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Cell Biology (BY1CB1) > Week 10 (Apoptosis) > Flashcards

Week 10 (Apoptosis) Flashcards

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1
Q

What is Apoptosis?

A

Cell death
–in normal physiology (death can be physiological)
–In disease

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2
Q

What is the function of apoptosis?

A
  • Removes damaged, unwanted or diseased cells

* Programmed cell death = Ordered cell deletion

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3
Q

C. elegans

A

–powerful model system
–191 predictable deaths in development
–highly tractable system
–study regulation, activation and execution of apoptosis
•Model systems have underpinned current knowledge

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4
Q

What is Apoptosis is crucial for?

A

–development
–maintenance
–control

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5
Q

Cell Population Control

A

Proliferation+
Differentiation -/+
Cell Death -

There is no net change in number of cells

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6
Q

Examples of diseases caused by Overactive Apoptosis?

A 
More cells dying than proliferating
–Neurodegeneration
–Immunodeficiency
–Stroke
–Coronary Heart Disease
–Transplant Rejection
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7
Q

Examples of diseases caused by Underactive Apoptosis

A

More cells proliferating than dying
–Cancer
–Autoimmune & Inflammatory conditions
–(e.g. SLE and rheumatoid arthritis)

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8
Q

The Importance of Apoptosis

A

Life-death imbalance can be desirable (physiological)

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9
Q

Why can Underactive Apoptosis be desirable?

A

–Allows cell accumulation (e.g. accumulation of cells during an immune response)

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10
Q

What why can Overactive Apoptosis be desirable?

A

–Returns cell populations to normal after challenge
–Neutrophil apoptosis during inflammation
–CTL death

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11
Q

What are the characteristics of apoptosis?

A 
Tightly controlleed/ programmed 
Cell shrinkage
•Organelle integrity
•Chromatin condensation
•Plasma membrane integrity
  • Thermodynamics uphill
  • Internal control
  • Purposeful
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12
Q

What are the characteristics of necrosis?

A 
Not tightly controlled (accidental/random), caysed by external factors 
•Cell swelling
•Organelle disruption
•Nuclear swelling
•Plasma membrane rupture
  • Thermodynamics downhill
  • External “control”
  • Accidental
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13
Q

Caspases

A
  • Cysteinyl ASPartate-specific proteASES
  • Key cysteine in active site QACxG
  • Aspartate at P1 of substrate tetrapeptide
  • Tetrapeptide defines caspase specificity
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14
Q

Three broad categories of caspases

A
  1. Inflammatory caspases
  2. Initiator caspase
  3. Effector caspase
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15
Q

Inflammatory caspases

A
  • Maturation of pro-inflammatory cytokines

* e.g. Caspases 1, 4, 5, 11, 12, 14

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16
Q

Initiator caspase

A
  • Kick off the caspase cascade

* e.g. Caspase 8, 9

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17
Q

Effector caspase

A
  • Cleavage of cellular substrates
  • Mediate the killing
  • e.g. Caspases 3,6, 7
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18
Q

Describe the activation of Caspases

A

•Caspases are produced as inactive zymogens
•Pro domain 23 - 220aa
–large pro-domain = initiator caspase (contains recruitment domains)
–Small pro-domain = executioner caspase
•Activation requires a minimum of 2 cleavages
Cleavage at the prodomain and formation of a tetramer

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19
Q

Cleavage of caspase substrates during apoptosis: what is the function of caspases?

A
  1. Pro-caspase (inactive) → active caspase
  2. Break down Structural proteins and DNA replication/repair enzymes
  3. Inactive nuclease → active nuclease
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20
Q

What is CAD?

A

caspase-activated DN-ase

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21
Q

What is ICAD?

A

inhibitor of CAD (caspase substrate)

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22
Q

End goal of apoptosis

A

detach cell from neighbours
Dismantle cell
destroy DNA
alter the cell surface

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23
Q

Cell suicide occurs in response to

A

cellular insults

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24
Q

Extrinsic Pathway

A

–Cell are instructed to die from outside
–Receptors (“Death Receptors”) on cell surface induce death when ligated

  1. Killer lymphocyte have a protein (fas ligand) on their surface
  2. Fas death receptor on pre apoptotic cell recognises the fas ligand
  3. Recruitment of FADD (adaptor protein) which has a death domain and a death effector domain
  4. Death domain joins the intracellular Fas death receptor
  5. Death effector domain recognised by caspases (8 or 10)
  6. FADD recruits procasapases which leads to initiation and activation of procaspases via cleavage
  7. Caspase cascade takes place
  8. Resulting in an apoptotic cell
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25
Q

Intrinsic pathway

A
  • cytochrome c released into the cytoplasm from damaged cell which binds to Apaf-1 (adapter protein)
  • this recruits inactive procaspases
  • activates then
  • caspase cascade initiated
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26
Q

Adaptor molecules are important in

A

recruiting initiator caspases and allowing their activation

27
Q

Control of cell death - Bcl-2 family

A

•Family of interactive proteins

  • Protect from apoptosis – Pro-survival
  • Suppress protection – Pro-death
  • Pro- death and pro-survival members
  • Bcl-2 - prototypic member of the family
28
Q

Bcl-2 Pro-survival members

A

•For example:
–Bcl-2
•Crucial for cell survival
•Essential for life

29
Q

Bcl-2 Pro-apoptosis members = Pro-death

Divided into 2 categories

A

Bax-like = BH123 members
–lack BH4 domain (BH123)
–form pores in mitochondria →release of Cyt c

BH3 only
– also called ‘Bad’ proteins
–central to life & death decisions of a cell
–activation during stress will dictate the outcome

30
Q

Bcl-2 Mechanism of Action

A

Guard mitochondrial integrity - Regulate Cyt c release

LIFE
Bcl-2 & Bax balance

31
Q

DEATH

A

BH3 only members disrupt the balance

Bax will form pores in mitochondria

32
Q

LIFE

A

Bcl-2 & Bax balance

33
Q

Bcl-2 prevents

A

mitochondrial disruption

34
Q

BH3 only proteins inhibit

A

Bcl-2 & tip the balance

35
Q

Control of Apoptosis: balancing act

A

•Pro v Anti-apoptosis signals
•Balance can be tipped by cell stress
–e.g. genotoxic damage can stabilise p53 and lead to transcription of pro-death members

36
Q

IAPs

A

–Inhibitors of apoptosis
–produced by certain viruses to prevent death

–Inhibit caspases via inhibition of
•activation of pro-caspases
•activity of active caspases

37
Q

The ultimate step in cell death

A
  • “Burial”
  • Cell surface changes act as “eat me” signals (recognised by phagocytes)
  • Viable cells eat the dying cell

safe and controlled removal of cells
prevents apoptotic cells falling apart
intracellular contents are detrimental
Cell Removal is the aim of apoptosis

38
Q

Apoptotic Cell Surface Changes (that are recognised by the phagocyte)

A

Redistribution of membrane lipids (especially phosphatidylserine)

39
Q

Receptors on phagocytes

A
  • Recognise apoptosis-induced surface changes
  • Apoptotic cells are eaten and degraded
  • A silent process

•Safe packaging
–failure leads to inflammation

40
Q

Biochemical/Cell Biological Features in apoptosis

A 
•Ligation (FAS ligand) of surface death receptors
–Generates a death-inducing signalling complex
•Mitochondrial Changes
–Release of cytochrome c
•Cysteine Protease Activity
–Protein cleavage after aspartate residues
•DNA cleavage
–Activation of nucleases (CAD)
–Cleavage of DNA into fragments
•Surface changes
–“eat me signals”
–Flip-out of phosphatidylserine
•Phagocytosis
41
Q

How often does cell death occurs

A

Up to 1million times in some tissues

42
Q

Phase 1

A
  1. Presence of signal
  2. Intracellular signalling pathways activated or disrupted
  3. Epopotosis machinery employed (caspase cascade)
  4. Phagocyte degradation
43
Q

Phase II

A
  1. Extracellular Signals: Cytosine deprivation, gentoxdic (chemical or radiation) DNA damage, death receptor ligation
  2. Intracellular signals: p53 transcribed, survival signals , caspase
  3. Both activate the apoptosis engine (caspase cascade)
44
Q

Which amino acid forms the active site of caspase?

A

Cysteine 1

45
Q

Are caspases always activated

A

No

Only when cells becomes apoptosis

46
Q

CNS caspases activate other caspases?

A

Yes

In turn the activated caspases can activate others

47
Q

What does a small prodomain indicate?

A

An effector caspase

48
Q

Are procaspases active or inactive?

A

Inactive

49
Q

What are the 4 domains I’d the Bcl-2 family?

A

BH4
BH3
BH1
bH2

50
Q

Describe apoptotic cell surface changes

A

These changes are recognised by phagocytes

  • In a healthy cell membrane the phosphadityl serine are facing the cytosol
  • When the cell become apoptotic some of the phosphadityl serine face the Extracellular space due to a biochemical change
51
Q

What type of caspase has a large prodomain?

A

Initiator casapase

52
Q

What are the 3 main caspase domains?

A

Prodomain
Large domain
Small domain

53
Q

What are the 3 main caspase domains?

A

Prodomain
Large domain
Small domain

54
Q

Which caspase has a small prodomain?

A

Effecror casapa

55
Q

Where do caspases cleave proteins?

A

At the P1 aspartase

56
Q

How does capsase activation occur?

A

1) Cleave of the prodomain
2) Cleavage and separation of the large/ small domains
3) joining of 2 capspases to form a tetramer

57
Q

Which end of the protein is the small domain?

A

Carboxyl end

58
Q

Which end of the protein is the prodomain?

A

Amino

59
Q

Do the survival members of the Bcl-2 family have all 4 domains?

A

Yes

60
Q

Which domains do the Bcl-2 pro death members have?

A

BH123

61
Q

What would be the effect of an upregulation of BH3?

A

Induce apoptosis

62
Q

How does Bcl-2 disrupt mitochondria?

A
  1. They have BH123 on their surface (inactive)
  2. Apoptotic stimulus
  3. BH123 complex changes in conformation and makes a pore in the mitochondrion
  4. Mitochondrion releases cytochromes
63
Q

When is BH123 inactive?

A

Pro-survival Bcl-2 protein blocks pore formation

An Apoptotic stimulus can replace the Bcl-2 protein thus allowing the BH123 to become a pore

Cell Biology (BY1CB1) (16 decks)

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