Apoptosis and Replicative Immortality - L4 Flashcards Preview

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What is apoptosis?

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


Why is apoptosis important during embryogenesis?

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


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


What do cancer cells do to apoptotic processes?

it is essential for cancer cells to deactivate apoptosis


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


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


What are the 3 classes of molecular components ?

Signal transduction


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


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


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


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


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


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


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


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

ICAD, iamin, vimentin and actin etc


What are BAK/BAX?

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


How many cancers have overexpression of bcl2 ?

over half of all cancers


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

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


What ratio is critical in apoptosis ?

the balance between bax and bcl2


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

Fas, TRAIL, TNF-alpha and TL1A


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


Why is evasion of apoptosis essential for tumour growth ?

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


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


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


What is a key research area in cancer?

reactivating apoptotic pathways


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


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


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

Terminal differentiation - they acquire an end functional purpose = highly specialised
Divide infrequently until death of the organism


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


What is senescence ?

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