absence of certain hormones can result in the induction of apoptosis in certain cell types. This has led to the suggestion that apoptosis may play a pivotal role in the maintenance of tissue organisation in vivo. It is thought that all cells are primed to undergo apoptosis and are prevented from doing so through constant stimulation by parakrine survival factors (18). If a cell is removed from its physiologically correct location, the absence of the appropriate survival signal will lead to the induction of apoptosis. This role of survival factors as regulators of cellular distribution in vivo may also have an impact on the development of serum-free media preparations for industrial-scale cell-culture processes, as described later.
The presence of receptor-ligand interactions can also lead to the induction of apoptosis. For instance, in the Fas-FasL system, binding of the Fas ligand to the Fas receptor can trigger apoptosis (19). This mechanism is responsible for the regulation of the immune system. Autoreactive B cells undergoing maturation (20) and autoreactive mature T cells (21) are eliminated by the Fas-mediated induction of apoptosis. Fas also acts as the "off' switch for the immune system by inducing apoptosis in antigen-activated B and T cells (22). Molecular dissection of the Fas-FasL system has provided important insights into the early stages of the signaling cascade that leads to the expression of the death pathway (see "Genetics of Apoptosis").
Induction by Viruses. A number of viruses have been shown to interact with the cellular apoptotic machinery. An apoptotic response to viral infection would appear to act as a protective mechanism that prevents viral replication by triggering the suicide of the infected cell. However, a number of virally encoded antiapoptotic genes have now been identified that suppress the expression of the death program, thereby providing the virus with the opportunity to propagate itself. Perhaps one of the most interesting examples of this anti-death mechanism from a biotechnology perspective is that of baculovirus, which has been synthesized at production scale by infection of insect cell lines, and has applications as a biological pesticide and, more recently, for the expression of recombinant proteins. A mutant was identified that induced high levels of apoptosis during infection of Sf21 insect cells. This was attributed to a mutation in the p35 viral gene that, in its wild-type form, acts as an antiapoptosis gene (23).
Arguably, the most important example of virus-induced apoptosis is that mediated by HIV (24-27). A number of reports have indicated that the binding of the viral gp 120 protein to the CD4+ receptor of T cells triggers the induction of apoptosis, thus leading to the depletion of this class of cells during HIV infection (28-30). Interestingly, HIV infection of CD4+ cells appears to provide protection from apoptosis. The viral Nef protein downregulates the expression of CD4 + , thus preventing the induction of apop-tosis. As a result, virus propagation in the infected cell is not prevented (31).
There have also been reports of virus-induced suicide of bacterial cells. Until recently, it was assumed that altruistic cell death was not possible in single-celled organisms, simply because the genes involved in such a phenomenon would be lost when the cell concerned dies. However, bac-teriophage infection in bacterial colonies has been reported to induce a suicide response, thus preventing the spread of the infection to the remainder of the colony (32). The genes that mediate such a response are propagated by other clones in the colony, thus preserving the altruistic nature of cellular suicide. Bacteria and viral expression systems have been used for the production of recombinant proteins. Clearly, the possibility that bacterial cells in such systems exhibit an apoptosis-like response needs to be investigated.
Free Radicals and Apoptosis. Free-radical-mediated cellular damage has become an important area of study. In recent years there have been numerous reports that cell death following oxidative stress occur by apoptosis. Moreover, generation of free radicals has been postulated as being a universal triggering event in the induction of apop-tosis (33-38). Indeed, for a period in the early 1990s, it was suggested that the widely studied antiapoptosis gene bcl-2 functioned as an antioxidant (39). However, this theory has been challenged by the demonstration that anoxia-induced apoptosis can also be suppressed by Bcl-2 in the absence of measurable levels of free radicals (8,40,41).
Induction by Toxins and Therapeutic Agents. Exposure to high levels of toxic chemicals results in necrotic death of the cell. However, long-term exposure at a low level can trigger an apoptotic response. Many of the agents used in chemotherapy exert their affect by inducing apoptosis in tumor and normal cells. Overexpression of genes such as bcl-2 has been linked to resistance to chemotherapy. Clearly, establishing the mechanism of induction of apop-tosis in response to such agents and providing strategies that minimize the affect of antiapoptotic genes should provide novel and more effective chemotherapeutic strategies (42).
Exposure of cells to ionizing radiation induces high levels of apoptosis in many normal tissues. Particularly susceptible are those cells from tissues that undergo rapid proliferation, such as spermatogonia (43) and lymphocytes (44). Such tissue would be especially prone to malignant transformation, and consequently the induction of apoptosis following DNA damage minimizes the likelihood of such an event. Irradiation of tumors can also lead to the induction of apoptosis (45-47). Notably, tumors that respond least favorably to irradiation exhibit the lowest level of apoptosis under such conditions (45). The induction of apoptosis following DNA damage is regulated by the product of the p53 gene, which has been referred to as the gaur-dian of the genome because of its central role in preventing the propagation of cells that may have sustained genetic damage and thus, potentially, malignant transformation (48).
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