Unit 6 - Apoptosis, advanced therapies and concepts of immuno-oncology Flashcards Preview

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Flashcards in Unit 6 - Apoptosis, advanced therapies and concepts of immuno-oncology Deck (107)
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1

4 reasons why cells die

  1. when they get old e.g. lifespan of RBC = 120 days
  2. irreversible damage - exposed to extensive damage e.g. ischaemia, stress e.g. pathophysiological conditions, fever
  3. when they become superfluous - tissue/organ development e.g. loss of interdigital web cells, loss of tadpole tail; elimination of superfluous immune cells after recovery from infectious disease
  4. when they become dangerous to the body/organism - virus infected cells, malignant/cancer cells

2

how do cells die

apoptosis - highly regulated, organised form of cell death

necrosis - dysregulated form of cell death

3

characteristics of apoptotic cells

programmed form of cell death

cell separates from neighbouring cells

cell shrinkage

membrane blebbing

chromatin condenses and the nucleus fragments

cell breaks up into apoptotic bodies which are phagocytosed, such that cellular components or waste products do not produce an inflammatory response

predictable, reproducible sequence of events

4

5

key differences between apoptosis and necrosis

APOPTOSIS

  • single cells die
  • cell shrinks
  • remnants are phagocytosed
  • neat, controlled
  • no trace left
  • no inflammation follows

NECROSIS

  • chunks of tissue die
  • cells swell and burst
  • remnants are not cleared
  • cell content released into EC space
  • inflammation follows

6

too little apoptosis

malignant and pre-malignant conditions

lymphoproliferative disorders

leukemias

lymphomas

solid tumours

7

too much apoptosis

alzheimer's

parkinson's

stroke

atherosclerosis (CV)

ischaemia/reperfusion injury (CV)

dysentery (intestinal)

diarrhea (intestinal)

8

phases of apoptosis

INITIATION

the cell makes the decision to kill itself

EXECUTION

cell commits itself to die and activates the machinery for cellular disassembly

CLEARANCE

the apoptotic cell/bodies are removed from the system

9

what initiates apoptosis

appearance of death signals

withdrawal of survival factors

10

categories of death signals that initiate apoptosis

EXTRINSIC

death signal can derive from environment of cell

hormones and cytokines e.g. death ligands secreted by immune cells can kill infected/cancerous cells

INTRINSIC

can derive from inside of cell

overwhelming stress/irreparable damage (DNA damage, hyperthermia, exposure to toxic compounds)

11

withdrawal of survival factors - initiate apoptosis

most cells in the body depend on the presence of growth factors

in their absence, apoptosis is initiated and cells die

e.g. immune cells depend on presence of IL e.g. T cells on IL-2 and IL-15

12

what are caspases

effectors of apoptosis

cysteine dependent aspartic acid specific proteases

co-ordinate destruction of cellular structures

hallmark of apoptosis - required

13

proteases

enzymes that catalyse the breakdown of proteins into smaller polypeptides or AAs

14

cysteine dependent

active site of the caspase contains cysteine residue that is required for its catalytic activity

15

aspartic acid specific

cleave substrate proteins at aspartic acid residues

16

how are caspases synthesised

as inactive precursors (pro-caspases)

17

2 groups of caspases

initiator - 8, 9, 10

effector - 3, 6, 7

initiator activate effector, which then mediate apoptosis through the proteolytic cleavage of 1000s of proteins

18

initiator caspases

8

9

10

19

effector caspases

3

6

7

20

extrinsic activation pathway is also known as

death receptor mediated pathway

21

intrinsic activation pathway is also known as

mitochondrial mediated pathway

22

death receptors involved in extrinsic pathway

when are they expressed

family involved

subset of TNFR superfamily - TNFR1, Fas, TRAIL-R1, TRAIL-R2

some receptors are constantly present on cell surface, while other are expressed only upon damage

external cysteine rich domain - involved in ligand binding

transmembrane domain

internal death domain (DD) - needed for binding of adapter proteins like FADD

23

MOA of extrinsic pathway

death receptors e.g. TNFR, FasR are transmembrane receptors present on cell surface

binding by death ligands e.g. Fas causes death receptor to oligomerise

death receptors change shape and recruit adaptor molecules e.g. FADD or TRADD

several pro-caspase-8 molecules recruited and transactivate each other

active caspase-8 (initiator caspase) cleaves other caspases promoting irreversible cascade and cell death

DISC - Death Inducing Silencing Complex

24

intrinsic cell death pathway

when is it activated

key event

family involved

activated in response to a variety of internal stresses including DNA damage, ER stress, growth factor deprivation

release of mitochondrial intermembrane space proteins is the key event in intrinsic cell death

mitochondrial mediated release of intermembrane space proteins is controlled by the BCL-2 family

25

BCL-2 family

function

what do they have

central controllers of intrinsic cell death

BCL-2 family members have at least 1 of 4 conserved motifs

bcl-2 homology 1 - 4' BH1, BH2, BH3, BH4

important in regulating interaction between family members

26

3 broad classes of BCL2 family members

pro-apoptotic effector proteins - BAX and BAK

anti-apoptotic protein - BCL2, BCL-XL, MCL1

pro-apoptotic BH3-only proteins - BID, BAM, BIM, NOXA

balance between pro and anti apoptotic BCL-2 family members determines cell fate

27

pro-apoptotic effector proteins

BAX

BAK

28

anti-apoptotic proteins

BCL2

BCL-XL

MCL1

29

pro-apoptotic BH3 only proteins

BID

BAD

BIM

NOXA

30

overview of intrinsic pathway