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CELLULAR PATHOLOGY > Cell Damage And Death > Flashcards

Cell Damage And Death Flashcards

1
Q

What are the 6 causes of cell death

A 
Genetic 
Inflammation 
Physical 
Traumatic damage 
Infection 
Chemical
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2
Q

State the 3 mechanisms of cell death

A

Apoptosis

Necrosis

Autophagic cell death

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3
Q

What is apoptosis

A

Programmed cell death

Eliminate unwanted host cells

SELECTIVE PROCESS

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4
Q

Functions of apoptosis

A

Deletion of superfluous (cells not needed by organism anymore)

Deletion of infected cells (viral cells)

Deletion of transformed cells (precancerous cells)

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5
Q

Give an example of apoptosis in embryogenesis

A

Cell death in embryonic hands to form individual fingers

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6
Q

Give an example of apoptosis in neuronal cells

A

All neuronal cells need to be surrounded by NGF (neuronal growth factor)

No NGF (GF deprivation) = apoptosis of neuronal cells

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7
Q

Example of apoptosis in endocrine dependent tissue atrophy

A

After breast feeding, the cells that produce milk are no longer needed
Therefore they undergo apoptosis

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8
Q

Describe autophagic cell death

A

degradation of NORMAL proteins
(for example during metamorphosis, ageing and differentiation)

AND

degradation of ABNORMAL proteins
(for example proteins that would accumulate in cancer)

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9
Q

Breast cancer cell death can be induced via tamoxifen. What type of cell death is this an example of?

A

autophagic cell death

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10
Q

what is the most common cause of cell death? And what is the function of it?

A) apoptosis
B) necrosis
C) autophagic cell death

A

B - NECROSIS

necrosis removes damaged cells from an organism

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11
Q

Necrosis occurs after stresses, such as..

A

ischaemia

trauma = inflammation

chemical injury

infection

cancer

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12
Q

what is necrosis?

is it reversible or non-reversible?

A

usually caused by lack of blood supply to cells or tissues

REVERSIBLE PROCESS

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13
Q

Describe the process of necrosis

A

lack of oxygen

no ATP = no energy

ion channel on cell membrane stops working

efflux of H2O not regulated

too much influx of H2O = swelling of the cell

ruptured lysosome
degradation of organelles and nuclear material by lysosome enzymes
(POINT OF NO RETURN)

cellular debris stimulates an inflammatory response

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14
Q

describe how necrosis can be reversible

A

at the point of the swelling of cell if oxygen is reintroduced, then the process can be reversed!

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15
Q

MICROSCOPIC APPEARANCE OF NECROSIS

- describe nuclear changes seen (3)

A

chromatin condensation (shrinkage)

fragmentation of nucleus

dissolution of chromatin by DNAse

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16
Q

MICROSCOPIC APPEARANCE OF NECROSIS

- describe cytoplasmic changes seen (2)

A

opacification: denaturation of proteins with aggregation

liquefactive necrosis: complete digestion of cells by enzymes causing cells to liquify

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17
Q

MICROSCOPIC APPEARANCE OF NECROSIS

- biochemical changes seen (2)

A

release of enzymes such as:

  • creatine kinase
  • lactate dehydrogenase

release of proteins such as myoglobin

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18
Q

What can be used in the clinic to measure the extent of tissue damage by necrosis in a patient?

A

blood tests can be done to measure the extent of necrosis

more creatine kinase = more necrosis

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19
Q

what is an astocytoma and what type of cell death is this an example of

A

highly aggressive brain tumour

example of necrosis cell death

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20
Q

what differences can be seen under a microscope between a normal and nephrotic kidney

A

SEE NOTES

normal cell = dark purple dots showing DNA intact

nephrotic cell = no dark purple dots within the cell because the DNA has been completely degraded

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21
Q

what is the function of necrosis and what can happen if necrosis cannot occur?

A

function is to remove damaged cells from an organism

failure to do so = chronic inflammation

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22
Q

describe the effect on pH and oxygen levels in a cell and is increases in distance from a blood vessel

A

further away from blood vessel

lower pH (acidic) 
lower oxygen concentration
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23
Q

what 3 factors influence the survival of cells

A

cell to cell AND/OR cell-matrix contacts

growth factors (PDGF)

cytokines (IL-2/4)

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24
Q

What 4 factors influence the apoptosis of cells

A

disruption of cell to cell AND/OR cell-matrix contacts

lack of growth factors (lack of NGF in neuronal cells = apoptosis)

DNA damaging agents

death domain ligands

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25
Q

State the 2 types of apoptosis and the difference between the 2

A

Intrinsic apoptosis (triggered from WITHIN the cell)

Extrinsic apoptosis (triggered from OUTSIDE the cell)

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26
Q

What are the examples of intrinsic apoptosis?

A
  1. DNA damage: P53 dependent pathway
  2. Interruption of the cell cycle
  3. Inhibition of protein synthesis
  4. Viral infection
  5. Change in redox state
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27
Q

What are examples of extrinsic apoptosis?

A
  1. Withdrawal of growth factors (eg: IL-3)
  2. Extracellular signalling (eg: TNF)
  3. T cells or natural killer cells (eg: granzymes)
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28
Q

What molecules cause apoptosis in cells?

A

CASPASES (cysteine aspartate-specific proteases)

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29
Q

what are caspases and how are they activated?

A

These are cysteine proteases that play a central role in the initiation of apoptosis

Most proteases are synthesised as inactive precursors, requiring activation (usually partial digestion by another protease)

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30
Q

how is inactive caspase Y activated

A
  • Active caspase X cleaves inactive procaspase Y at 2 sites; cleaving off the NH2 domain and COOH domain
  • The NH2 domain is then removed
  • The COOH domain forms a dimer with the large subunits remaining producing an active caspase Y
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31
Q

how are effector caspases produced?

A

· Active initiator caspase X (8 or 9) will convert inactive caspase Y —> active caspase Y

· Active caspase Y will go on to convert inactive caspase Z —> active caspase Z

· Subsequent caspases that are activated (Y and Z) are known as effector caspases (1, 3, 6, 7)

32
Q

what are the effector caspases?

A

caspases 1, 3, 6, 7

33
Q

function of active caspase Y

A

cleavage of cytosolic proteins

34
Q

function of active caspase Z

A

cleavage of nuclear lamina

35
Q

what characteristic morphological changes are seen in the cell upon caspase activation

A

shrinkage of cell

chromatin condensation

DNA fragmentation

plasma membrane blebbing

36
Q

why do cells appear rounded and small after caspase activation

A

After caspase activation one of the first things that occurs is the cleavage of actin filaments and microtubules = no actin cytoskeleton = cell becomes rounded

37
Q

plasma membrane blebbing can be seen in a cell upon caspase activation. State 2 ways in which you can view these changes

A

TEM (transmission electron micrograph)

SEM (scanning electron micrograph)

38
Q

what is found inside the plasma membrane blebbing that occurs upon caspase activation?
what happens to these blebs?

A

Intact mitochondria + other organelles

These blebs will bud off the cell and be recognised by phagocytes and macrophages to be engulfed and removed

39
Q

in a DNA gel electrophoresis how can you differentiate between different types of cell death (necrosis vs apoptosis)?

A

apoptosis shows orderly degradation
(clear fragment intervals)

necrosis has no clear fragment intervals

40
Q

which one is reversible and which is non-reversible?
A) necrosis
B) apoptosis

A

apoptosis = non-reversible

necrosis = reversible (via O2)
upto a certain point, once lysosome has burst = no return

41
Q

in terms of the amount of cells affected, how are necrosis and apoptosis different

A

necrosis = whole group of cells are affected

apoptosis = single or few cells selected

42
Q

what is the purpose of blebbing in apoptosis

A

The orderly packaging of organelles and nuclear fragments in membrane bound vesicles occurs.

43
Q

in terms of an inflammatory response, what is the difference between necrosis and apoptosis?

A

necrosis = inflammatory response stimulated by cellular debris

apoptosis = no inflammatory response

44
Q

why is there no inflammatory response in apoptosis

A

New molecules expressed on vesicle membranes stimulate phagocytosis

NO INFLAMMATORY RESPONSE (unlike necrosis)

45
Q

MICROSCOPIC APPEARANCE OF APOPTOSIS

- describe the nuclear changes (2)

A

Nuclear chromatin condense

DNA cleavage

46
Q

MICROSCOPIC APPEARANCE OF APOPTOSIS

- describe cytoplasmic changes (5)

A

Shrinkage of cell

Organelles packaged into membrane vesicles.

Cell fragmentation, membrane bound vesicles bud off.

Phagocytosis of cell fragments by macrophage and adjacent cell.

No leakage of cytosolic components.

47
Q

MICROSCOPIC APPEARANCE OF APOPTOSIS

- describe biochemical changes (2)

A

Expression of charged sugar molecules on outer surface of cell membranes (recognized by macrophages = enhances phagocytosis)

Protein cleavage by proteases, caspases.

48
Q

Caspase cleaves Lamin A and B. What is the function of this?

A

Cleaves nuclear envelope

49
Q

Caspase cleaves PARP. What is the function of this?

A

stops DNA repair

50
Q

Caspase cleaves DNA-PK. What is the function of this?

A

stops DNA repair

51
Q

Caspase cleaves Topoisomerase II. What is the function of this?

A

stops DNA replication

52
Q

Caspase cleaves Raf-1. What is the function of this?

A

stops signalling

53
Q

Caspase cleaves Akt/PKB. What is the function of this?

A

stops cell survival

54
Q

Caspase cleaves STAT1. What is the function of this?

A

stops signalling

55
Q

Caspase cleaves elf4. What is the function of this?

A

stops translation

56
Q

Initiatior caspase X (8 or 9) can go on to activate inactive caspase Y.

BUT what activates the initiator caspase 8 in the first place?

  • what kind of apoptotic pathway is this: intrinsic or extrinsic
A

activated via ligand induced dimerisation

EXTRINSIC PATHWAY

• TNF binds to TNFR and induces the formation of a DISC
• TNF binds to TNFR = dimerisation of nearby TNFR
• TNFR will bind to FADD
• FADD will bring together closely molecules of procaspase 8
• Close proximity of procaspase 8 molecules = autoproteolysis
• The procaspase molecules activate each other and therefore undergo self cleavage
ACTIVE INITIATOR CASPASE 8

CASPASE CASCADE

57
Q

structure of TNFR

A

has 2 domains

  1. ligand binding domain (for TNF)
  2. death domain (intracellular)
58
Q

structure of FADD (death adaptor)

A

has 2 domains

  1. death domain
  2. death effector domain
59
Q

structure of inactive initiator caspase 8

A

has 2 domains

  1. death effector domain
  2. protease domain
60
Q

what is DISC and what is it composed of?

A

DISC = death inducing signalling complex

TNF
TNFR
FADD
inactive initiator caspase 8

61
Q

Initiatior caspase X (8 or 9) can go on to activate inactive caspase Y.

BUT what activates initiator caspase 9 in the first place?

  • what kind of apoptotic pathway is this: intrinsic or extrinsic
A
  • Cytochrome C released from the mitochondria via BAX
  • Cytochrome C binds to APAF-1
  • APAF-1 dimerisation
  • APAF-1 brings together in close proximity the procaspase-9 molecules = autoproteolysis

Production of active caspase 9

CASPASE CASCADE

INTRINSIC PATHWAY

62
Q

which is the intrinsic and extrinsic apoptotic pathway?

A) ligand TNF induced dimerisation

B) cytochrome C induced apoptosis

A

A = extrinsic pathway

B = intrinsic pathway

63
Q

structure of APAF-1

A

Cytochrome C binding site

  • APAF domain
    apoptosis protease activating factor

CARD
- caspase recruitment domain

64
Q

structure of procaspase 9

A

CARD

protease domain

65
Q

REGULATION OF CYTOCHROME C PATHWAY (INTRINSIC APOPTOSIS)

name 2 anti-apoptotic proteins

A

Bcl-2

Bcl-XL

66
Q

REGULATION OF CYTOCHROME C PATHWAY (INTRINSIC APOPTOSIS)

name 3 pro-apoptotic proteins

A

Bax

Bad

Bid

67
Q

Bcl-2 family proteins form dimers. These dimers can go on to inhibit or promote apoptosis.

Bcl2&Bcl2

  • type of dimer?
  • action?
A

homomer

inhibits apoptosis

68
Q

Bcl-2 family proteins form dimers. These dimers can go on to inhibit or promote apoptosis.

Bcl-2&Bad

A

heteromer

can go either way

69
Q

Bcl-2 family proteins form dimers. These dimers can go on to inhibit or promote apoptosis.

Bad&Bad

A

promotes apoptosis

70
Q

what is Bax? and what is its function in apoptosis?

A
  • Bax (pro-apoptotic) is a hexamer protein found on the mitochondrial membrane
  • Releases cytochrome C from the inner mitochondrial membrane into the cytosol
  • This cytochrome C can then go on to activate APAF-1 = activation of caspase 9
  • CASPASE CASCADE = apoptosis
71
Q

what happens in the cell if bcl-2 and Bax form a dimer?

A

Bcl-2 (anti-apoptotic) can form a dimer with Bax (pro-apoptotic) = inhibits release of cytochrome C = contains the cytochrome C within the mitochondria. This means the overall effect is anti-apoptotic because cytochrome C cannot go on to activate caspase 9

72
Q

What occurs in the cell if the cell is receiving survival signals? (in terms of changes to Bad protein)

A

Survival signal = phosphorylation of Bad (pro-apoptotic) via PKB/Akt = inactivation of Bad activity = no apoptosis

73
Q

What occurs as a result of survival factor withdrawal?

changes to Bad, Bcl-2 etc

A
  • Cell stops receiving survival signal = No PKB/Akt = no phosphorylation of Bad = active Bad
  • Bad can then bind to BcL-2 forming a dimer structure
  • This removes Bcl-2 from blocking the Bax pore on the mitochondrial membrane
  • This means the cytochrome C can move through the pore into the cytosol to activate APAF-1 = activate caspase 9 = apoptosis (cell death)
74
Q

Describe how P53 can induce apoptosis

P53, Bax, etc

A

DNA damage cannot be repaired

this activates P53 (TF)

P53 activates the expression of Bax gene = more Bax protein produced

this means more Bax proteins on the mitochondrial membrane

more release of cytochrome c into the cytosol

more activation of intrinsic apoptotic pathway

75
Q

How does P53 relate to cancer?

A

Many cancers are treated using DNA damaging drugs. The aim of this is to damage DNA of cancer and therefore activate P53 to induce apoptosis of the cancerous DNA/cells.

Mutations in the P53 gene are the most common mutations in cancer
Some mutations destroy the ability of P53 to induce apoptosis
This means that the damaged DNA can go on to replicate and multiply
(this means that these cancers will be resistant to DNA damaging drugs)

CELLULAR PATHOLOGY (10 decks)

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