Elsevier

Human Pathology

Volume 32, Issue 10, October 2001, Pages 1029-1038
Human Pathology

Current Topics
The biology of apoptosis

https://doi.org/10.1053/hupa.2001.28250Get rights and content

Abstract

Apoptosis is a complex process that removes aging or injured cells from the body and occurs in a wide variety of organisms. Cell death has always been an integral aspect of the study of pathology, but only over the last 30 years or so has the interest in apoptosis gained appreciation in this field. This review analyzes pertinent aspects of apoptosis, from Virchow's initial dexriptions of necrobiosis to more modern research, and reviews some of the key events and molecules involved in the process. Finally, the role of apoptosis in certain diseases and its importance in the clinical setting is addressed. HUM PATHOL 32:1029-1038. Copyright © 2001 by W.B. Saunders Company

Section snippets

History

The father of modern pathology, Rudolf Virchow, was the first to describe organ injury and disease states as alterations in individual cells.7 Furthermore, in a series of lectures to colleagues at the Institute of Pathology in Berlin in 1858, he described a type of cell death he called “necrobiosis,” which was a result of “spontaneous wearing out of living parts.” In addition, he was clear in defining this type of cell death as differing from necrosis.8 Although it was not considered an

Nuclear changes

Since these initial reports describing apoptosis, there has been further characterization of morphologic events that occur during the apoptotic process. In addition to cellular macroscopic changes, apoptosis also involves nuclear changes. As discussed above, nuclear condensation is a common feature of apoptotic cells. Further examination of the chromatin within apoptotic nuclei has revealed changes in DNA–histone interactions and in the DNA itself. Using a monoclonal antibody to the histone

Apoptosis and disease

Because many disease states involve cell loss or a lack thereof, the study of apoptosis in pathology is crucial to the understanding and eventual treatment of many conditions. The following sections examine apoptosis in major diseases, describe methods of apoptosis detection, and analyze possible therapeutic potential. Because a more thorough review of each is beyond the scope of this review, these topics are covered briefly, with our apologies to the colleagues whose work we have omitted.

Summary

Apoptosis is a complex process that has supported a major research effort in the biomedical sciences. It occurs normally in mammary gland involution and tissue remodeling after lactation131 as well as in the menstrual cycles.132 Apoptotic cells can be seen normally in a number of other organs, such as the eye, intestines, skin, uterus, and between digits during development,27, 30, 133 the so-called degenerations that Glücksmann had discovered nearly 50 years ago.10 Therefore, with the large

References (133)

  • G Kroemer et al.

    Mitochondrial control of apoptosis

    Immunol Today

    (1997)
  • X Liu et al.

    Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c.

    Cell

    (1996)
  • ES Alnemri et al.

    Human ICE/CED-3 protease nomenclature

    Cell

    (1996)
  • J Yuan et al.

    The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme

    Cell

    (1993)
  • M Miura et al.

    Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3

    Cell

    (1993)
  • BB Wolf et al.

    Suicidal tendencies: Apoptotic cell death by caspase family proteinases

    J Biol Chem

    (1999)
  • Z Song et al.

    Death by design: Mechanism and control of apoptosis

    Trends Biochem Sci

    (1999)
  • S Kumar et al.

    Prodomains-adaptors-oligomerization: the pursuit of caspase activation in apoptosis

    Trends Biochem Sci

    (1999)
  • RU Janicke et al.

    Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis

    J Biol Chem

    (1998)
  • BB Wolf et al.

    Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation

    J Biol Chem

    (1999)
  • D Tang et al.

    Cleavage of DFF-45/ICAD by multiple caspases is essential for its function during apoptosis

    J Biol Chem

    (1998)
  • AM Chinnaiyan

    The apoptosome: heart and soul of the cell death machine

    Neoplasia

    (1999)
  • L Zhu et al.

    Modulation of mitochondrial Ca2+ homeostasis by bcl-2

    J Biol Chem

    (1999)
  • SL Schendel et al.

    Ion channel activity of the BH3 only Bcl-2 family member, BID

    J Biol Chem

    (1999)
  • S Nagata

    Apoptosis by death factor

    Cell

    (1997)
  • GB Cohen et al.

    Modular binding domains in signal transduction proteins

    Cell

    (1995)
  • S Nawaz et al.

    Hormonal regulation of cell death in rabbit uterine epithelium

    Am J Pathol

    (1987)
  • RJ Rotello et al.

    Coordinated regulation of apoptosis and cell proliferation by transforming growth factor β1 in cultured uterine epithelial cells

    Proc Natl Acad Sci U S A

    (1991)
  • LE Gerschenson et al.

    Apoptosis and cell proliferation are terms of the growth equation, in Apoptosis: The Molecular Basis of Cell Death

  • LT da Costa et al.

    Converting cancer genes into killer genes

    Proc Natl Acad Sci U S A

    (1996)
  • SW Lowe et al.

    Apoptosis in cancer

    Carcinogenesis

    (2000)
  • CR Casella et al.

    Mechanisms of lymphocyte killing by HIV

    Curr Opin Hematol

    (1997)
  • RS Cotran et al.

    Cellular injury and cellular death

  • R Virchow

    Passive processes. Fatty degeneration, in Cellular Pathology as Based Upon Physiological and Pathological Histology

  • A Glücksmann

    Cell deaths in normal vertebrate ontogeny

    Biol Rev

    (1951)
  • JFR Kerr

    Shrinkage necrosis: A distinct mode of cellular death

    J Pathol

    (1971)
  • JFR Kerr et al.

    Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics

    Br J Cancer

    (1972)
  • LE Gerschenson et al.

    Apoptosis: A different type of cell death

    FASEB J

    (1992)
  • SJ Zunino et al.

    Immunodetection of histone epitopes correlates with early stages of apoptosis in activated human peripheral T lymphocytes

    Am J Pathol

    (1996)
  • OS Frankfurt et al.

    Apoptosis in breast carcinomas detected with monoclonal antibody to single-stranded DNA: Relation to bcl-2 expression, hormone receptors, and lymph node metastases

    Clin Cancer Res

    (1997)
  • PR Walker et al.

    Evidence that DNA fragmentation in apoptosis is initiated and propagated by single-strand breaks

    Cell Death Differ

    (1997)
  • F Oberhammer et al.

    Apoptotic death in epithelial cells: Cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation

    EMBO J

    (1993)
  • GM Cohen et al.

    Formation of large molecular weight fragments of DNA is a key committed step of apoptosis in thymocytes

    J Immunol

    (1994)
  • GR Bicknell et al.

    Formation of high molecular mass DNA fragments is a marker of apoptosis in the human leukaemic cell line, U937

    J Cell Sci

    (1994)
  • HM Beere et al.

    Investigation of the mechanism of higher order chromatin fragmentation observed in drug-induced apoptosis

    Mol Pharmacol

    (1995)
  • H Steller

    Mechanisms and genes of cellular suicide

    Science

    (1995)
  • MM Compton

    A biochemical hallmark of apoptosis: Internucleosomal degradation of the genome

    Cancer Metastasis Rev

    (1992)
  • AH Wyllie

    Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

    Nature

    (1980)
  • RJ Rotello et al.

    Biochemical evidence for programmed cell death in rabbit uterine epithelium

    Am J Pathol

    (1989)
  • RJ Rotello et al.

    Characterization of uterine epithelium apoptotic cell death kinetics and regulation by progesterone and RU 486

    Am J Pathol

    (1992)
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    Address correspondence and reprint requests to F. Jon Geske, PhD, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206.

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