independent of survival activity. Bcl-2 induces differentiation in human neural-crest
derived tumor cells (Zhang et al., 1996) and rat pheochromocytoma PC12 cells (Sato
et al., 1994). In a comparison of Bcl-xL and Bcl-2 in staurosporine-treated
neuroblastoma cells, Bcl-xL, but not Bcl-2, was associated with robust neuronal
differentiation of surviving cells (Yuste et al., 2002).
The use of Bcl-2 or Bcl-xL to maintain survival of FDCPMix(A4) cells (Spooncer
et al., 1986) also revealed remarkable differences between these proteins in a
nonapoptotic phenotype (L.Haughn and D.Hockenbery, unpublished results). In
this case, both Bcl-2 and Bcl-xL enable hematopoietic differentiation, but along
restricted and divergent pathways. High-level expression of Bcl-xL in FDCPMix(A4)
cells resulted in selective recovery of erythroid (E) cells in the absence of IL-3 or other
growth factors, while Bcl-2 expression yielded granulocytic/monocytic (G/M) cells
(Figure 1). This result was not due to differential survival since virtually complete
viability was maintained in each instance.
Thus, specialization in antiapoptotic BH proteins may emerge from investigations
of phenotypes associated with expression in nonlethal contexts. Specific interactions
between Bcl-2 survival proteins and cytoplasmic signaling pathways may dictate
multiple cell-fate decisions for the antiapoptotic proteins with redundant survival
functions.
6.
SummaryIf there is a predominant theme to the history of investigations on the Bcl-2 family
of proteins in the last 15 years, it is one of expansion into multiple disciplines, both
unanticipated and enlightening. Bcl-2 research has incorporated approaches from
mitochondrial bioenergetics, membrane electrophysiology, macromolecular
structure, ion transport, metabolic control, cell structure and dynamics,
proteintrafficking, and chemical biology. Among other tangible benefits, this has
ensured a steady supply of new investigators to the Bcl-2 field bringing fresh
perspectives.
There remains an underlying dichotomy in current efforts to understand how these
proteins function in apoptosis (Vander Heiden and Thompson, 1999). On the one
hand, there is the view that determining the critical event during apoptosis that is
regulated by BH proteins (e.g., cytochrome c release via a defined mitochondrial
channel) will reveal their essential functions in a straightforward manner. On the
other hand, a different perspective on these proteins as ‘integrators’ of cell signaling
and metabolic pathways, with less direct effects on apoptosis, informs attempts to
look below the ‘tip of the apoptosis iceberg’ for more general functions. Undoubtedly,
we can look forward to additional insights into the complex networks that govern
cell survival in the next few years as these strategies bear fruit.
MAKING SENSE OF THE BCL-2 FAMILY OF APOPTOSIS REGULATORS 69