GM-CSF following T-cell receptor-mediated mitogenic signaling. Increased levels of
Bcl-2 inhibited nuclear translocation of NFAT, which requires dephosphorylation
by calcineurin to unsheath a nuclear localization signal. Shibasaki et al. (1997)
demonstrated a tight association between Bcl-2 and calcineurin, dependent on the
N-terminal BH4 domain of Bcl-2. Bcl-2-bound calcineurin retained activity, but this
group speculated that sequestration of calcineurin at mitochondrial sites prevented
its acting on cytoplasmic substrates, including NFAT. Bax expression resulted in
disruption of Bcl-2-calcineurin interactions. This model fits known examples of
differential targeting of serine-threonine phosphatases via interactions with regulatory
subunits (Cohen, 2002).
A complementary study in fibroblasts by Vairo et al. (2000) determined that Bcl-2-
mediated delays in G1 progression require p27 and the pRB relative p130, and are
associated with increased expression of these proteins. Bcl-2 overexpression increased
formation of the p130-E2F4 complex, characteristic of quiescent cells, which may
act as a transcriptional repressor in this circumstance (Lind et al., 1999; Vairo et al.,
2000).
A possible regulatory role for Bcl-2 in cell-cycle events is indicated by the
observation that Bcl-2 phosphorylation, initially described after treatment of cells
with microtubule inhibitors, represents a cell-cycle-dependent phosphorylation
during G2/M (Scatena et al., 1998; Yamamoto et al., 1999). Mutational studies
suggest that phosphorylation of Bcl-2 at Ser^70 , Ser^87 , and Thr^69 inactivates the
prosurvival activity of Bcl-2 following taxol treatment (Yamamoto et al., 1999). Both
stress-activated kinases, ASK1 and JNK1, and the HHV8 viral cyclin-CDK6 complex
are involved in G2/M phosphorylation of Bcl-2 (Yamamoto et al., 1999; Ojala et al.,
2000).
5.
Specialists or generalists?Why is there such apparent redundancy among both pro—and antiapoptotic BH
proteins? In the case of the proapoptotic proteins, it has been suggested that the large
number of pro-death family members is indicative of specialization, rather than
redundancy (Ferri and Kroemer, 2001). The emerging pattern for proapoptotic BH
proteins is one of latent lethality requiring new targeting, post-translational
modifications, or conformation changes for activation. The unique localization,
protein associations, and mechanism of activation found for the individual
proapoptotic members Bax, Bad, Bid, Bim, and Bmf support the hypothesis that each
acts as a ‘sentry’ for distinct damage signals, thereby increasing the range of inputs
for endogenous death pathways.
The antiapoptotic proteins Bcl-2 and Bcl-xL may have nonhomologous functions
in hematopoietic development. A reciprocal pattern of expression for these proteins
has been described in developing T and B cells, and subsets of adult human and
murine bone-marrow cells (Gratiot-Deans et al., 1994; Merino et al., 1994; Park et
al., 1995; Grillot et al., 1996). BH proteins are linked to cell differentiation decisions
68 GENETICS OF APOPTOSIS