8: Necrosis and Apoptosis 2

Question 1

PCD: essential for? examples?

Answer 1

development and maintenance of multicellular organisms: formation of fingers/toes, formation of functional synapses (since surplus cells have to be eliminated)

Question 2

PCD: required to destroy cells that? 4 ex?

Answer 2

cells that represent a threat to the integrity of the organism: cells infected with viruses. cells of immune system. cells with DNA damage. cancer cells.

Question 3

3 forms of PCD? when do they occur?

Answer 3

type 1 = nuclear/apoptotic. 2 = autophagic. 3 = cytoplasmic. various forms occur in specific nuclei and at specific developmental stages. can also be induced by insults like DNA damage, misfolded protein accumulation.

Question 4

death in the NS may trigger?

Answer 4

stem cell proliferation and survival = cell death pathways can be potential points of entry for therapeutics of neurodegen diseases

Question 5

best characterized form of PCD = ? 3 pathways?

Answer 5

Type 1, aka apoptosis. intrinsic, extrinsic, caspase independent.

Question 6

intrinsic pathway: aka? conservation? propensity for cell to undergo apoptosis determined by?

Answer 6

mitochondrial pathway, largely conserved from worms to mammals. balance between the anti and pro apotoic members of the Bcl-2 family of proteins

Question 7

intrinsic pathway: gatekeepers of apoptosis process? what executes the program?

Answer 7

members of the B-cell leukemia/lymphoma 2 family of proteins. caspases, aka cysteine aspartate proteases execute the program

Question 8

BCl-2 family: anti apoptotic? what domain?

Answer 8

Bcl-2 and Bcl XL. have the B4 domain.

Question 9

bcl2 family: 3 types of pro-apoptoic proteins and what domains they have?

Answer 9

multi domain proteins BH 1 = 3. BH3 only. BH3 only de-repressors.

Question 10

multi domain bcl2 proteins: 2 examples? have?

Answer 10

BAX and BAK. have Bcl2 homology domains 1 -3

Question 11

BH3 only proteins: example? what does it do?

Answer 11

BIM: activates BAX and BAK, likely participate in mitochondrial pore formation

Question 12

BH3 only de-repressors: 3 examples? action?

Answer 12

PUMA, NOXA, BAD. sequester anti-apoptotic Bcl2 and BclXL proteins and other proteins with BH1-4 domains which allows BH1-3 proteins to permealize the mitoch. membrane

Question 13

BH4 domain: who has it?

Answer 13

only the anti-apoptotic members of the bcl2 family have it

Question 14

formation of mitochondrial pore causes release of 2 things?

Answer 14

pro-apoptotic proteins: cytochrome C and SMAC/DIABLO released into cytoplasm

Question 15

what does cytochorme C do? then?

Answer 15

induces heptamerization of cytosolic protein APAF-1 (apoptosis activating factor), which then binds caspase 9 = formation of apoptosome.

Question 16

formation of apoptosome results in (3)?

Answer 16

activation and cleavage of effector caspases 3 and 7, then you get digestion of structural proteins and chromosomal DNA, then phagocytosis of cell.

Question 17

activated effector caspases can be held in check by? ex? but what inhibits those?

Answer 17

IAPs = inhibitors of apoptosis, for example XIAP. SMAC/diable can inhibit IAPs and thus apoptosis can proceed.

Question 18

extrinsic pathway: aka? 5 examples of ligands?

Answer 18

death receptor pathway: FasL/FasR. TNFa/TNFR1, Apo3L and 2L onto DR3, 4, 5.

Question 19

basic events in extrinsic pathway

Answer 19

pro-apoptotic ligand binds death receptor. caspase 8 activation, followed by caspase 3, 6, 7, and apoptosis

Question 20

Fas and TNF receptors are?

Answer 20

integral membrane proteins, with receptor domains exposed at surface of cell

Question 21

Fas receptor: binds what ligand? causes?

Answer 21

trimeric fas ligand = FasL. causes recruitment of FADD through Fas’s death domain.

Question 22

what does FADD do?

Answer 22

recruits capspase 8 through FADD’s death effector domain. activates 8, which then activates effector caspases 3 and 7.

Question 23

how can extrinsic pathway interact with intrinsic pathway?

Answer 23

caspase 8 cleavage of BID to make tBID.. which then triggers intrinsic pathway