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Proteasome Inhibition and Apoptosis

  • Chapter
Proteasome Inhibitors in Cancer Therapy

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

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Abstract

Programmed cell death is an energy-dependent process of cellular elimination that is necessary in all stages of life, including development, tissue homeostasis, and aging in multicellular organisms. Work by Wyllie, Kerr, and Currie identified the large phenotypic changes in the morphology of cells undergoing programmed cell death such as nuclear condensation and the dismantling of cellular material into membrane-enclosed packages; they termed these changes apoptosis. In 1972 they published a seminal paper that correctly predicted the physiologic and pathophysiologic relevance of their findings (1), and Wyllie went on to explore some of the biochemical characteristics that are signs of apoptosis, describing the cleavage of DNA into discrete nucleosomal multimers (DNA ladders) (2). In the 1970s Horvitz and colleagues described the loss of 131 cells during the development of the nematode Caenorhabetitis elegans. Mutagenesis studies subsequently implicated three genes in this process (ced-3, ced-4, and egl-1) that when inactivated caused the retention of the normally eliminated cells (3,4). A fourth gene (ced-9) was identified that promoted cell survival, in that its loss resulted in the death of more cells than normal (5). These proapoptotic gene products, EGL-1, CED-3, and CED-4, along with their antiapoptotic counterpart, CED-9, proved to be components of an evolutionarily conserved, biochemical cascade responsible for cellular elimination.

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  1. Simon A. Williams
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  2. David J. McConkey
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  1. Infinity Pharmaceuticals Inc., Cambridge, MA, USA

    Julian Adams PhD

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Williams, S.A., McConkey, D.J. (2004). Proteasome Inhibition and Apoptosis. In: Adams, J. (eds) Proteasome Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-794-9_7

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  • DOI: https://doi.org/10.1007/978-1-59259-794-9_7

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