Genetics of Apoptosis

1.

Death receptors in apoptosis

Rajani Ravi and Atul Bedi

1.

Introduction

The requirement of cell death to preserve life is no paradox for multicellular animals.
Programmed cell death, or apoptosis, enables the physiologic culling of excess cells
during embryonic development and tissue remodeling or regeneration in adult
animals. In addition to maintaining homeostasis by controlling cell number in
proliferating tissues, apoptosis plays an instrumental role in the selective attrition of
neurons that fail to establish functional synaptic connections during the development
of vertebrate nervous systems. The vertebrate immune system uses apoptosis to delete
lymphocytes with inoperative or autoreactive receptors from its repertoire, and to
reverse clonal expansion at the end of an immune response. Cytotoxic T cells and
natural killer cells induce apoptosis of target cells to effect innate and adaptive immune
responses to intracellular pathogens, cancer cells, or transplanted tissues. The altruistic
demise of cells in response to cellular stress or injury, or genetic errors, serves to
preserve genomic integrity and constitutes an important mechanism of tumor
surveillance.
Given the crucial role of apoptosis in such a diverse array of physiologic functions,
it is no surprise that aberrations of this process underlie a host of developmental,
immune, degenerative, and neoplastic disorders. This appreciation has fueled a
furious investigation of the molecular determinants and mechanisms of apoptosis and
a search for the key regulators of this process (Hengartner, 2000). The molecular
execution of cell death involves activation of members of a family of cysteine-
dependent aspartate-specific proteases (caspases) by two major mechanisms. One
mechanism, termed the ‘intrinsic’ pathway, signals the release of prodeath factors
from the mitochondria via the action of pro-apoptotic members of the Bcl-2 family
(Green and Reed, 1998; Gross et al., 1999a; Green, 2000). An alternative mechanism
of activating caspases and mitochondrial disruption, termed the ‘extrinsic’ pathway,
is triggered by engagement of cell-surface ‘death receptors’ by their specific ligands
(Ashkenazi and Dixit, 1998).
In this chapter, we review our current understanding of the molecular determinants
and mechanisms of death receptor-induced apoptosis, and identify the key regulators