hid no longer inhibits IAps, which become active and block apoptosis. MAp kinase, mitogenactivated protein kinase.
underlying mechanism is poorly understood, but the external exposure of phosphatidylserine is likely to depend on caspase cleavage of some protein involved in phospholipid distribution in the membrane. A variety of soluble “bridging” proteins interact with the exposed phosphatidylserine on the apoptotic cell. These bridging proteins also interact with specific receptors on the surface of a neighboring cell or macrophage, triggering cytoskeletal and other changes that initiate the engulfment process.
Macrophages do not phagocytose healthy cells in the animal—despite the fact that healthy cells normally expose some phosphatidylserine on their surfaces. Healthy cells express signal proteins on their surface that interact with inhibitory receptors on macrophages that block phagocytosis. Thus, in addition to expressing cell-surface signals such as phosphatidylserine that stimulate phagocytosis, apoptotic cells must lose or inactivate these “don’t eat me” signals that block phagocytosis.
Either Excessive or Insufficient Apoptosis Can Contribute to Disease
There are many human disorders in which excessive numbers of cells undergo apoptosis and thereby contribute to tissue damage. Among the most dramatic examples are heart attacks and strokes. In these acute conditions, many cells die by necrosis as a result of ischemia (inadequate blood supply), but some of the less affected cells die by apoptosis. It is hoped that, in the future, drugs that block apoptosis—such as specific caspase inhibitors—will prove useful in saving such cells.
There are other conditions where too few cells die by apoptosis. Mutations in mice and humans, for example, that inactivate the genes that encode the Fas death receptor or the Fas ligand prevent the normal death of some lymphocytes, causing these cells to accumulate in excessive numbers in the spleen and lymph glands. In many cases, this leads to autoimmune disease, in which the lymphocytes react against the individual’s own tissues.
Decreased apoptosis also makes an important contribution to many tumors, as cancer cells often regulate their apoptotic program abnormally. The Bcl2 gene, for example, was first identified in a common form of lymphocyte cancer in humans, where a chromosome translocation causes excessive production of the Bcl2 protein; indeed, Bcl2 gets its name from this B cell lymphoma. The high level of Bcl2 protein in the lymphocytes that carry the translocation promotes the development of cancer by inhibiting apoptosis, thereby prolonging lymphocyte survival and increasing their number; it also decreases the cells’ sensitivity to anticancer drugs, which commonly work by causing cancer cells to undergo apoptosis.