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Cell Death Flashcards

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1
Q

Learning Outcomes

A
  • Understand the concept of apoptosis
  • Understand the role of caspase in apoptosis
  • describe the intrinsic and extrinsic pathways
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2
Q

Reading:

A
  • Alberts et al. Molecular Biology of the Cell, Ch10
  • Alberts et al. Essential Cell Biology, Ch11
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3
Q
A

Necroptosis – recent studies identified a regulated cell death with necrotic phenotypes
(caspase independent)

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3
Q

Apoptosis vs. Necrosis

A
  • Swell and burst
  • Spill contents to the neighbours and cause inflammation
  • Energy depletion leads to metabolic defects and loss of the ionic
    gradients that normally exist across the cell membrane
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3
Q
A

Necrosis – cell death derived by acute insults (unregulated) e.g., a trauma and a lack of
blood supply – normally necrotic cells swell and burst

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4
Q

Cell death

A

The growth (proliferation), development and maintenance (homeostasis) of multicellular
organisms depend not only on the production of cells (by cell cycle/division) but also on
mechanisms to destroy them. E.g., the maintenance of tissue size requires that cells die at
the same rate as they are produced.
Programmed cell death occurs by a process called apoptosis (highly regulated by caspase
signaling)

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5
Q

Apoptosis vs. Necrosis

A
  • Nuclear chromatin condenses and breaks up into fragments
  • Cytoskeleton collapses
  • Nuclear envelope disassembles
  • If large, breaks up into membrane-enclosed fragments,
    apoptotic bodies
  • Phagocytic cells (e.g., macrophages) engulfs them quickly before
    spilling contents (lead inflammation)
  • Adult human loses ~ 50-70 billion cells (out of ~ 37 trillion) each
    day due to apoptosis
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6
Q

Apoptosis eliminates unwanted cells

A

Apoptosis can shape during development
* Self destructing cells with abnormalities
* Self destructing cells not required anymore for normal development

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7
Q

Apoptosis eliminates unwanted cells

A

Sculpting the digits in the developing mouse paw by apoptosis
* Special bright green labelled for apoptotic cells (A)
* Interdigital cell death eliminated the tissue after one day (B)
forming individual digits

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7
Q

Caspase mediate apoptosis

A

caspases = proteases with a cysteine at their active site and cleave their target proteins at
specific aspartic acids

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8
Q

Apoptosis eliminates unwanted cells

A

Metamorphosis of a tadpole to a frog
* Massive cells death in tadpole tail
* Eliminating unwanted tissues (cells)

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8
Q

Caspase mediate apoptosis

A

Apoptosis is triggered by members of a family of specialized intracellular proteases,
caspases, which cleave specific sequences in numerous proteins inside the cells, thereby
bringing about the dramatic changes that lead to cell death and engulfment.

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9
Q

Caspase mediate apoptosis

A

Caspases are synthesized in the cell as inactive precursors and are activated only during
apoptosis

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10
Q

Caspase mediate apoptosis

A

2 major classes of apoptotic caspases: initiator caspases and executioner caspases

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10
Q

Initiator caspase and executioner caspase

A

Executioner caspase
* Normally inactive dimer
* Cleaved by initiator caspases at a site in the
protease domain = activation
* One initiator caspase can activate many
executioner caspases = amplifying proteolytic
cascade
* Once activated, executioner caspases catalyse
the widespread protein cleavage events that kill
the cell

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10
Q

Initiator caspase and executioner caspase

A
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11
Q

Initiator caspase and executioner caspase

A

Initiator caspase
* Begin the apoptotic process
* Assemble active caspase by forming dimer of
initiator caspases and adaptor proteins
* Dimer then cleaves its partner at a specific site in
the protease domain to stabilise the active complex
* Major function = activate executioner caspase

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12
Q

Caspases cause irreversible breakdown of proteins

A

Nuclear lamina rupture during cell division
(prometaphase – telophase) and during apoptosis

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12
Q

Caspases cause irreversible breakdown of proteins

A

Nuclear envelope rupture during apoptosis
* Caspase 3 dependent
* Caspase can also inhibit cytoskeleton and cell-cell
adhesion molecules to make engulfing easier

13
Q

Caspase also mediate DNA fragmentation

A
  • Endonuclease CAD associated with its inhibitor, iCAD in
    healthy cells
  • Activated executioner caspase cleaves iCAD leading CAD
    activation
  • Active CAD produce fragmented DNA
14
Q

Caspases cause irreversible breakdown of proteins

A

Nuclear envelope rupture during cell division
* Disassembly of the nuclear lamina and M phasespecific phosphorylation of lamins by Cdc2 kinase
(Cdk1)

15
Q

Extrinsic vs. intrinsic pathways

A

Cells use at least two distinct pathways to activate initiator caspase and trigger a caspase
cascade leading to apoptosis:
* Extrinsic pathway – activated by extracellular ligands binding to cell-surface death
receptors
* Intrinsic pathway – activated by intracellular signals generated when cells are stressed

16
Q

Caspase also mediate DNA fragmentation

A
17
Q

Extrinsic pathway via death receptors

A
  • Extracellular signal proteins (Fas ligand
    in killer lymphocyte) bind to cellsurface death receptors (Fas death
    receptor)
  • Death receptors are homotrimers and
    belong to the tumor necrosis factor
    (TNF) receptor family e.g., TNF and Fas
    * Fas ligand-death receptor binding
    activates the cytosolic tails of Fas death
    receptors to form DISC with
    intracellular adaptor proteins leading
    to the binding of initiator caspases
    (primarily caspase-8)
  • Activated initiator caspases cleave their
    partners and activate executioner
    caspases to induce apoptosis
17
Q

Extrinsic vs. intrinsic pathways

A

Each pathway uses its own initiator caspases, which are activated in distinct activation
complexes:
* Extrinsic pathway – death receptors recruit caspase-8 via adaptor proteins to form the
DISC (death-inducing signaling complex)
* Intrinsic pathway – cytochrome c released from the intermembrane space of
mitochondria activates Apaf1, which assembles into an apoptosome and recruits and
activates caspase-9

18
Q

Extrinsic pathway via death receptors

A
  • Some cells use the extrinsic pathway to recruit the intrinsic
    apoptotic pathway to amplify the caspase cascade
  • To restrain the extrinsic pathway, some cells produce FLIP
    proteins, which resembles an initiator caspase but has no
    protease activity (lacking the key cysteine) – preventing
    inappropriate activation of the extrinsic pathway of apoptosis
18
Q

Intrinsic pathway depends on mitochondria

A
  • Cells can also activate apoptosis
    from inside, often in response to
    stresses, such as DNA damage, or
    in response to developmental
    signals
  • Depends on the release of
    mitochondrial proteins from
    intermembrane of mitochondria
    to cytosol
19
Q

Extrinsic pathway via death receptors

A
20
Q

Intrinsic pathway depends on mitochondria

A
21
Q

The intrinsic pathway of apoptosis

A
22
Q

Bcl2 family controls the release of cytochrome c

A
  • Mammalian Bcl2 family proteins regulate the intrinsic
    pathway of apoptosis mainly by controlling the release
    of cytochrome c and other intermembrane
    mitochondrial proteins into the cytosol
  • Some Bcl2 family proteins are pro-apoptotic and
    promote apoptosis by enhancing the release
  • Others are anti-apoptotic and inhibit apoptosis by
    blocking the release
  • Pro- and anti-apoptotic proteins can bind to each other
    in various combinations to form heterodimers in which
    the two proteins inhibit each other’s function – will
    eventually decide whether cell lives or dies by the
    intrinsic pathway of apoptosis
22
Q

Bcl2 family controls the release of cytochrome c

A
23
Q

BH3-only and anti-apoptotic Bcl2 in the intrinsic pathway

A

Inactive intrinsic pathway
* In the absence of an apoptotic stimulus, anti-apoptotic
Bcl2 family proteins bind to and inhibit the effector Bcl2
family proteins on the mitochondrial outer membrane (1)
and in the cytosol (2) – inhibiting the oligomerisation of
pro-apoptotic effector Bcl2 family proteins

23
Q

Pro-apoptotic effector in the intrinsic pathway

A
24
Q

BH3-only and anti-apoptotic Bcl2 in the intrinsic pathway

A

Activated intrinsic pathway
* In the presence of an apoptotic stimulus, BH3-only
proteins are activated and bind to the anti-apoptotic Bcl2
family proteins – no longer inhibiting the formation of
effector Bcl2 family proteins oligomers

25
Q

BH3-only and anti-apoptotic Bcl2 in the intrinsic pathway

A
26
Q

Survival factor can control cell number

A
  • Extracellular signal molecules can stimulate apoptosis - stimulation can be important during vertebrate
    development: a surge of thyroid hormone in the bloodstream, for example, signals cells in the tadpole
    tail to undergo apoptosis at metamorphosis
27
Q

Survival factor can control cell number

A
  • However, extracellular signal molecules can also inhibit apoptosis – survival factor
  • Nerve cells are produced in excess in the developing nervous system then compete for limited amounts
    of survival factors that are secreted by the target cells that they normally connect to
  • Nerve cells that receive enough survival signals live, while the others die – the number of surviving
    neurons is automatically adjusted by the number of target cells they connect with
27
Q

Survival factor can control cell number

A
28
Q

Survival factors inhibit apoptosis

A

Increase anti-apoptotic Bcl2
family protein
* Activated receptor upon
binding of survival factor
activates and translocates
transcription regulator to
nucleus
* Increased encoding of
anti-apoptotic Bcl2
proteins inhibit apoptosis

29
Q

Survival factors inhibit apoptosis

A

Inactivate pro-apoptotic
BH3-only protein
* Activated receptor upon
binding of survival factor
activates Akt kinase
* Active Akt kinase
dissociate the binding of
Bcl2 (anti-apoptotic) and
BH3-only protein (e.g.,
Bad)
* Phosphorylated Bad
become inactive while
dissociated Bcl2 (antiapoptotic) become active
* Active anti-apoptotic Bcl2
proteins inhibit apoptosis

30
Q

Survival factors inhibit apoptosis

A
31
Q

Phagocytes remove the apoptotic cell

A

Apoptotic cell death is a remarkably tidy process
(esp. compared to necrosis)
* cell and its fragments do not break open and
release their contents
* remain intact as they are efficiently eaten – or
phagocyted– by neighboring cells
* leave no trace – no inflammatory response

32
Q

Phagocytes remove the apoptotic cell

A

Engulfment process depend on chemical
changes on the surface of the apoptotic cells
* Distribution of the negatively charged
phospholipid, phosphatidylserine on the
cell surface
* Apoptotic cells show flipping of
phosphatidylserine from inner leaflet of
the lipid bilayer to the outer leaflet

33
Q

Phagocytes remove the apoptotic cell

A
34
Q

Chemotherapy by stimulating apoptosis

A

Stimulating apoptosis = treating cancers
* decreased apoptosis contributes to many cancers
* Small molecule inhibiting anti-apoptotic Bcl2 family
proteins such as Bcl2 and BclXL
* Chemicals with high affinity to the hydrophobic
groove on anti-apoptotic Bcl2 family proteins –
blocking their function in essentially the same way
that BH3-only proteins do

35
Q

Chemotherapy by stimulating apoptosis

A

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