Bcl-2-family proteins and hematologic malignancies: history and future prospects

Abstract

BCL-2 was the first antideath gene discovered, a milestone that effectively launched a new era in cell death research. Since its discovery more than 2 decades ago, multiple members of the human Bcl-2 family of apoptosis-regulating proteins have been identified, including 6 antiapoptotic proteins, 3 structurally similar proapoptotic proteins, and several structurally diverse proapoptotic interacting proteins that operate as upstream agonists or antagonists. Bcl-2-family proteins regulate all major types of cell death, including apoptosis, necrosis, and autophagy. As such, they operate as nodal points at the convergence of multiple pathways with broad relevance to biology and medicine. Bcl-2 derives its name from its original discovery in the context of B-cell lymphomas, where chromosomal translocations commonly activate the BCL-2 protooncogene, endowing B cells with a selective survival advantage that promotes their neoplastic expansion. The concept that defective programmed cell death contributes to malignancy was established by studies of Bcl-2, representing a major step forward in current understanding of tumorigenesis. Experimental therapies targeting Bcl-2 family mRNAs or proteins are currently in clinical testing, raising hopes that a new class of anticancer drugs may be near.

Figure 1

Bcl-2 suppresses apoptosis, necrosis, and autophagy. ROS indicates reactive oxygen species; Cyt-c, cytochrome-c; EndoG, endonuclease G; AIF, apoptosis-inducing factor; and IAP, inhibitor of apoptosis protein.

Figure 2

Functional interactions among the types of mammalian Bcl-2–family proteins at mitochondrial membranes.

Figure 3

Nonfamilial interactions with antiapoptotic proteins Bcl-2 or Bcl-X_L and with proapoptotic proteins Bax or Bak. (A) The depicted protein interactions have been reported for either Bcl-2 or Bcl-X_L. (B) The depicted protein interactions have been reported for Bax or Bak. In many cells, Bax is present in a latent (inactive) conformation in the cytosol, in which its C-terminal transmembrane domain is folded onto the protein. Activators of Bax induce conformational changes that promote Bax's insertion into membranes of mitochondria, followed by BH3-induced oligomerization in membranes. Several proteins that modulate these steps have been reported.