Diacylglycerol Signaling

190 M.E. Reyland and A.P. Bradford
1972, 1973; Kerr 2002). This process was recognized and originally referred to
as “shrinkage necrosis” as the subcellular organelles such as mitochondria and
ribosomes appeared to be intact (Kerr 1971), and was later coined “apoptosis” after
the Greek “dropping off.” A critical observation of these early studies was that this
mode of cell death appeared to follow a predetermined program; hence it also came
to be known as “programmed cell death.” Kerr and colleagues concluded that this
process regulates “the size of cell populations under both normal and pathological
conditions” (Kerr 2002). Nonapoptotic cell death programs such as autophagy have
also been the focus of intense study recently. Interestingly, autophagy and apoptosis
both appear to contribute to processes such as development and chemotherapeutic
cell death, suggesting cross-talk between these seemingly distinct modes of cell
death (Gozuacik and Kimchi 2007; Levine et al. 2008).
The protein kinase C (PKC) family of serine/threonine protein kinases consists
of 11 isoforms that regulate a wide variety of biological functions including cell
proliferation and differentiation, cell survival and cell death (Reyland 2007). Many
isoforms including PKCa, −b, −d, −e, and −z show widespread tissue expression,
while others such as PKCg and −h have a more tissue specific expression pattern
(Wetsel et al. 1992). Despite overlapping expression patterns and common
substrates, many of the functions of PKC appear to be isoform-specific. This may
be achieved in part by changes in subcellular localization which facilitate interaction
with specific signaling modules. A clear role in apoptosis and/or cell survival has
been demonstrated for a subset of PKC isoforms, in particular PKCa, −d, −e, and
−z. The function of these isoforms may vary with cell type, suggesting that the
distinct composition of PKC isoforms in a cell determines the ultimate response.
PKC isoforms are also well integrated into both proliferation and apoptotic signaling
networks; hence the specific “wiring” of other regulatory pathways in the cell may
also contribute to signal transduction by this family of kinases. Given their central
role in proliferation and apoptosis, it is not surprising that expression or activation
of PKC isoforms is altered in some human diseases, particularly cancer.
This review will focus on the contribution of specific PKC isoforms to the regulation
of cell survival and apoptosis.
9.2 Apoptosis and Human Disease
Early studies suggested a role for apoptosis during normal development, in endocrine
tissues upon hormone withdrawal, and in breast carcinomas (Kerr and Searle
1972; Kerr et al. 1972). More recent studies from mice lacking specific components
of the apoptotic cascade show that disruption of caspase-3, 7, 8 or 9, or Bcl-2 results
in either embryonic or perinatal death, indicating a critical role in development
(Varfolomeev et al. 1998; Zheng and Flavell 2000; Ranger et al. 2001). It is now
appreciated that in addition to physiological stimuli, cells respond to a wide range
of cellular toxins by inducing this suicide pathway. Moreover, too much or too little
apoptosis can have drastic consequences for tissue homeostasis and for disease