Deciphering the pathways of life and death

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Abstract

Caspase recruitment and oligomerization mediated by adaptor proteins constitute a basic mechanism of caspase activation. The complex phenotypes of the caspase knockout mice indicate that multiple mechanisms of caspase activation operate in parallel and that death signal transduction pathways are both cell-type and stimulus specific. The BH3-domain-containing pro-apototic members of Bcl-2 family may be one of the critical links between the initial death signals and the central machinery of apoptosis.

Introduction

Apoptosis, or programmed cell death, is a cell-intrinsic process that is essential for animal development and tissue homeostasis. Malfunction or dysregulation of this tightly controlled mechanism of cell suicide may result in cancer, neurodegenerative diseases, or other pathological conditions. A variety of extracellular and intracellular signals can trigger an apoptotic response, including cross-linking of so-called ‘death receptors’ (such as Fas and tumor necrosis factor [TNF] receptors), ultraviolet (UV) and ionizing radiation, anticancer drugs, growth factor deprivation, and overexpression of certain oncogenes or tumor suppressor genes. Despite the diversity of these signals and of the immediate downstream pathways which transduce them, the execution of apoptosis is uniformly mediated through the activation of caspases — an evolutionarily conserved family of cysteine proteases that catalyze the cleavage of target proteins at sites downstream of specific aspartic acid residues.

Although much has been learned over the last five years or so about this final common pathway of apoptosis, we still know little about the mechanisms by which cells channel the various death signals into this pathway of caspase activation. Here, we review recent progress in elucidating the mechanisms of caspase activation in various model systems with the aim of providing a better understanding of the connection between death signal transduction and the basic apoptotic machinery.

Section snippets

Activation of long-prodomain caspases through recruitment and oligomerization

Caspases — which share sequence and other structural similarities with the CED-3 protein of the nematode Caenorhabditis elegans — are synthesized as proenzymes that are composed of three domains: an amino-terminal prodomain and two other domains corresponding to the large subunit (about 20 kDa) and the small subunit (about 10 kDa) of the mature protein [1]. Procaspases can be activated through proteolytic cleavage events at two sites: one site between the pro-domain and the large subunit and

Lessons learned from knockout mice lacking caspases or cognate adapter proteins

Analysis of the phenotypes of knockout mice provides important insights into the functions of the corresponding gene products in vivo. Recent characterization of knockout mice lacking specific caspases or their corresponding adapter proteins has shed light on the roles of these proteins in apoptosis (Table 1). Several important conclusions can be drawn from the complex phenotypes of these knockout mice.

First, different death stimuli induce apoptosis by distinct signaling pathways. For example,

Bcl-2 homology 3 (BH3)-domain-containing members of the Bcl-2 family: intracellular transducers of death signals

Mitochondria have been implicated as important sensors and amplifiers in intracellular death signaling pathways. Mitochondrial damage — as revealed by morphological and biochemical changes such as swelling, disruption of the outer membrane, depolarization, and the release of the pro-apoptotic factor cytochrome c — is evident early during apoptosis. Both, Bcl-2 and Bcl-xL, the mammalian structural and functional homologs of C. elegans CED-9 proteins, play important roles as protectors of

Conclusions

Recent biochemical and genetic studies have substantially increased our understanding of death signal transduction pathways. Analyses of caspase knockout mice have not only established distinct roles for each of these proteases in different death pathways, but also provided clues for the design of specific inhibitors of apoptosis. It is now clear that apoptosis is not a single-lane one-way street. Multiple parallel pathways have been identified. Thus, when one pathway is blocked, as in caspase

Acknowledgements

This work was supported by an Established Investigatorship from the American Heart Association (to Junying Yuan) and a postdoctoral fellowship from the National Institute of Aging (Honglin Li).

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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