REGULATION OF LYMPHOCYTE SURVIVAL BY THE BCL-2 GENE FAMILY

The control of cell survival is of central importance in tissues with high cell turnover such as the lymphoid system, and its disruption may be a critical step in tumorigenesis. Genes homologous to bcl-2, the o ncogene implicated in human follicular lymphoma, play a key role in re gulating physiologic cell death (apoptosis). Bcl-2 and its relatives b cl-x and bax encode intracellular membrane-bound proteins that share h omology in three domains with a wider family of viral and cellular pro teins. The Bcl-2 and Bcl-x proteins enhance the survival of lymphocyte s and other cell types but do not promote their proliferation. High le vels of Bar or of a smaller Bcl-x variant antagonize the survival func tion of Bcl-2. The mechanism by which Bcl-2 promotes cell survival rem ains unknown, but it appears to require association with Bar. Bcl-2 ma y combat the action of cysteine proteases thought to trigger apoptosis . Bcl-2 is not essential for embryogenesis or lymphoid development. Ho wever, upregulation of Bcl-2 appears to be the normal mechanism for po sitive selection of developing lymphocytes, and its continued expressi on is critical for survival of mature peripheral B and T cells. Consti tutive expression of Bcl-2 does not abrogate deletion of self-reactive lymphocytes, nor disturb T lymphoid homeostasis; however, it substant ially increases the pool of mature noncycling B cells. The risk of B l ymphoid tumors is also enhanced, probably because Bcl-2 can counterman d the apoptotic action of other oncoproteins such as Myc. Expression i n tumors of bcl-2 and other cell survival genes may constitute a major barrier to the success of genotoxic cancer therapy.