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Biology of Cancer SSC > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

What is apoptosis characterised by?

A

A series of dramatic perturbations to cellular architecture

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2
Q

What do these dramatic disturbances to cellular architecture contribute to?

A

Cell death
Preparation of cells for removal by phagocytes
Prevent unwanted immune response

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3
Q

Which protein family orchestrate the demolition phase of apoptosis?

A

Caspase family of cysteine proteases

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4
Q

What is a caspase?

A

Family of proteases with an essential cysteine residue in their active site

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5
Q

What are the two types of caspase?

A

Initiator and Effector

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6
Q

When are initiator caspases typically activated?

A

In response to particular stimuli

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7
Q

What are effector caspases important for?

A

Ordered dismantling of vital cellular structures

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8
Q

Why is apoptosis controlled?

A

To minimise damage and disruption to neighbouring cells.

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9
Q

How quickly are cells that undergo apoptosis replaced?

A

Within a few hours

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10
Q

How does the cell undergoing apoptosis initially appear from outside?

A

Becomes rounded and retracts from neighbouring cells

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11
Q

What follows cell rounding and retraction?

A

Plasma membrane blebbing. Blebs pinch off to form apoptotic bodies.

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12
Q

Why is phagocytic engulfment of cells undergoing apoptosis remarkable?

A

Phagocytes normally recognise and remove foreign/non-self entities. The phagocytes recognise a difference between apoptotic cells and their viable counterparts.

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13
Q

What do the many alterations in internal architecture do?

A
  • Minimise activation of the immune system

- Increase the efficiency of disposal process

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14
Q

What is the most noticeable feature of apoptosis within the cell?

A

The condensation and fragmentation of the nucleus

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15
Q

What else undergoes fragmentation in apoptosis?

A
  • Golgi apparatus
  • ER
  • Mitochondrial networks
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16
Q

What is released from the inter-membrane space of mitochondria?

A

Numerous proteins, including Cytochrome C

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17
Q

What does Cytochrome C do?

A

Triggers the assembly of caspase-activating complex (the apoptosome) on release into the cytosol.

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18
Q

What is the apoptosome?

A

A large protein complex that recruits pro-caspase-9 and allosterically activates caspase-9. Consists of cytochrome c and APAF1 (apoptotic protease-activating factor 1)

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19
Q

What are most proteolysis and cellular events in apoptosis due to?

A

Caspase-mediated cleavage of particular substrate proteins.

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20
Q

What is necrosis accompanied by?

A

Rapid loss of membrane integrity and release of cellular contents into the ECF

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21
Q

How does the immune system respond to necrotic and apoptotic cells?

A

Differently

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22
Q

How do necrotic cells trigger inflammation?

A

By releasing DAMPs (danger associated molecular patterns) stimulating receptors on neutrophils, macrophages, and other innate immune system elements.

23
Q

How are caspases normally present (i.e. in a healthy cell)?

A

As zymogens (inactive precursor enzymes)

24
Q

How many main routes to apoptosis associated caspase activation are there?

A

3

25
Q

What are the major effector caspases?

A

Caspase-3, caspase-6, and caspase 7

26
Q

What cytoskeleton components are substrates for caspases in apoptosis?

A
  • Actin
  • Actin-associated proteins - myosin, spectrins, alpha-actinin, gelsolin, filamin
  • Tubulins, microtubule-associated proteins
27
Q

What is a consequence of weakening the cytoskeleton?

A

Blebbing - this requires areas of the plasma membrane to be unsupported so blebs can form in these areas. Also requires some areas of intact filaments.

28
Q

How do surrounding cells fill the gap left by dead cells?

A

Dying cell signal for the formation of actin cables within it’s neighbours. These cables contract and extrude the dying cell.

29
Q

What does BCL-2 stand for?

A

B-cell lymphoma-2

30
Q

What is the BCL-2 family?

A

Family of proteins crucial in regulation of apoptosis

31
Q

How do BCL-2 proteins regulate apoptosis?

A

Regulate mitochondrial cytochrome c release

32
Q

How many BCL-2 subfamilies are there?

A

3

33
Q

What are the 3 BCL-2 subfamilies?

A
  • Anti-apoptotic subfamily
  • Pro-apoptotic BAX-like subfamily
  • BH3-only proteins
34
Q

What do BH3-ony proteins do?

A

Promote apoptosis when overexpressed

35
Q

How many BH3-only proteins are transcriptionally upregulated byp53?

A

3 (NOXA, PUMA and BID)

36
Q

What happens to some BH3-only proteins during cytockeleton disruption?

A

They are released from the cytoskeleton, where they are tethered, to promote apoptosis

37
Q

What do anti-apoptotic BCL-2 family members do?

A

Block apoptosis by preventing BH3-only proteins from inducing the pro-apoptotic family members.

38
Q

How do caspases act functionally?

A

As heterotetramers

39
Q

Do all mammalian caspases participate in apoptosis?

A

No

40
Q

Why does the nucleus fragment in apoptosis?

A

Dunno, no-one’s worked it out yet. Possibly to do with contributing to the irreversiblility of the death process.

41
Q

What can result in delay to the onset of DNA fragmentation?

A

Mutant forms of lamins in the nuclear lamina that resist caspase-mediated proteolysis

42
Q

How do cells undergoing apoptosis retract from neighbouring cells?

A

Caspase-dependant dismantling of cell-matrix focal adhesion points, and cell-cell adhesion complexes

43
Q

What is a cadherin?

A

A transmembrane protein that plays a role in cell adhesion.

44
Q

What do caspases do to cadherin?

A

Degrade them by proteolysis

45
Q

What else do caspases target?

A

Proteins that function in transcription and translation, and rRNA.

46
Q

What degrades DNA during apoptosis?

A

Caspase-activaed DNase (CAD)

47
Q

How is CAD normally found?

A

In healthy cells, CAD is found with its inhibitor in a complex.

48
Q

What happens to the CAD/ICAD complex in apoptosis?

A

Caspases cleave the ICAD to liberate CAD

49
Q

What is the last act of the dying cell?

A

The generation of binding sites for phagocytes and the release of chemoattractant molecules

50
Q

What are BCL-2 antagonists?

A

Cancer therapy that blocks the action of BCL-2 in cancer to promote apoptosis

51
Q

What have BCL-2 antagonists proved effective in treating?

A

Chronic lymphocytic leukaemia

52
Q

What are SMAC mimetics?

A

New targeted drug therapy that induce apoptotic death of cancer cells

53
Q

What is IAP?

A

Inhibitor of Apoptosis protein - normally inhibit caspases to protect against inadvertent cell death. Expressed in excess in many human cancers.

54
Q

What do SMAC mimetics do?

A

Induce proteasomal degradation of IAPs

Biology of Cancer SSC (16 decks)

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