control of apoptosis and autophagy by cellular signalling pathways
TRANSCRIPT
MINIREVIEW SERIES
Control of apoptosis and autophagy by cellularsignalling pathwaysPaul Clarke
Biomedical Research Institute, Ninewells Hospital & Medical School, University of Dundee, UK
Cell death by the controlled process of apoptosis plays
central roles in metazoan biology. Apoptosis is respon-
sible for the removal of cells during developmental
tissue remodelling and for tissue homeostasis in the
adult. This mechanism of cell suicide is also induced by
cellular stresses and DNA damage that might otherwise
generate dangerously defective cells. Clearly, apoptosis
must be tightly regulated to ensure that unwanted or
damaged cells can be removed efficiently while unneces-
sary cell death does not occur. Defects in the control of
apoptosis are thought to occur in many major human
diseases, including cancer.
Cellular signalling pathways involving protein kinases
play critical roles in determining the balance between cell
death and survival, and they are the subjects of this mini-
review series. One very important control point in the
intrinsic pathway for apoptosis is at the level of the mito-
chondria, mediated by anti-apoptotic proteins of the
B-cell lymphoma 2 (Bcl-2) family, their related functional
antagonists Bcl-2 associated x protein (Bax) and Bcl-2
antagonist/killer (Bak), and other pro-apoptotic proteins
that are related to Bcl-2 only in their Bcl-2 homology 3
(BH3) domains. In their minireview, Gillings et al.
describe the regulation of this control point through the
phosphorylation and ubiquitination of the BH3-only
protein Bcl-2 interacting mediator of cell death (Bim), an
apoptotic initiator that is repressed by growth factor sig-
nalling. Gillings et al. discuss the potential implications
of these mechanisms for the treatment of cancer.
Bcl-2 family proteins act on mitochondria to control
the release of cytochrome c and other factors through
the outer mitochondrial membrane. In the cytosol,
cytochrome c initiates the activation of an initiator
enzyme, caspase-9, which in turn activates other
caspases (apoptotic endoproteases) to bring about the
destruction of the cell. The activation of caspase-9, in a
large complex with its partner apoptotic peptidase acti-
vating factor 1 (Apaf-1), is subject to tight control,
including the inhibitory phosphorylation of caspase-9 in
response to growth factors, cellular stresses such as
hyperosmolarity, and during cell division. The phos-
phorylation of caspase-9 and its role in the control of
apoptosis are discussed by Allan & Clarke.
Regulation of apoptosis by DNA damage is the sub-
ject of the review by Bitomsky & Hofmann, who focus
on apoptotic roles for the tumour suppressor p53, which
include the transcriptional control of BH3-only proteins
and direct effects on mitochondria. They also describe
the roles of p73, a relative of p53 that is thought to play
critical roles in DNA damage responses. Bitomsky &
Hofmann review the functions of the homeodomain-
interacting protein kinase 2 (HIPK2), which acts, in
part, through phosphorylation of p53 and also through
p53-independent routes to induce apoptosis.
In recent years it has also become clear that auto-
phagy, the lysosome-dependent catabolic process that is
responsible for clearing damaged organelles and main-
taining cellular homeostasis, also has important func-
tions in cell survival and in the initiation of cell suicide.
Autophagy has been implicated in cancer and other dis-
eases and may be linked to apoptosis through common
regulators such as Bcl-2. Corcelle et al. review recent
advances in understanding the mechanism of autophagy
and its regulation by mitogenic and stress-signalling
pathways. They discuss the importance of autophagy in
cancer and the potential for targeting the signalling
pathways that control autophagy.
These minireviews highlight some of the significant
developments that have been made in recent years in
understanding the molecular mechanisms underlying
the control of cell death and cell survival. Research in
this field has provided some remarkable new insights
into fundamental cellular processes, and no doubt
further developments await us. One challenge for
future years will be to use this knowledge to develop
new therapeutic strategies for disease.
Paul Clarke is Professor of Cancer Cell Biology at the University of Dundee. Previously he was at the University of
Manchester (1994–1998) and he was a research fellow in the group of E. Karsenti at the European Molecular Biology
Laboratory, Heidelberg (1991–1994). As a student, he read Biochemistry at Bristol and carried out research for his PhD
with D. G. Hardie at Dundee. He has received a Royal Society-Wolfson Research Merit Award and research fellowships
from The Wellcome Trust and Cancer Research UK. Professor Clarke’s research group studies molecular mechanisms
controlling cell division and cell death with relevance to cancer.
doi:10.1111/j.1742-4658.2009.07328.x
FEBS Journal 276 (2009) 6049 ª 2009 The Author Journal compilation ª 2009 FEBS 6049