Apoptosis and Replicative Immortality - L4 Flashcards Preview

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Flashcards in Apoptosis and Replicative Immortality - L4 Deck (43):
1

What is apoptosis?

PROGRAMMED CELL DEATH
it is a normal physiological process in development/health of multicellular organisms involving active cell suicide

2

Why is apoptosis important during embryogenesis?

it is important because it sculpts the organism
- about 50% of neurons die by apoptosis during brain development

3

What is the link between apoptosis and homeostasis ?

apoptosis is a means of cells talking to each other to ensure the correct number of cells within a tissue
- regulates the total number of cells
- removes unwanted cells like potential tumour cells, virally infected cells and damaged cells

4

What do cancer cells do to apoptotic processes?

it is essential for cancer cells to deactivate apoptosis

5

What are the stages of apoptosis ?

1) cellular membrane disruption
2) cytosol extruded causing BLEBBING
3) cytoplasmic and nuclear skeletons are broken down
4) chromosomes are degraded
5) nuclear condensation and fragmentation

6

What are the 2 overlapping pathways controlling apoptosis ?

INTRINSIC PATHWAY= responds to internal stress/damage within the cell- cell knows something is wrong with it
EXTRINISIC PATHWAY= responds to signals from other cells- another cell is telling its neighbour that its not needed anymore

7

What are the 3 classes of molecular components ?

Sensors
Signal transduction
Effectors

8

What are the sensors purpose in apoptosis ?

intrinsic= molecules induced by cellular stress- p53, HIF-alpha and E2F1
extrinsic= the "death" receptors pairing of extracellular ligands with cells surface death receptors - FAS-R, DR3-5, TNF-alpha-R1

9

What stress signals activate p53, HIF-alpha and E2F1 ?

p53- DNA damage - too much damage to repair then apoptosis is induced
HIF-alpha- hypoxia
E2F1- oncogene activation - activates apoptotic pathways

10

What are the signal transduction molecules purpose in apoptosis ?

intrinisic= bcl2 and family members, cytochrome c(released from mitochondria) and apaf-1
extrinsic= FADD and TRADD - death inducing signalling complex= DISC

11

What is bcl2?

it is an oncogene that maintains the integrity of mitochondria, prevents them releasing cytochrome c
apoptotic signals want to release cytochrome c

overexpressed a lot in cancers

12

What are the effector molecules purpose in apoptosis ?

caspases= cysteine-aspartic acid proteases - split into initiator and executioner - intrinsic and extrinsic pathways converge onto caspases
caspase activated DNase (CAD)- actually degrades DNA

13

What is the main decision of the intrinsic apoptotic pathway ?

key decision is at the mitochondrion, deciding whether or not to release cytochrome c - this is influence by the bcl2 family

14

What happens when cytochrome c is released ?

1) it forms an apoptosome with apaf-1 and the initiator caspase pro-caspase 9
2) pro-caspase 9 is activated to form capsase 9
3) caspase 9 then activates the executioner capsases
4) DIABLO is another mechanism coming out of the mitochondria which increases apoptosis by inhibiting IAPs which inhibit apoptosis
5) executioner caspases cleave essential cellular proteins

15

What are examples of essential cellular proteins cleaved by executioner capsases?

ICAD, iamin, vimentin and actin etc

16

What are BAK/BAX?

they are tumour suppressors which respond to apoptotic signals and try to degrade mitochondrial membranes to release cytochrome c

17

How many cancers have overexpression of bcl2 ?

over half of all cancers

18

What are examples of proteins that try to prevent bcl2 taking control ?

NOXA, Poma, Bad, HrK, Bim, Bmf and Bik

19

What ratio is critical in apoptosis ?

the balance between bax and bcl2

20

What are examples of ligands that bind to death receptors in the extrinsic pathway ?

Fas, TRAIL, TNF-alpha and TL1A

21

When death receptors are activated what happens?

1) they recruit FADD (or TRADD and FADD) and pro-caspase 8 or 10
2) this forms a death inducing signalling complex DISC
3) pro-caspase 8/10 is activated to form caspase 8/10
4) this leads to activation of executioner capsases

22

Why is evasion of apoptosis essential for tumour growth ?

because...
- excessive DNA damage and mutations occur
- loss of growth factor/survival signalling
- resistance to detachment induced cell death- anoikis
- dysregulation of cell cycle

23

What is anoikis?

it is a particular type of cell death when cells lose adherence to their neighbours
its a way of preventing cells floating off around the body

24

What are different ways in which cancer cells evade apoptosis ?

- overepression of bcl2
- mutated bax
- apaf-1 methylated in melanoma
- IPA-1 is amplified and overexpressed
- methylated capsase 8
- caspase 3 down regulated

25

What is a key research area in cancer?

reactivating apoptotic pathways

26

What is replicative immortality ?

it is the limitless potential to grow/divide in appropriate conditions
NO INDIVIDUAL CELL is immortal- but some give an immortal lineage of parent/daughter cells

27

What types of cells are immortal?

germ cells= subset of stem cells
stem cells= divide very slowly, asymmetrically and continuously
cell lines= grown in incubators
cancer cells= probably immortal

28

What are the processes that occur when a cell is not immortal ?

Terminal differentiation - they acquire an end functional purpose = highly specialised
Apoptosis/Phagocytosis/Necrosis
Divide infrequently until death of the organism
Senescence

29

What do normal cells do ?

they divide finite number of times known as the Hayflick limit - this describes a molecular counter
cells can be frozen for decades and still remember their replicative lifespan

30

What is senescence ?

permanent cell cycle arrest accompanied by whole scale changes in gene expression

31

Why does timing of senesence vary with conditions ?

the number of divisions depends on growth conditions- too much oxygen or wrong growth medium reduces number of divisions

32

What do senescent cells look like ?

their cell shape changes -flatter and more squashed out
express beta galactosidase
changes in nuclear structure- heterochromatin foci are present in senescent cells

33

Why is the activity of p53 important ?

if p53 is active then cells enter senescence
if p53 is inactivated the cells continue to divide leading to crisis

34

What happens in crisis?

crisis- cells continue to divide inducing numerous mutations , rapid proliferation and death
chromosome fusion can occur, massive cell death can occur and some cells emerge with ability to fix themselves and it is these cells that are immortal

35

What does it mean by senescence being double back up plan ?

- natural halt on division after enough have occurred (telomeres signal to p53/pRb)
- induced permanent halt after oncogenic/physical distress

36

Why are senescent cells rare in humans ?

because cells never reach the hay flick replicative limit, apoptosis occurs instead
macrophages may scavenge them

may get odd ones in old persons skin

37

What are telomeres ?

1000s of repairs of DNA sequence TTAGGG doesn't code for anything
they protect chromosome ends from recognition by DNA repair machinery

38

What happens to telomeres?

They get shorter after every division due to end replication problem

39

What happens if telomere erosion occurs ?

the ends of chromatids are unprotected and this can cause the ends of the 2 chromatids to fuse together and this prevents the cell functioning

40

Why are telomeres not recognised as double strand breaks of DNA?

because there are lots of telomere binding proteins that recognise the sequence and form a protective cap

41

When does alternative lengthening of telomeres (ALT) occur?

found in tumours where hTERT is not active

42

What does the end replication problem cause?

causes DNA damage and activates p53

43

how many cancers is hTERT activated ?

>90%, others utilise ALT