Apoptosis

Question 1

Name 3 tissues where apoptosis is especially important

Answer 1

skin
gut
immune system (lymphocytes: T-cells 95-99% rejection rate)
Nerves (only correct connections at correct time kept/ best connections)
Development: between fingers and toes die

Question 2

Name a pathology caused by failure of apoptosis

Answer 2

NEW***

autoimmune lymphoproliferative syndrome

Question 3

Name a pathology caused by inappropriate apoptosis

Answer 3

Alzheimer’s

Question 4

Describe necrosis

Answer 4

1. Mitochondria fail - can no longer maintain ionic gradient needed for oxidative phosphorylation.
2. Cell runs out of ATP - membrane ion pumps fail, water floods into cell - swells
3. Cell bursts- small intracellular molecules are intensely pro inflammatory
4. Immune response - wbc, especially macrophages arrive and remove debris- resolve injury- form scar (if stroma damaged)

Question 5

What causes necrosis?

Answer 5

ischemia
physical/ chemical trauma
infection

Question 6

How is apoptosis different from necrosis?

Answer 6

normal and predictable: result of relatively minor injury
physiological death- not mechanical
expected and implies renewal (like leaves off trees in fall)

Question 7

What is the defining feature of apoptosis?

Answer 7

collapse of the nucleus

Question 8

What happens during nuclear collapse?

Answer 8

Chromatin-> super-condensed (crecents- spherical featureless beads)
Fragmentation of DNA by endonuclease (180bp lengths)

Cell can only repair a few simultaneous DSBs=> even if it survives nuclear collapse, THE CELL WILL NEVER DIVIDE AGAIN!

Question 9

What are the cytoplasmic and plasma membrane events of apoptosis?

Answer 9

cell loses up to 1/3 of volume (pulls away from neighbors)
Boiling action of plasma membrane (ZEIOSIS) ->

Cell tears itself apart into apoptotic bodies

Question 10

Why are apoptotic cells phagocytose d?

Answer 10

so they cannot spill their dangerous contents

Question 11

Describe the phospholipid phosphatidylserine (PS) system of apoptosis

Answer 11

Phospholipid phosphatidylserine (PS) usually within inner leaflet of lipid bilayer

SCRAMBLASE: allows PS to become equal on each side of membrane

Phagocytic cells have receptors for PS- recognize-> bind-> ingest cells once they commit to apoptosis before they lyse

Question 12

What is the function of flipase

Answer 12

returns PS to inner leaflet of lipid bilayer in healthy cells

Question 13

What are the key differenced between phagocytosis of apoptitic cells and necrotic cells?

Answer 13

APOPTOSIS:
0 inflammatory response
normal
physiological & silent

NECROSIS:
opposite

Question 14

How is apoptosis related to tumor formation/ progression?

Answer 14

Theory that mutation causes cell to continue growing -> when faced with lack of resources SECOND mutation prevents/ makes cell more resistant to apoptosis -> survives and continues

Estimated 7 mutations necessary to reach clinical malignancy

Mutations inhibiting death = stimulate growth in tumor cells

Question 15

What initiates the intrinsic pathway of apoptosis?

Answer 15

Mitochondrial outer membrane function compromised (withdraw growth factor/ other signal)

Question 16

What are the “anti-apoptotic” proteins?

Answer 16

Bcl-2
Bcl- XL
Ususally guard outer mitochondrial membrane

Question 17

What are the “pro-apoptotic” proteins?

Answer 17

Bim
PUMA
replace Bcl-‘s
allowing Bak and Bax to act on membrane

Question 18

what effect do Bak and Bax have on the cell membrane?

Answer 18

Make it permeable -> cytochrome C released into cytoplasm

Question 19

Describe the signaling cascade once cytochrome C enters cytoplasm

Answer 19

cytochrome C -> Apaf-1 activated -> protease caspase-9 activated -> caspase 3 activated => APOPTOSIS

Question 20

What are the nicknames of caspase 9 and caspase 3?

Answer 20

caspase-9: signal caspase

caspase-3: executioner

Question 21

How do cytotoxic killer T (CTL) cells induce extrinsic apoptosis?

Answer 21

CTL -> activate Fas/CD95 -> transduces signal across membrane -> recruits FADD-> activates caspase 8 -> activates caspase 3 -> APOPTOSIS

Question 22

What is the root cause of autoimmune lymphoproliferative syndrome?

Answer 22

failure of cells to die (v. uncontrolled proliferation)

Question 23

What is the importance of hte FLIP family of enzymes in viral infections?

Answer 23

FLIPs and v-FLIPS (viral) compete with caspase-8 to bind with FADD -> slowing apopotosis pathway and making cell a “zombie” that produces new viral copies

Herpes
Kaposi’s sarcoma

Question 24

Why are mutations to lymphocytes especially dangerous?

Answer 24

minor changes (binding of antigen to cell receptor) can drive lymphocyte into rapid cycle: 1 cell => 64,000 cells in 4 days!!
- if mutated- change locked in!
"better dead than wrong"