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C gel electrophoresis of dna from apoptotic cells

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Unformatted text preview: ophoresis of DNA from apoptotic cells, showing its degradation to fragments corresponding to multiples of 200 base pairs (the size of nucleosomes) at 14 hours following induction of apoptosis. (B, courtesy of D. R. Green/La Jolla Institute for Allergy and Immunology; C, courtesy of Ken Adams, Boston University.) This material cannot be copied, reproduced, manufactured, or disseminated in any form without express written permission from the publisher. 2009 Sinauer Associates, Inc. UNCORRECTED PAGE PROOFS CELL DEATH AND CELL RENEWAL 3 Normal cell Cytosol Outside of cell Phosphatidylserine Apoptosis FIGURE 17.2 Phagocytosis of apoptotic cells Apoptotic cells and cell fragments are recognized and engulfed by phagocytic cells. One of the signals recognized by phagocytes is phosphatidylserine on the cell surface. In normal cells, phosphatidylserine is restricted to the inner leaflet of the plasma membrane, but it becomes expressed on the cell surface during apoptosis. Receptor Phagocytic cell usually fragmented as a result of cleavage between nucleosomes. The chromatin condenses and the nucleus then breaks up into small pieces. Finally, the cell itself shrinks and breaks up into membrane-enclosed fragments called apoptotic bodies. Apoptotic cells and cell fragments are efficiently recognized and phagocytosed by both macrophages and neighboring cells, so cells that die by apoptosis are rapidly removed from tissues. In contrast, cells that die by necrosis swell and lyse, releasing their contents into the extracellular space and causing inflammation. The removal of apoptotic cells is mediated by the expression of so-called "eat me" signals on the cell surface. These signals include phosphatidylserine, which is normally restricted to the inner leaflet of the plasma membrane (see Figure 13.2). During apoptosis, phosphatidylserine becomes expressed on the cell surface where it is recognized by receptors expressed by phagocytic cells (Figure 17.2). Pioneering studies of programmed cell death during the development of C. elegans provided the critical initial insights that led to understanding the molecular mechanism of apoptosis. These studies in the laboratory of Robert Horvitz initially identified three genes that play key roles in regulating and executing apoptosis. During normal nematode development, 131 somatic cells out of a total of 1090 are eliminated by programmed cell death, yielding the 959 somatic cells in the adult worm. The death of these cells is highly specific, such that the same cells always die in developing embryos. Based on this developmental specificity, Robert Horvitz undertook a genetic analysis of cell death in C. elegans with the goal of identifying the genes responsible for these developmental cell deaths. In 1986 mutagenesis of C. elegans identified two genes, ced-3 and ced-4, that were required for developmental cell death. If either ced-3 or ced-4 was inactivated by mutaThis material cannot be copied, reproduced, manufactured, or disseminated in any form without express written permission from the publisher. 2009 Sinauer Associates, Inc. The term apoptosis is derived from the Greek word describing the falling of leaves from a tree or petals from a flower. It was coined to differentiate this form of programmed cell death from the accidental cell deaths caused by inflammation or injury. 17.1 WEBSITE ANIMATION Apoptosis During apoptosis, chromosomal DNA is usually fragmented, the chromatin condenses, the nucleus breaks up, and the cell shrinks and breaks into apoptotic bodies. UNCORRECTED PAGE PROOFS 4 CHAPTER 17 KEY EXPERIMENT Identification of Genes Required for Programmed Cell Death Genetic Control of Programmed Cell Death in the Nematode C. elegans Hilary M. Ellis and H. Robert Horvitz Massachusetts Institute of Technology, Cambridge, MA Cell, 1986, Volume 44, pages 817829 The Context By the 1960s cell death was recognized as a normal event during animal development, implying that it was a carefully regulated process with specific cells destined to die. The simple nematode C. elegans, which has been a critically important model system in developmental biology, proved to be key to understanding both the regulation and the mechanism of such programmed cell deaths. Microscopic analysis in the 1970s established a complete map of C. elegans development so that the embryonic origin and fate of each cell was known. Importantly, C. elegans development included a very specific pattern of programmed cell deaths. In particular, John Sulston and H. Robert Horvitz reported in 1977 that the development of adult worms (consisting of 959 somatic cells) involved the programmed death of 131 cells out of 1090 that were initially produced. The same cells died in all embryos, indicating that the death of these cells was a normal event during development, with cell death being a specific developmental fate. It was also notable that all of these dying cells underwent a similar series of morphological changes, suggesting that these programmed cell deaths occurred by a common mechanism. Based on these considerations, Horv...
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This note was uploaded on 08/25/2009 for the course BIO 315 taught by Professor Steiner during the Spring '08 term at Kentucky.

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