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    Apoptosis and Cancer

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    priyaa
    Apoptosis is programmed cell death that removes damaged or unnecessary cells. It was discovered in the 1970s and involves cells shrinking, blebbing, and breaking into fragments that are phagocytosed. Apoptosis can be triggered intrinsically via mitochondrial pathways or extrinsically through death receptor signaling like Fas ligand binding. The tumor suppressor p53 plays a key role in apoptosis and defects in these pathways contribute to cancer by allowing abnormal cell accumulation and survival.

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    Apoptosis and Cancer

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    priyaa
    201 views20 pages
    Apoptosis is programmed cell death that removes damaged or unnecessary cells. It was discovered in the 1970s and involves cells shrinking, blebbing, and breaking into fragments that are phagocytosed. Apoptosis can be triggered intrinsically via mitochondrial pathways or extrinsically through death receptor signaling like Fas ligand binding. The tumor suppressor p53 plays a key role in apoptosis and defects in these pathways contribute to cancer by allowing abnormal cell accumulation and survival.

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    Apoptosis is programmed cell death that removes damaged or unnecessary cells. It was discovered in the 1970s and involves cells shrinking, blebbing, and breaking into fragments that are phagocytosed. Apoptosis can be triggered intrinsically via mitochondrial pathways or extrinsically through death receptor signaling like Fas ligand binding. The tumor suppressor p53 plays a key role in apoptosis and defects in these pathways contribute to cancer by allowing abnormal cell accumulation and survival.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    201 views20 pages

    Apoptosis and Cancer

    Uploaded by

    priyaa
    Apoptosis is programmed cell death that removes damaged or unnecessary cells. It was discovered in the 1970s and involves cells shrinking, blebbing, and breaking into fragments that are phagocytosed. Apoptosis can be triggered intrinsically via mitochondrial pathways or extrinsically through death receptor signaling like Fas ligand binding. The tumor suppressor p53 plays a key role in apoptosis and defects in these pathways contribute to cancer by allowing abnormal cell accumulation and survival.

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    of 20

    Apoptosis and

    Cancer
    What is Apoptosis?
    • Apoptosis is “programmed cell death”.

    • Apoptosis is a normal physiological process:


    – Foetal development: finger and toe development requires loss of
    tissue between.
    – Removal of endometrium at menstruation.
    – Formation of synapses in brain requires loss of surplus cells.

    • Apoptosis is need to remove cells that pose a threat:


    – Cytotoxic T lymphocytes kill viral infected cells by inducing
    apoptosis.
    – Effector cells of the immune system must be removed after the
    response.
    – Damaged cells must be removed if they cannot be repaired.
    Apoptosis
    • Apoptosis from Greek, meaning “to fall
    away from.”

    • The release of apoptotic bodies from


    cells is supposed to be analogous to
    “leaves falling from trees.”

    • Pronounced A-po-toe-sis
    Discovery of Apoptosis
    • Kerr, J.F.R, Wyllie, A.H. Currie, A.R., 1972. Apoptosis:
    a basic biological phenomenon with wide ranging
    implications in tissue kinetics. British Journal Cancer
    26, 239-257.

    • They observed a “necrosis-like” process in the livers


    of rats where the portal supply of blood had been
    interrupted.

    • No inflammation was observed (typical of necrosis).

    • Histologically, the cells appeared as small particles


    of chromatin surrounded by cytoplasm.
    Apoptosis in Cells
    • Cells that undergo apoptosis:
    – Shrink.
    – Develop bubble-like blebs on their surface.
    – Chromatin (DNA + protein) begins to degrade.
    – Mitochondria break up releasing cytochrome c
    – Cells break into small membrane wrapped fragment
    – The phospholipid, phosphatidylserine is exposed on
    surface
    – Cell fragments are removed by phagocytosis.

    • The process is very orderly and hence the name


    “programmed cell death”

    • An intrinsic property of normal cellular metabolism.


    What Does it Look Like?
    Defects in Apoptosis
    • Defects in the regulation of apoptosis
    contributes to many diseases.

    • Diseases where cell accumulation occurs


    – Cancer

    • Excessive cell loss


    – Stroke
    – Heart failure
    – Neuro-degeneration
    – Aids
    What Causes these
    Changes?
    • The changes in cell morphology are caused by the action of
    proteases.

    • These are cysteine proteases which cleave proteins at


    aspartic acid residues. These are known as caspases.

    • Cysteine Aspartate Specific ProteASEs

    • These proteins are present as inactive zymogens in


    essentially all cells.

    • Proteolytic cleavage of the caspases at conserved aspartic


    acid residues activates enzymes of 10 and 20kDa subunits.
    Mechanisms of Apoptosis
    • Three different mechanisms by which a cell commits
    suicide by apoptosis.

    1. Generated by signals arising within the cell


    (Intrinsic).
    2. Triggered by death activators binding to receptors at
    the cell surface (extrinsic):
    – Tumour necrosis factor-α (TNFα )
    – TNF-β (Lymphotoxin)
    – A molecule that binds to the Fas cell surface receptor
    (Fas ligand: FasL)
    1. Triggered by cell damage by, for example, reactive
    oxygen species (extrinsic).
    Intrinsic (Mitochondrial)
    Apoptosis
    • Outer membrane of mitochondria express the proto-
    oncogene Bcl-2

    • Bcl-2 is normally bound to a protein called Apaf1


    – Apaf1: apoptotic protease activating factor 1

    • Internal cell damage causes Bcl-2 to release Apaf1


    which allows a related protein Bax to penetrate
    mitochondria.
    – Causes release of cytochrome c

    • Cytochrome c, Apaf1 and caspase 9 form a complex


    – Apoptosome
    Intrinsic (Mitochondrial)
    Apoptosis
    • Apoptosome complexes aggregate in the
    cytoplasm

    • Caspase 9 cleaves and activates other caspases


    – Digestion of structural proteins in cells
    – Degradation of chromosomal DNA

    • Phagocytosis of cells.
    Pathway Summary

    Apaf1
    Bcl-2
    Apoptosis

    Mitochondria Bcl-2

    Bax
    Caspase cascade

    Apaf1
    Caspase 9
    Cytochrome c
    Internal Death Signal

    Apoptosome
    Extrinsic Mechanisms of apoptosis
    (Death Receptor Pathway)
    • The Fas and TNF receptors are integral cell
    membrane proteins

    • The binding of TNF or FasL (death activators) to the


    cell membrane causes up-regulation and activation
    of caspase 8.

    • Caspase 8, like caspase 9 initiates a cascade of


    caspase activation leading to phagocytosis of the
    cell undergoing apoptosis.
    Death Receptor Pathway
    DNA damage and Apoptosis
    P53 and Apoptosis
    • Bcl-2 and Bax genes regulate the release of
    cytochrome c.

    • The promoter for the Bax gene contains P53


    binding sites.
    – Upregulated in response to DNA damage.
    – P53 can also repress Bcl-2

    • Reactive oxygen species are powerful inducers of


    apoptosis.

    • Fas:FasL interaction causes the caspase cascade


    leading to apoptosis.
    – Fas expression is thought to be P53 dependent.
    P53 summary
    Apoptosis and Cancer
    • Loss of P53 activity in some 50% of all human tumours can
    disrupt the normal apoptosis pathway.

    • HPV virus and cervical cancer E6 oncoprotein can also


    disrupt apoptosis by degradation of P53.

    • Epstein Barr virus associated with some lymphomas


    produces a Bcl-2 homolog and stimulates Bcl-2 production in
    infected cells
    – Bcl-2 is an anti-apoptotic protein.
    – Translocation (t14:18)

    • Some B-cell leukaemias express high levels of Bcl-2


    – Oncogenic translocation of Bcl-2 gene to region for antibody
    production
    Apoptosis and Cancer
    • Melanomas avoid apoptosis by inhibiting the
    expression of Apaf1.

    • Some lung and colon cancer cells express a protein


    that binds to FasL.
    – Cytotoxic T cells cannot bind and induce apoptosis.

    • There are examples of cancer cells expressing high


    levels of FasL.
    – Can kill cytotoxic T cells since T cells express their own
    Fas)
    Summary
    • Define apoptosis

    • Discovery of apoptosis

    • What happens to apoptotic cells

    • Routes to apoptosis
    – Intrinsic (Mitochondrial)
    – Extrinsic (death signal)
    • Cytotoxic T cells mediated

    • Role of P53 in Apoptosis

    • Apoptosis and cancer


    – Mechanisms of avoiding apoptosis

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