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Cell Biology > Lecture 11 - Apoptosis > Flashcards

Lecture 11 - Apoptosis Flashcards

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1
Q

Why is apoptosis necessary?

A
  • essential for the development of a multi-cellular organism

- must destroy cells when they become superfluous

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2
Q

What is apoptosis required for in embryogenesis?>

A
  • required for normal tissue development

- ew.g. removal of interdigital tissues

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3
Q

What are some of the roles of apoptosis?

A
  • Development (e.g. metamorphasis in insects)
  • Tissue homeostasis (e.g. intestinal microvilli generation/death)
  • Elimination of premalignant cells (p53 activation)
  • removal of damaged cells (e.g in infection, cytoxic T lymphocytes and gransymes induce apoptosis)
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4
Q

What are the differences between necrosis and apoptosis?

A

Apoptosis

  • Physiological
  • Cellular condensation
  • Nuclear fragmentation
  • Rapid phagocytosis
  • lack of inflammation
  • Blebbing
  • Clustereed nuclear pores

Necrosis

  • Pathological
  • Organelles swell
  • Membranes ruptures
  • Leakage of cell contents
  • Marked inflammation
  • Lesions
  • Even nuclear pores
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5
Q

What is the series of morphological changes that occur in apoptosis?

A

Mild convolution
Chromosome compaction and segregation
Condensation of cytoplasm

Nuclear fragmentation
Blebbing
Cell fragmentation

Phagocytosis of the apoptotic bodies

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6
Q

How are trophic factors involved in apoptosis?

A
  • most cells require trophic signals to stay alive

- removal of trophic factors can activate apoptosis

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7
Q

What are the two main types of Bcl-2 proteins that are involved in apoptisus?

A

Anti-apoptotic proteins(e.g. Bcl-2, Bcl-XL)

Pro-apoptotic proteins (e.g. Bax, Bid, Bad)

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8
Q

What are the three subgroups of Bcl-2 proteins?

A

Group I proteins (Bcl-2, Bcl-XL) [AA]
Group II proteins (Bax) [PA]
Group III proteins (Bid, Bad) [PA]

Determined by their various different domains

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9
Q

What is the process of blebbing?

A

small pockets of membrane containing cellular contents are formed, and phagocytosed by white blood cells, phagocytes, lymphocytes and delivered to the lysosome

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10
Q

What are features of the Bcl-2 family?

A
  • Intracellular regulators of apoptosis
  • control the release of cytochrome C and other apoptotic regulators from mitochondria
  • have either pro- or anti-apoptotic functions (
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11
Q

What are the domain similarities and differences between different Bcl-2 proteins?

A

Bim, Bax, Bcl-2, Bid

  • Bim, Bax and Bcl-2 have transmembrane domains
  • All contain BH3 domains (Bcl homology domain 3)
  • Bcl-2 has a BH4 domain (excerts anti-apoptotic activity)
  • Bcl-2 and Bax have BH1 domains
  • Bcl-2 and Bax have BH2 domains
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12
Q

What are the interactions between the Bcl-2 family of proteins and Cytochrome C?

A
  • Bcl-2/Bcl-2 homodimer or Bcl-2/Bcl-XL heterodimers inhibit cytochrome C release from the mitochrondia
  • The function of Bad is normally inhibited by being bound to 14-3-3, but if phosphorylated Bad is released from 14-3-3 and recruited to the mitochrondia
  • Once activated, Bad can bind to Bcl-2 (or Bcl-XL) dimers and inhibit their function
  • This recruits Bax to the mitchondrial membrane, increasing mitchondrial membrane permeability allowing cytochrome C to be released
  • cytochrome C initiates an intracellular apoptosis signalling cascade, mediated by caspases
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13
Q

How can the spectrum of Bcl-2 proteins expressed by a cell determine it fate?

A

The balance between anti-/pro- Bcl-2 proteins decides whether cell lives/dies

if the amount of Bcl-2 > Bax the cell is protected from apoptosis
if the amount of Bcl-2 < Bax, the cell is susceptible to apoptosis

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14
Q

What are the features of caspases?

A
  • 11 known caspases in humans
  • Two groups of caspases (Initiators/activators, cleave other caspases [2,8,9,10,12] and Effectors/excecutioners [3, 6, 7])
  • Cysteine proteases that cleave their substrates on the C-terminal of aspartate residues
  • synthesised as inactive zymogens (proenzymes) and require proteolytic modification to be activated
  • have homodimeric structure, chains from each monomer required for two active sites
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15
Q

How are procaspases activated by cleavage?

A
  • two inactive procaspase molecues have their pro domains cleaved off to allow caspases to dimerise and form an active caspase molecule
  • with one large subunit and one small subunit
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16
Q

How are initiated caspases and effector caspases activated?

A
  • Initiator caspases are initiated by dimerisation
  • Effector caspases are activated cleavage then dimerisation to become active. When 2 are cleaved they form a homodimeric active enzyme with 2 catalytic sites
17
Q

What is the amplifying caspase cascade?

A
  • one molecule of an initator caspase cleaves and activates effector caspases
  • these go on to cleave subsequent caspases
  • amplifying the signal
18
Q

What is the sequence of events following the release of cytochrome C that leads to cell death?

A
  1. Cytochrome C binds Apoptotic activating factor 1 (Apaf1)
  2. This recruits procaspase 9 to the apoptosome
  3. Dimerisation anf cleavage of procaspase 9 by Apaf1 results in active caspase 9 (inititator caspase )
  4. Active caspase 9 activates excecutioner caspases (procaspase 3 to active caspase 3)
  5. leads to degradation od intracellular substrates and cell death
19
Q

How is procaspase 9 recruited to the apoptosome?

A
  • Apaf1 and procaspase 9 contain CARD domains
  • When Apaf1 is bound to cytochrome C it allows binding to the CARD domain of procaspase 9, forming a large oligomeric apoptosome complex
20
Q

How do caspases acheive nuclear fragmentation, disruption of the cytoskeleton, membrane blebbing and cell fragmentation ?

A
  • Initiator caspases (caspase 9) target effector caspases (caspase 3,6,7)
  • more than 40 target protein substrates
  • caspases cleave nuclear (laminins) and cytoskeletal (actin) proteins
  • > cleave and activate gelsolin, induces actin severing
  • another key target = Initiator of Caspase Activated DNAase (ICAD)
  • > ICAD is cleaved resulting in the release of CAD (DNAase) which fragments DNA
  • leads to nuclear fragmentation, disruption of the cytoskeleton, membrane blebbing and cell fragmentation
21
Q

What are trophic factors?

A

Factors that induce differentiation/survival e.g.
NGF (nerve growth factor)
EDF (Epidermal growth factor)
PDGF (platelet derived growth factor and others)
-binding of growth factors can activate downstream signals e.g.
pI3-kinase/Akt signalling
Ras/Raf/MAPK signalling pathways

22
Q

What is the prcess of PI3-kinase/Akt signalling?

A
  1. In the presence of a trophic factor, pI-3 kinase is stimulated to activate Akt (PKB) which phosphorylates Bad
  2. Phospho-Bad forms a complex with the 14-3-3 protein preventing Bad from interacting with Bcl-2
23
Q

What can engagement of the death receptors lead to and what inhibits this pathway?

A

growth factor independent mechanism of apoptosis

  • the activation of proapoptopic proteins (Bid, Bik) and cause apoptosome assembly and the initiation of the caspase cascade
  • inhibited by Z-VAD
24
Q

What growth factor deprivation lead to and what inhibits this pathway?

A

the activation of proapoptopic proteins (Bad) and cause apoptosome assembly and the initiation of the caspase cascade
-inhibited by Akt

25
Q

What can nuclear damage lead to?

A

the activation of proapoptopic proteins (Rad-9), or stimulation of p53 to activate Bax/Noxa and cause apoptosome assembly and the initiation of the caspase cascade

26
Q

What are death receptors?

A

growth factor independent mechanism of apoptosis
cell surface receptors that initiate apoptosis following ligand binding e.g.
-Fas (CD95/APO-1) with FasL (CD95L) ligans
-TNF-R1 (tumour necrosis factor 1) with TNFα or TRAIL (TNF-related apoptosis-inducing ligand)

27
Q

What is the process of Fas/FasL mediated apoptosis?

A
  1. FasL binds to the Fas death receptor
  2. Ras interacts with an adaptor protein FADD (Fas-associated death domain)
  3. FADD complexes with procaspase 8 (a DED-caspase (death effector domain) to activate it via dimerisation
  4. caspase 8 cleaves Bid to tBid,activating it. tBid can then inhibit Bcl-2 in the mitochondrial membrane and the release of cytochrome C, leading to activation of caspase 9 via apoptosome formation
  5. Active caspae 8 also activates caspase 3/7 (excecutioner caspases) forming a death inducing signal complex (DISC - FADD and caspase and ligand and receptor)) which also leads to the inhibition of Bcl-2 in the mitochondiral membrane and release of cytochrome C
28
Q

how do death receptors interact with adaptor proteins?

A

through mutual death domains

29
Q

What is the role of Fas in AIDS?

A
  • normally, all CD4+ T cells express Fas, but HIV infected cells also express high levels of FasL
  • this induces non infected cells to commit suicide resulting in failure of the immune response
  • infected cells survive as high FasL levels prevent interaction with their own Fas
30
Q

What is the role of Fas in influenza defence?

A
  1. Target cell is infected with influenza. MHCI presents the viral peptide on the surface of the infected cell
  2. MHCI interacts with the cytotoxic T cells via the T cell receptor and FasL on the T cells interacts with Fas on target cells inducing apoptosis

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