Genetics of Apoptosis

3.

Making sense of the Bcl-2 family of apoptosis

regulators

Loralee Haughn and David Hockenbery

1.

Introduction

Although they were the first identified regulators of mammalian programmed cell
death/apoptosis and have been the focus of intensive study, we have more unanswered
questions about Bcl-2 and its relatives than other apoptotic factors with more recent
histories. Conflicting results have appeared in the literature concerning the subcellular
localizations, interactions with self and other binding partners, intracellular site of
action, and primary function(s) of this enigmatic protein family. Several of these areas
of confusion can be attributed to the physicochemical properties of these proteins:
targeting to various intracellular membranes, mitochondrial residence, pore-forming
activity, and existence of different conformational states. Other issues stem from the
still-evolving conceptions of apoptotic cell death, such as the opposing death and
survival functions of Bcl-2 homology (BH) proteins, the suitability of linear substrate-
product pathways as a model of mammalian apoptotic programs, and the lack of
models to explore the functions of these proteins in healthy cells. In this review, we
will examine several as yet unresolved issues relating to the BH protein family as
regulators of apoptosis.

2.

Internecine warfare or private agendas

One of the most intriguing aspects of the BH family of proteins is its division into
anti—and proapoptotic branches. The founding member, Bcl-2, was discovered as
the predominant oncogene in follicular lymphomas, located at one reciprocal
breakpoint of the t(14;18) (q32;q21) chromosomal translocation (Tsujimoto et al.,
1984; Cleary et al., 1986). Although lacking in transforming activity, cells transduced
with Bcl-2 remained viable for extended periods in the absence of growth factors and,
in combination with the c-myc oncogene, made murine B-cell precursors tumorigenic
(Vaux et al., 1988). The first proapoptotic BH protein to be identified, Bax, was co-
immunoprecipitated with Bcl-2 in stoichiometric amounts (Oltvai et al., 1993). Bax-
transfected cells died faster in the absence of growth factor than control cells and,