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