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    Apoptosis: Proliferation, Differentiation and Apoptosis Are Crucial To Development

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    Insyirah Johari
    1. Apoptosis, or programmed cell death, is an essential process for normal development and homeostasis. It involves the carefully coordinated collapse and degradation of cells. 2. Apoptosis can be initiated through either extrinsic or intrinsic pathways. The extrinsic pathway involves death ligands binding to cell surface death receptors, while the intrinsic pathway is triggered by intracellular stresses like DNA damage and involves the release of cytochrome c from mitochondria. 3. Both pathways activate a cascade of caspases, cysteine proteases that cleave cellular proteins and DNA, leading to the characteristic morphological changes of apoptosis including cell shrinkage, nuclear fragmentation, and membrane blebbing to form apoptotic bodies that are phagocytosed.

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    Apoptosis: Proliferation, Differentiation and Apoptosis Are Crucial To Development

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    Insyirah Johari
    85 views21 pages
    1. Apoptosis, or programmed cell death, is an essential process for normal development and homeostasis. It involves the carefully coordinated collapse and degradation of cells. 2. Apoptosis can be initiated through either extrinsic or intrinsic pathways. The extrinsic pathway involves death ligands binding to cell surface death receptors, while the intrinsic pathway is triggered by intracellular stresses like DNA damage and involves the release of cytochrome c from mitochondria. 3. Both pathways activate a cascade of caspases, cysteine proteases that cleave cellular proteins and DNA, leading to the characteristic morphological changes of apoptosis including cell shrinkage, nuclear fragmentation, and membrane blebbing to form apoptotic bodies that are phagocytosed.

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    1. Apoptosis, or programmed cell death, is an essential process for normal development and homeostasis. It involves the carefully coordinated collapse and degradation of cells. 2. Apoptosis can be initiated through either extrinsic or intrinsic pathways. The extrinsic pathway involves death ligands binding to cell surface death receptors, while the intrinsic pathway is triggered by intracellular stresses like DNA damage and involves the release of cytochrome c from mitochondria. 3. Both pathways activate a cascade of caspases, cysteine proteases that cleave cellular proteins and DNA, leading to the characteristic morphological changes of apoptosis including cell shrinkage, nuclear fragmentation, and membrane blebbing to form apoptotic bodies that are phagocytosed.

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    85 views21 pages

    Apoptosis: Proliferation, Differentiation and Apoptosis Are Crucial To Development

    Uploaded by

    Insyirah Johari
    1. Apoptosis, or programmed cell death, is an essential process for normal development and homeostasis. It involves the carefully coordinated collapse and degradation of cells. 2. Apoptosis can be initiated through either extrinsic or intrinsic pathways. The extrinsic pathway involves death ligands binding to cell surface death receptors, while the intrinsic pathway is triggered by intracellular stresses like DNA damage and involves the release of cytochrome c from mitochondria. 3. Both pathways activate a cascade of caspases, cysteine proteases that cleave cellular proteins and DNA, leading to the characteristic morphological changes of apoptosis including cell shrinkage, nuclear fragmentation, and membrane blebbing to form apoptotic bodies that are phagocytosed.

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    of 21

    APOPTOSIS

    proliferation, differentiation and apoptosis


    are crucial to development
    Cell death by injury

    -Mechanical damage

    -Exposure to toxic chemicals

    Cell death by suicide (Apoptosis)

    -Internal signals

    -External signals
    Apoptosis or programmed cell death, is
    carefully coordinated collapse of cell, protein
    degradation , DNA fragmentation followed
    by rapid engulfment of apoptotic vesicles by
    neighbouring cells.
    Essential part of life for every multicellular
    organism .
    Apoptosis plays a major role from
    embryonic development to senescence.
    Why should a cell commit suicide?
    Apoptosis is needed for proper development
    Examples:
    –The formation of the fingers and toes of the fetus
    –The sloughing off of the inner lining of the uterus
    –Maintenance of proper cell number in tissues,
    –The formation of the proper connections between neurons in the
    brain.
    Apoptosis is needed to destroy cells
    Examples:
    –Cells infected with viruses
    –Cells of the immune system
    –Cells with DNA damage
    –Cancer cells
    Why should a cell commit suicide?
    A form of apoptosis is a normal part of embryonic
    development. For example, the development of the
    nervous system uses apoptosis to destroy neurons that
    have not made the proper connections with target cells.
    Neurons are produced in excess, and more than 50% of
    developing neurons are eliminated by programmed cell
    death. Those neurons that have made the correct
    connections survive by secreting growth factors that
    block apoptosis.
    Necrosis vs. Apoptosis

    Necrosis Apoptosis
    • Cellular swelling • Cellular condensation
    • Membranes are broken • Membranes remain intact
    • ATP is depleted • Requires ATP
    • Cell lyses, eliciting an • Cell is phagocytosed, no
    inflammatory reaction tissue reaction
    • DNA fragmentation is • Ladder-like DNA
    random, or smeared fragmentation
    • In vivo, whole areas of • In vivo, individual cells
    the tissue are affected appear affected
    NECROSIS Vs APOPTOSIS

    Wilde, 1999
    APOPTOSIS: Morphological events
    cell shrinkage
    organelle reduction
    mitochondrial leakage
    chromatin condensation
    nuclear fragmentation
    membrane blebbing & changes
    Blebbing & Apoptotic bodies
    The control retained over the cell
    Bleb membrane & cytoskeleton allows intact
    pieces of the cell to separate for
    recognition & phagocytosis .

    Apoptotic body

    M M
    Apoptosis can be initiated by several stimuli:
    - by injury, radiation, free radicals or other toxins,
    - withdrawal of growth factors or hormones,
    - binding of pro-apoptotic cytokines,
    - or interactions with cytotoxic T cells in the
    immune system.
    - Apoptosis can protect organisms from the
    negative effect of mutations by destroying cells
    with irreparably damaged DNA before they
    proliferate.

    Just as an excess of a growth signal can produce an


    excess of unwanted cells, the failure of apoptosis
    to remove excess or damaged cells can
    contribute to the development of cancer.
    Apoptosis: Pathways
    “Extrinsic Pathway”

    Death Death Initiator


    Ligands Receptors Caspase 8

    Effector
    “Intrinsic Pathway”
    Caspase 3 Cell
    death
    DNA da Initiator
    mage Mitochondria/
    & p53 Cytochrome C Caspase 9
    1- Extrinsically or Receptor-
    mediated apoptosis results from the
    interaction of a ligand with a specific
    transmembrane receptor, the most important
    are the Fas receptor and tumor necrosis factor
    receptor (TNFR).
    FasL
    Apoptosis TNF

    Fas TNF-R1
    Mit
    TRADD
    FADD Cyt c
    Cas8
    Caseff Protein degradation

    DNase Cell death


    FasL: Fas ligand (cytokines, interferons, interleukins)
    Fas: Fas surface receptor (CD95 or APO1)
    FADD: Fas-associated death domain Cas8: cysteine-dependent
    aspartate-specific cysteine protease, caspase 8
    Mit: mitochondrion Cyt c: cytochrome cCaseff: effector caspase
    TNF: tumor necrosis factor TNF-R1: tumor necrosis factor receptor
    TRADD: tumor necrosis factor-associated death domain
    2- Intrinsically through DNA damage
    Radiation, hypoxia, free radicals and chemical agents as
    chemotherapy produce DNA damage. These changes
    produce activation of p53, which produces arrest of cell
    cycle and allows for DNA repair or activate the apoptotic
    pathway through activation of the apoptotic gene i.e.
    Bax gene. Loss of protein Bax function as a result of
    gene mutation is associated with cancer development e.g.
    gastric adenocarcinoma. BcI-2 is an antiapoptotic
    protein that acts through binding with protein Bax and
    produces its inactivation. Increased level of Bcl-2 is
    associated with cancer development. In normal cells,
    both proteins Bax and Bcl-2 are present in
    balance.
    Apoptosis is initiated by activation of certain
    proapoptotic protein factors that result in
    the following cascade:
    • 1-Release of cytochrome c from the
    mitochondria to the cytosol.
    • 2- The release of cytochrome c produces
    an activation cascade that leads to
    activation of caspases. These are a group
    of enzymes that split cellular proteins (a
    type of cysteine proteases that hydrolyze
    the peptide bonds attached to the
    carboxylic group of aspartate residues of
    polypeptide chains).
    • 3- Also, caspases produce activation of
    endonucleases that split DNA, termed
    caspase activated DNase (CAD). CAD
    produces a series of DNA fragments
    varying in length by approximately 200 bp
    (nucleosomal fragments and their
    multiples), these fragments have
    characteristic ladder appearance on gel
    electrophoresis (it is a diagnostic test).
    • Importance of Apoptosis: Apoptosis plays
    a very important role in embryonic
    development, aging, autoimmune
    diseases and cancer development. In
    case of menstrual cycle, programmed cell
    death is initiated in uterine endometrial
    cells by fall in the levels of progesterone
    and estradiol in blood and precipitating
    menstruation.
    • Excess apoptosis
    – Neurodegenerative diseases

    • Deficient apoptosis
    – Cancer
    – Autoimmunity
    Apoptosis signal to kill infected cells
    Cytolytic lymphocyte/CTL (& natural killer lymphocyte)
    presents Fas ligand/CD178 on its surface to tell the infected
    cell to die

    Fas ligand

    CTL Virally
    infected Externally driven
    Apoptotic signals
    cell
    Cytochrome c

    Initiator caspases
    The immunological
    synapse holds the cells
    much tighter together
    Execution caspases
    than shown here

    Apoptosis events
    Fas/ CD95 is the
    ‘death receptor’

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