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Caspase Activation by the Extrinsic Pathway

  • Chapter
Death Receptors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Apoptosis, or programmed cell death, has been an area of extensive study since the early 1990s, largely due to its essential role in the development and maintenance of homeostasis and its implication in numerous diseases, ranging from cancer and autoimmunity to neurodegeneration and immunodeficiency (1). To date, one of the most important insights into the molecular mechanism of apoptosis is the discovery that apoptosis is executed by a family of intracellular proteases known as caspases. Caspases are cysteine aspases, i.e., they use cysteine as the nucleophilic group in their active site to cleave proteins after aspartic acid residues. This discovery initially came a decade ago with the cloning of CED-3, a Caenorhabditis elegans gene required for developmental cell death. During the development of this small organism, 1090 somatic cells are generated, 131 of which are deleted by apoptosis (2,3). Genetic analysis has revealed a core apoptotic program in C. elegans comprised of three genes: CED-3, CED-4, and CED-9, with the first two promoting apoptosis and the latter inhibiting it. Epistatic analysis has identified CED-3 as the most downstream component of this program, suggesting that the functions of CED-4 and CED-9 are to control CED-3 activity. CED-3 encodes a protein this is significantly similar to the only other caspase identified at that time, caspase-1, or interleukin(IL)-1β converting enzyme (ICE), which, as its name indicates, is responsible for processing pro-IL-1β to its mature form, a potent inflammatory cytokine (4,5). This finding has placed caspases at the center of apoptosis study, leading to earnest efforts to identify additional caspases in a range of organisms and extensive investigation of their functions and regulation. Presently, fourteen caspases have been found in mammals, five in Drosophila, and three in C. elegans. A large number of studies using inhibitors of caspases (either small peptide inhibitors or protein inhibitors encoded by viruses) and cells and animals deficient in caspases have confirmed a critical role of some caspases in apoptosis (6–8). However, other caspases appear to mainly function in nonapoptotic processes such as inflammation. Mammalian caspases are named according to the order in which they were identified (9). The apoptosis caspases include caspase-2, -3, -6, -7, -8, -9, -10, and -12, and the inflammatory caspases are caspase-1, -4, -5, and -11 (Fig. 1).

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA

    Xiaolu Yang PhD

  2. Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA

    Xiaolu Yang PhD

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  1. Xiaolu Yang PhD
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Editors and Affiliations

  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  3. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

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© 2005 Humana Press Inc., Totowa, NJ

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Yang, X. (2005). Caspase Activation by the Extrinsic Pathway. In: El-Deiry, W.S. (eds) Death Receptors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-851-X:111

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  • DOI: https://doi.org/10.1385/1-59259-851-X:111

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-172-1

  • Online ISBN: 978-1-59259-851-9

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