Apoptosis

5 Key excerpts on "Apoptosis"

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  eBook - ePub

  Biochemistry of Signal Transduction and Regulation

  • Gerhard Krauss(Author)
  • 2014(Publication Date)
  • Wiley-VCH

    (Publisher)

  17 Apoptosis

  Eukaryotic cells can self-destruct in an orderly, highly controlled process known as Apoptosis. The term Apoptosis, which was first coined following investigations of the nematode Caenorhabditis elegans, is of Greek origin and describes the “falling of leaves.” Activation of the apoptotic program involves the coordinated demolition of intracellular structures by members of the caspase family of proteases. This is accompanied by characteristic changes in cell morphology, such as condensation of the chromatin, the degradation of DNA, cell shrinkage, fragmentation of the cell nucleus, and disassembly into membrane-enclosed apoptotic vesicles.

  Apoptosis is based on a genetic program that forms an indispensable part of the development and function of an organism, and serves to eliminate any undesired or superfluous cells in a targeted manner. The functions of Apoptosis target the major biological processes of the cell, including:

  • tissue homeostasis;
  • the elimination of cells during differentiation and development;
  • the elimination of cells during immune responses; and
  • the elimination of damaged cells to avoid propagation of mutations and degeneration into tumor cells.

  The major part of the apoptotic program, which exists in the cell in a latent, inactive form, requires only an apoptotic stimulus to activate the program and to induce Apoptosis. Thus, apoptotic processes may be initiated within a short timescale, without the activation of transcription. Some forms of Apoptosis are also known that are dependent on transcription. Due to the potential deleterious consequences of an inappropriate activation of Apoptosis in normal cells, the apoptotic program is strictly controlled by the balanced input of pro-apoptotic and anti-apoptotic signals originating from internal and external sources. Many signals that feed into the apoptotic program are transmitted via cellular signaling pathways involved in the control of cell proliferation and homeostasis. Furthermore, all signaling pathways that form part of stress responses and DNA-damage checkpoints have links to the apoptotic program and can induce its activation.

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  Apoptosis and Beyond

  The Many Ways Cells Die

  • James A. Radosevich(Author)
  • 2018(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  Apoptosis. Apoptosis can be simply defined as a set of biochemical cytoplasmic and mitochondrial events that may lead to the execution phase of nuclear events.

  A wide array of stress stimuli can trigger the apoptotic process, and the biochemical signal can then be amplified in the cytoplasm and mitochondria by both extrinsic and intrinsic pathways. The convergence of the apoptotic signal is considered the activation of a family of cysteine aspartyl-specific proteases (caspases), composed of 12 proteins strictly involved in the apoptotic cell death process. The dying cells activate the execution pathway that leads to the appearance of blebs and to the “pinching off” of many of them, forming “apoptotic bodies,” which may be rounded and retracted from their own tissue. Subsequently, the immune system cells are able to eliminate the apoptotic bodies through an engulfment cell process. The morphological and biochemical features during the apoptotic process are not fully understood.

  At the nuclear level, it is well established that endonucleases and exonucleases may hydrolyze the DNA into small fragments (200 pb) [1]. The nuclear events depend on caspase activation. Caspase 3 is considered the most important protease of the executioner pathway, and is activated by different initiator caspases. For instance, caspase 8 is activated from the death receptor, caspase 9 is involved in the mitochondrial apoptotic process, and caspase 10 is involved in the Perforin/granzyme (PFN/Gzm) pathways. The cleaved caspase 3 cleaves the endonuclease caspase-activated DNase (CAD), degrading the DNA at nucleosomal linkers [2,3], which generates small DNA fragments (∼50–300 kb). The subsequent processing of the DNA by exonucleases and endonucleases leads to the formation of 200 bp fragments. Many organelles, such as the Golgi apparatus, endoplasmic reticulum (ER), lysosomes, and mitochondria, can be recycled or eliminated, depending on the apoptotic stimuli. It is important to note that mitochondria play a pivotal role in Apoptosis, since they can release cytochrome c (cyt c) and endonuclease D (endo D), leading to cell death [4,5].

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  The Molecular Biology of Cancer

  A Bridge from Bench to Bedside

  • Stella Pelengaris, Michael Khan(Authors)
  • 2013(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  All cells live under the shadow of death and when the inevitable happens, at least under normal physiological conditions, this usually occurs by Apoptosis. A staggering 50 billion or more cells die each day in the human adult. Just to balance the books each one of us replaces around 70 kg of cells every year (enough to make a full-sized adult human clone – all be it minus some neurons).

  Apoptosis, a characteristic form of programmed cell death often termed “cell suicide,” is a fundamental process that is essential for development, maintenance of tissue homeostasis, and the elimination of damaged cells. However, too much or too little Apoptosis may lead to diseases such as neurodegenerative disorders, diabetes, or cancer. It is now widely accepted that putative cancer cells must avoid Apoptosis in order for tumors to arise (see Chapters 6 and 7) and this is regarded as one of the “hallmark” features of cancer. This knowledge has fueled global research efforts into elucidating signal transduction pathways that mediate Apoptosis as well as the mechanisms that have enabled cancer cells to avoid it (for example, through the loss of p53 tumor suppressor or overexpression of BCL-2 protein). For obvious reasons, a key objective in cancer research is to develop candidate drug molecules that can rekindle the suicidal urges of cancer cells and restore their sensitivity to Apoptosis.

  An Historical Perspective

  There is only one ultimate and effectual preventive for the maladies to which flesh is heir, and that is death.

  Harvey Cushing

  Although studies on cell death are thought to have been performed centuries ago by Aristotle, and later by Galen, who described the regression of larval and fetal structures during development (and probably first used the term “necrosis”) it was not until after the formulation of the “cell theory” by Jacob Schleiden and Theodore Schwann in 1838 that nineteenth-century pathologists, in particular those of the “German school,” started to take interest in the process of cell death as a physiological phenomenon. Initially, it was appreciated that cells can die (in fact this was implicit from the time it was first realized that cells existed and were alive), but such death was assumed to be a passive response with cells as the victims of circumstances, such as poisons, and trauma, including death of the organism, largely beyond their control. This view began to change in the latter half of the nineteenth century, although it would be over a century later that cell death was first recognized by modern biology as a normal feature of multicellular organisms, and moreover, that this might be a process involving the active participation of the cell. In 1842, Carl Vogt suggested that cell death could be an important part of normal development based on observations in amphibian metamorphosis. This was followed by Rudolf Virchow, widely regarded as the father of modern pathology, who in 1858 described what he called “degeneration, necrosis and mortification.”

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  Rediscovering Cancer: From Mechanism to Therapy

  • Sayali Mukherjee, Somali Sanyal, Sonia Chadha(Authors)
  • 2018(Publication Date)
  • Apple Academic Press

    (Publisher)

  Developmental process and health of multicellular organisms are maintained by a physiological process termed as Apoptosis. A balance between cell death and cell proliferation ultimately maintains the cellular homeostasis. Apoptosis is a controlled cellular death; a process that activates death-signaling pathways for deleting cells from tissues. Two major pathways execute the complex process of Apoptosis. Deregulated apoptotic pathways drive normal cells toward carcinogenesis and ultimately therapy resistance. Therefore knowledge about the role of death genes, death signals, signaling pathways involved in Apoptosis regulation is highly warranted. During tumorigenesis process, aberrant expression or loss of lead protein members of apoptotic pathways have been indicated. Inactivation of these proteins leads to impairment of Apoptosis and contributes to cellular growth and proliferation. Such events ultimately cause a serious imbalance in growth dynamics, an essential root of cancer. Cancer cells have been reported to evolve a strategy to evade Apoptosis. The present review discusses about the recent knowledge related to regulatory mechanism of Apoptosis in cancer with particular emphasis on key proteins like Bcl-2 protein family, inhibitor of Apoptosis protein or IAPs, p53 and caspases. Damage to DNA due to exogenous or endogenous stimuli activates and stabilizes p53 and triggers extrinsic and intrinsic apoptotic pathways. Understanding the regulatory mechanism of Apoptosis in cancer from this review might expose new scopes to therapeutic approaches.

  6.1 Introduction

  A homeostatic balance between cell growth and death is a major responsible factor for the development and maintenance of biological systems. This balance is maintained by a physiological process termed Apoptosis, which is a programmed event of cell death occurring in an orchestrated manner. This is a process found in all multicellular organisms for killing and removing specific cells not required by the system so as to maintain cellular equilibrium. It being an evolutionarily conserved process is observed from nematodes and flies to mice and humans. The process is also a pivotal constituent for the development of plant cells [1 ]. Apoptosis is considered as an inevitable process, essential for normal cell turnover, immune system functioning, hormone-mediated cellular atrophy, normal embryonic development, unwanted cell elimination, and homeostatic maintenance [2 ]. Dysregulation in cellular homeostasis due to restricted or inadequate apoptotic event may accelerate progression of cancer or development of autoimmunity. On the contrary, excessive cell death by Apoptosis culminates into chronic neurodegeneration, deficiency in the immune system and impairment of fertility. Apoptotic signaling is essential for maintenance of genomic integrity; while impairment of this pathway contribute to carcinogenesis and subsequently rendering cancer cells resistant to therapy. Evasion of Apoptosis, a mechanism utilized by cancerous cells, is considered as a notable indication of tumor development and metastasis [3 ,4

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  Mammalian Toxicology

  • Mohamed Abou-Donia(Author)
  • 2015(Publication Date)
  • Wiley

    (Publisher)

  Specific cell types have distinct thresholds for each of these stresses to cause cell death. These thresholds for damage depend not only on the role of the cell, but also – more importantly – on how readily replaceable that cell may be. Neurons for example, are very difficult and often impossible to replace should they undergo cell death. Consequently, neurons are wired to be highly resistant to cell death – both from a loss of survival signals or damage-induced stress. In contrast, lymphocytes and many other hematopoietic cells are being constantly being replaced via the hematopoietic stem cell production of new lineage-committed daughter cells. These cells are highly reliant on survival signals and are very susceptible to cell stress and death mechanisms. Consequently, the need to balance cell replacement with cell death will greatly influence the threshold at which cellular stress or dependence on survival signals can induce death. This type of balance plays a key role in the pathological effects of many toxins. For example, those toxins that broadly target cells throughout the body will have a greater effect on the most sensitive cells, while other cells may sustain damage but resist the death that could potentially follow. The advantage of this strategy is that cells are maintained in precious and difficult-to-replace tissues; however, the disadvantage is that some of those surviving cells may have longlasting detrimental effects of toxin-induced cellular damage.

  4.3 Forms of Cell Death

  Kerr and Wyllie first defined the process of Apoptosis in 1972 [4] when, by using electron micrography, they showed that dying cells treated with toxic agents underwent a well-defined and reproducible morphological process referred to as ‘Apoptosis.’

  Apoptosis is defined by physical changes in cell shape and patterns, and the molecular details that have been recognized to drive and mediate the process will be described in the following sections. A cellular stress to induce Apoptosis is initially characterized by the release of cells from their extracellular contacts and neighbors; in cell culture, this results in the cells becoming rounded and beginning to shrink. In addition to overall cell shrinkage, the intracellular organelles become smaller, with the nucleus in particular condensing. Chromatin also condenses into electron-dense regions, and at this point the plasma membrane initiates a ‘blebbing’ process during which invaginations and protrusions of the plasma membrane result in the release of small vesicular structures termed ‘apoptotic bodies.’ Importantly, the plasma membrane remains intact throughout this process so that the cellular contents are prevented from exiting into the surrounding environment (this aspect of Apoptosis may play a key role in restraining viral spread). The neighboring cells then encroach and engulf the apoptotic cell, targeting the cell corpse towards lysosomes for its efficient degradation and clearance. The entire process of release, condensation, blebbing and engulfment is quite rapid, and may occur in less than one hour, cleanly and efficiently packaging the damaged cells for clearance and engulfment.

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