Cell Death

Question 1

What are the differences between necrosis and apoptosis?

Answer 1

Necrosis produces an inflammatory response as cells burst and toxins leak out where as Apoptosis is carried out in a controlled manner without inflammation.

Question 2

What are some key pathways that lead to apoptosis?

Answer 2

Embryology - lumen of tubes (via apoptosis)

Response to growth signal- menstrual cycle (via apoptosis)

Inflammation - resolution, death of neutrophils (via apoptosis)

Immune defence - T and Natural Killer cell responses. (via apoptosis)

Tumour prevention - prevent mutation (via apoptosis)

Autoimmune disease - self destruct (via apoptosis)

HIV AIDS - HIV and activated T cell death (via apoptosis)

Question 3

What is the role of the Bcl2 family ?

Answer 3

They are involved in check and balances

BCL2 travels in pairs (homodimerise - 2 molecules travelling together that are the same) - The 2 BCL2 prevent cell death

Another member of the family is BAX also travel in a homodimerise fashion but they promote cell death. (they do this by triggering the intrinsic apoptotic pathway).

Cell dies or lives depending on the balance of this family.

Question 4

How did caspases get their name ?

Answer 4

Caspases are key mediators

They get their name from;
• cysteine in the active site : “C”
• cleavage after aspartate: “asp”
• protease: “ase”

Question 5

Define anoikis ?

Answer 5

An epithelial cell dies after losing contact with basement
membrane/extra cellular matrix

Can cause a tumour to spread as if it gains the ability to not require a basement membrane then it can travel and form a tumour.

Question 6

Define pyroptosis ?

Answer 6

Pyroptosis is where skin cells die by losing their nucleus and retaining their keratin.

Its a little like some apoptosis and some necrosis caused by the microbial trigger Salmonella

Pyrop - means fever

Question 7

What can caspases target?

Answer 7

• cleave ICAD -> destroy genetic information
• cleave PARP -> prevent DNA repair
• cleave lamin -> break down nuclear architecture
• cleave keratin -> break down cytoplasmic architecture

Question 8

Why are apoptotic cells phagocytosed?

Answer 8

Keep

Question 9

What is reversible cell injury ?

Answer 9

Reversible cell injury is a cell losing its ability to homeostasis but it has not died yet

Question 10

What conditions to doctors work to save reversible cell injury and why is this important ?

Answer 10

In patients who have had stroke and heart attacks you have killed some cells but you have some cells around that which are sub-lethally injured and you can save them and reverse some symptoms

Question 11

What toxin is produced from the electron transport chain ?

Answer 11

Oxygen becomes reactive due to electrons producing free radicals (O2-). These free radicals then become Hydrogen Peroxide (H2O2) which is damaging to cells.

Question 12

What can free radicals cause?

Answer 12

Sublethal/leathal injuries to cells.

Question 13

What happens in cells that have underwent lethal injury ?

Answer 13

Cells that experience lethal injury break normal homeostasis and necrosis occurs.

Seen in stroke and heart attacks as cells cannot produce energy and die.

Question 14

How can a thrombus cause lethal injury ?

Answer 14

A thrombus prevents oxygenated blood from reaching Glycolysis in a cell and this causes Anaerobic glycolysis.

In anaerobic glycolysis a little ATP is made but so is Lactate which goes through a series of processes and activates phospholipases, which causes cell membrane damage, leading to cell necrosis.

Question 15

What is Necrosis?

Answer 15

Necrosis is a complete loss of energy balance in a cell.

It is the death of tissues following bioenergetic failure and loss of plasma membrane integrity

It induces inflammation and repair due to toxins being outside the cell which aren’t wanted

Caused by ischaemia, metabolic, trauma

Question 16

What are the 6 types of necrosis ?

Answer 16

• Coagulative necrosis in most tissues; firm pale area, with ghost outlines on microscopy
• Colliquative necrosis is seen in the brain; the dead area is liquefied
• Caseous necrosis is seen in tuberculosis; there is pale yellow semi-solid material
• Gangrene is necrosis with putrefaction: it follows vascular occlusion or certain infections and is black
• Fibrinoid necrosis is a microscopic feature in arterioles in malignant hypertension
• Fat necrosis may follow trauma and cause a mass, or may follow pancreatitis visible as multiple white spots

Question 17

What is Apoptosis ?

Answer 17

A protective mechanism where you remove a cell in a controlled fashion.

The apoptotic body contains secondary lysosomes which break down cell material and trapped them in membranes which can be safely phagocytosed.

Apoptosis doesn’t cause inflammation as their membranes don’t let any water in so cells cannot burst

Question 18

What is the difference between programmed cell death and apoptosis ?

Answer 18

Programmed cell death is an intention where as Apoptosis is a morphology (fragmentation and budding of cells).

Question 19

What does Apoptosis usually involve the use of?

Answer 19

DNA fragmentation

Question 20

What can we target in cancer chemotherapy to influence life or death of cells?

Answer 20

PARP (Poly ADP-RIbose polymerase)

ICAD (Inhibitor of caspase activated DNase)

Question 21

How are apoptotic membranes removed and how is a apoptotic cell recognised?

Answer 21

Apoptotic cells (once they have fragmented) flip the lipids in their membrane (reorganisation of phosphatidylserine), which allows macrophages to recognise their phosphotidylserine signal and phagocytose them without an inflammatory response.

Question 22

What is involved in extrinsic influenced apoptosis ?

Answer 22

Receptors and T cells are extrinsic factors which trigger apoptosis in cells

-Receptor Mediated-

Question 23

What is involved in intrinsic influenced apoptosis ?

Answer 23

Stress, metabolic stress, DNA damage, Free radicals and p53 are intrinsic factors which trigger apoptosis in cells

• Intracellular stress -

Question 24

What intrinsic factor is mutated and found in 50% of cancer patients?

Answer 24

gene for p53 in DNA - Can be caused by damage to DNA

Question 25

Explain what happens in the extrinsic apoptotic pathway?

Answer 25

The 3 main triggers of extrinsic apoptosis is TNF family, Fas CD95 and inflammation.

A trigger factor outside the cell like TNF binds to a TNF receptor (TNFR) in the cell membrane and causes a docking protein to bind to the transmembrane receptor and get activated. This binds to and activates procaspase 8 which becomes caspase 8 once activated. This activates procaspases 3, 6 and 7 to become caspase 3, 6 and 7 which activate Endonucleuses (by PARP), nuclear proteins (by Laminators) or Cytoskeletal proteins (by a-fodrin). All of these result in apoptosis of a cell.

The key features in this process is; receptor interaction, cytoplasmic signals and caspase cascade

Question 26

What happens in a T cell mediated response?

Answer 26

T cells directly hit the target cell

T cells engage with receptors which can induce extrinsic apoptosis

T cells also inject Perforin into the cell which activates the caspase enzymes

Both of these cause fragmentation of DNA and the breakdown of cytoskeleton and cell breaks up into apoptotic bodies to be removed.

This is an extrinsic response

Question 27

Explain what happens in the intrinsic apoptotic pathway?

Answer 27

Mitochondria becomes leaky then the products it may leak are very harmful to cells (i.e calcium and oxygen radicals)

Cytochrome C is released from the mitochondria which activates the caspases and caspase 3 is the final effector which causes the fragmentation of DNA and the breakdown of cytoskeleton and cell breaks up into apoptotic bodies to be removed.

Question 28

What is an apoptosome?

Answer 28

Theapoptosomeis a large quaternary protein formed in the process of apoptosis.

Its formation is triggered by the release of cytochrome c from the mitochondria in response to a stimulus.

Cells are in balance so apoptosome’s concentrate the pro-apoptotic components to outcompete the effects of the normal suppressor components to cause cell death.

Question 29

How does the body react to radiation ?

Answer 29

Radiation damages DNA and causes strand breaks which are recognised by gene p53, a transcription factor which when activated generates a whole host of new genes to be expressed which cause cell cycle arrest, DNA repair or trigger cell death

P53 responding to DNA damage leads to a series of events which protects the body by stopping a cell from growing, repairing a cell or killing a cell preventing cancer

Question 30

What caspase is the main one to cause apoptosis of a cell?

Answer 30

Caspase 3

Question 31

What can abnormal BCL2 cause?

Answer 31

Abnormal BCL2 causes cancers as too much BCL2 will cause homdimerisation of BCL2 triggering anti-death signals (cells won’t die).

Difficult to treat these slow growing cancers

Question 32

What is the function of IAP?

Answer 32

They inhibit apoptosis by inhibiting caspases.

Question 33

What would we wan drugs to do to treat cancers?

Answer 33

Drugs that act against inhibitors of apoptosis can treat cancers and cause cell death

Question 34

What is. the process of activating caspases called?

Answer 34

Proteolysis/procaspase activation (changing procaspaces into caspases)

Question 35

What can override apoptosis?

Answer 35

Survival factors like growth factors

Question 36

How does a lower intake of calories lower the risk of cancers?

Answer 36

Lower calorie intake causes a lower oxidative stress which reduces the likelihood of Apoptosis happening.

Question 37

What 3 things can be caused by Apoptosis going wrong?

Answer 37

Autoimmune diseases
Cancers
Neurodegeneration

Question 38

What pathways components can we use drugs to target?

Answer 38

• Bcl2 in lymphoma
• Caspase 3 in Alzheimers Disease
• IAP in cancer