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BMG2002 CC > L12 - Apoptosis > Flashcards

L12 - Apoptosis Flashcards

1
Q

What is apoptosis?

A

Programmed cell death – cellular suicide

Derived from a Greek word ‘to fall away’

Occurs by a precise mechanism

Accompanied by defined morphological changes

Different to cell death by necrosis

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2
Q

What happens during necrosis?

A
  • The cell swells
  • Mitochondria dilate & other organelles dissolve
  • Plasma membrane ruptures releasing cytoplasm
  • Often elicits an inflammatory response
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3
Q

What happens during apoptosis?

A
  • The cytoplasm shrinks
  • Chromatin condenses & nucleus fragments
  • The plasma membrane blebs
  • The cell fragments
  • Membrane doesn’t rupture – contents of cytoplasm aren’t released so no inflammatory response
  • Apoptotic bodies are cleared by phagocytotic cells
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4
Q

Why is apoptosis important?

A

Some cells need to die for multiple reasons:

  1. Organism maintenance – old & dysfunctional cells
  2. Response to damage
    For example:
    • Excessive UV-mediated DNA damage – sunburn & peeling
    • Invasion of plant by pathogen – hyposensitive response
  3. Development
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5
Q

Studies with C. elegans

A

Of 947 non gonadal cells (somatic cells), 131 die & undergo apoptosis during development

Proper development requires the 131 cells to die during development

Doomed cells = cells that usually undergo apoptosis

CONCLUSIONS
• Ced-3&4 promote apoptosis
• Ced-9 inhibits apoptosis
• Ced-9 is upstream of Red-3

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6
Q

Apoptotic pathway conservation

A

C. elegans has direct counterparts in vertebrates
Similar pathways & similar conserved structure

Ced-9 homologue in vertebrates is Bcl-2

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7
Q

What is Bcl-2 involved in?

A

Isolated during studies on from human follicular lymphomas (blood cancer)

In these cancer cells a chromosomal translocation results in the overexpression of Bcl2

This overexpression of Bcl2 prevents apoptosis (keeps cancer cells alive when they should have been programmed to die)

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8
Q

What are caspases?

A

They bring about apoptosis (& can be involved in inflammation)

Cysteinyl-aspartate-specific proteases

Have a cysteine residue at active site

Different caspases have different target preferences

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9
Q

Human caspases

A

There are 11 human caspases but not all of them are involved in cell death

Can be divided into 2 groups

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10
Q

2 groups of human caspases

A

Caspase 1 family
• Not involved in apoptosis
• Involved in cytokine processing

CED-3 family
• Involved in apoptosis
• Can be divided further into 2 more groups

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11
Q

What are the 2 categories of CED-3 family caspases?

A

Initiator caspases
• Activate executioner caspases

Executioner caspases
• Cleave substrates to bring about apoptosis

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12
Q

Activation of initiator caspases

A

When activated they bring about cell death so have to be carefully controlled

Present as inactive monomers (procaspases) – have a big pro domain at their N terminal

Apoptosis inducing signals result in interaction with an adaptor protein and dimerization

Cleavage of adjacent procaspase results in the formation of an active dimer

Pro domain is released

Active caspase made of the large subunit and the small subunit

Initiator caspase then cleave and activate executioner caspases

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13
Q

Activation of executioner caspases

A

Present as inactive dimers

These are cleaved by initiator caspases to bring about the formation of an active dimer

Cleaved between the large & small subunits

Active dimers cleave their substrate proteins

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14
Q

Caspase cascade

A

One initiator caspase can act on many downstream executioner caspases

These can then active many more caspases

Amplification signal

Important that the cell controls the activation of the initiator caspase very closely

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15
Q

What is the difference between the intrinsic & the extrinsic pathway in apoptosis?

A

In the intrinsic pathway the cell kills itself because it senses cell stress

In the extrinsic pathway the cell kills itself because of signals from other cells

Weak external signals may also activate the intrinsic pathway of apoptosis

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16
Q

The intrinsic pathway in apoptosis

A

The central role of the mitochondria
• Responsible for ATP production

Also plays a key role in the decision of cell to live or die by apoptosis

In response to adverse stimuli mitochondria become permeablized

Leads to the release of proteins that promote apoptosis

A key protein is cytochrome c

17
Q

Activation of the intrinsic pathway of apoptosis

A
  1. Cytochrome C is present in the inter-membrane space of the mitochondria
  2. Cytochrome C is released when an apoptotic stimulus occurs
  3. When released in binds to an adaptor protein Apaf1 & once bound, there is the assembly of the apoptosome which is made up of 8 sections
  4. Apoptosome recruits caspase 9
  5. Caspase 9 becomes activated & then cleaves & activates executioner caspases
18
Q

What is CARD?

A

Caspase recruitment domain

19
Q

What do the Bcl-2 family of proteins regulate?

A

Regulate mitochondria permeabilisation

Some INHIBIT apoptosis – pro-survival
Some PROMOTE apoptosis – pro-apoptosis

20
Q

Pro-survival members of the Bcl-2 family of proteins

A

Pro-survival members all have a transmembrane domain & different BH domains

Have BH4, BH3, BH1 & BH2

21
Q

Pro-apoptotic members of the Bcl-2 family of proteins

A

Pro-apoptotic members can be split into 2 groups:
– Effectors – have a BH3, BH1 & BH2 domain
– BH3 only – only have a BH3 domain

22
Q

Regulation of mitochondrial permeability by Bcl proteins

NORMAL CELL

A

No apoptotic signals

Pro survival Bcl-2 proteins prevent the pro-apoptotic Bcl proteins from forming a pore in the membrane

23
Q

Regulation of mitochondrial permeability by Bcl proteins

STRESSED CELL

A

Apoptotic signals

BH3-only proteins inhibit the pro-survival Bcl-2 proteins

This allows pro-apoptotic Bcl proteins (Bak, Bax) to form a pore in the membrane

Once pores have formed, cytochrome C can be released from mitochondria

p53 will upregulate specific BH3 only genes

24
Q

What are IAPs?

A

Inhibitors of apoptosis

A mechanism to ensure caspases are activated only when appropriate

25
Q

Action of IAPs

A

IAPs have BIR (baculovirus IAP repeat) domains

BIR domains allow binding to and inhibition of activated caspases

Anti-IAPs such as Hid (Drosophila) Smac/Diablo & Omi (mammals) overcome this inhibition

26
Q

The extrinsic pathway of apoptosis

A

Relies of specific receptors at plasma membranes called death receptors

27
Q

What are death receptors?

A

Involved in the extrinsic pathway of apoptosis

They are a subgroup of the TNF receptor (TNF-R) family

28
Q

Structure of death receptors

A

All have a transmembrane domain

Ligand binding section (CRD) is extracellular

The death domain is intracellular & controls intracellular signalling

29
Q

Signalling from death receptors

A

Ligand binding results in trimerisation and activation of receptor

Facilitates the binding of adaptor proteins to death domain

Adaptor proteins bind through their own death domains

Adaptor proteins facilitate the recruitment of initiator caspases

Active initiator caspases activate executioner caspases and thus apoptosis

30
Q

What are Fas ligands?

A

Transmembrane protein that belongs to the tumor necrosis factor (TNF) family

Its binding with its receptor induces apoptosis

Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer

31
Q

Fas signalling

A

When stimulated Fas induces apoptosis in the Fas-bearing cell.

The ligand for Fas, (called FasL), is chiefly expressed on cytotoxic T-cells and TH1 (T-helper) cells.

Apoptosis triggered by Fas is involved in an array of immune-system functions
For example:
– Elimination of used effector cells
– Elimination of peripheral autoreactive lymphocytes

32
Q

What happens if you have mutations in Fas or its ligand?

A

Autoimmune disease

33
Q

Fas signalling pathway

A
  1. Killer lymphocyte expresses the Fas ligand
  2. Target cell is expressing the death receptor at its surface
  3. Killer lymphocyte interacts with target cell through ligand interacting with receptor
  4. Trimerisation of the receptor
  5. Allows binding of adaptor proteins called FADD
  6. FADD has its own death domain & death effecter domain
  7. Death domain on FADD interacts with death domain in death receptor
  8. Allows assembly of DISC
  9. Initiator caspases bind to the adaptor domain through the death domain
  10. Cleavage & activation of caspase 8
  11. Caspase 8 is an initiator caspase so goes on & activates downstream caspases
  12. It also brings about apoptosis
34
Q

How does caspase activation promote DNA fragmentation?

A

Executioner caspases cause the CAD to become active

Once CAD is active it breaks up DNA between nucleosomes

Leads to fragmentation

35
Q

What does CAD do?

A

Breaks up DNA between nucleosomes

Leads to fragmentation

36
Q

What are extracellular survival factors that inhibit apoptosis?

A

Survival factors

Require signalling from other cells to avoid apoptosis – pro-survival signalling

Can inhibit apoptosis by a variety of mechanisms

37
Q

What is the apoptosome?

A

Large quaternary protein structure formed in the process of apoptosis

Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus.

BMG2002 CC (10 decks)

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