Apoptosis

Question 1

key features of necrosis

Answer 1

• triggered by sustained ischemia, physical, or chemical trauma
• cells swell, organelles damaged, chromatin randomly degraded
• cells lyse, organelles destroyed
• leads to inflammation

Question 2

key features of apoptosis

Answer 2

• triggered by specific signals that activate certain genes
• cells shrink, organelles are intact, chromatin degraded systematically
• membrane blebs, cell contents retained
• cells are phagocytosed

Question 3

classes of inducers of apoptosis

Answer 3

• physiologic
• damage-related
• therapy associated

Question 4

modulation of apoptosis

Answer 4

Bcl proteins (intrinsic only)

Question 5

executioners of apoptosis

Answer 5

-caspases followed by endonucleases

Question 6

-physiologic inducers of apoptosis

Answer 6

• TNF-a
• FasL
• growth/survival factor withdrawal
• glucocorticoids

Question 7

damage related activators

Answer 7

• viral infection
• heat shock
• toxins
• tumor suppressors
• oxidants/free radicals

Question 8

therapy associated activators

Answer 8

• UV/gamma radiation

- chemo

Question 9

Bcl family proteins

Answer 9

• both pro and anti apoptotic
• ratio determines if the cell will live or apoptose
• these work exclusively through the intrinsic pathway via the mitochondria
• antiapoptotic Bcl: prevent phosphorylation of channel proteins on the mitochondrial membrane, inhibiting the release of cytochrome c
• pro-apoptotic Bcl: phosphorylates channel proteins on the mitochondrial membrane, opening the channel and allowing cyt c to leak out into the cytoplasm

Question 10

TNF-a and Fasl

Answer 10

• both mediate the extrinsic pathway

- upon binding their receptor on the cell surface, the caspase cascade is initiated within the cell

Question 11

intrinsic pathway steps

• stimulus
• intracellular mech

Answer 11

• stimulated by withdrawal of growth factor or hormones
• pro-apoptotic Bcl proteins phosphorylate channel proteins on the mitochondria
• this allows cyt c to leak out into the cytoplasm
• cyt c then intiates the caspase cascade
• cyt c also causes DNA damage, causing a build up of p53 which is another pro-apoptotic protein

Question 12

extrinsic pathway steps

Answer 12

• mediated by death receptors: TNF-1 and FasR
• TNF-a binds to its receptor on the cell membrane
• on the intracellular side of the TNF-ar, the caspase cascade is initiated

Question 13

Fasl and immunological privilege

Answer 13

• the cap beds in the eyes and the testis are immunologicaly privileged sites
• endothelial cells in these vessels express FasL, so that when leukocyts come through the vessel (which all express FasR) they will be triggered to initiate apoptosis so they do not create an inflammatory response
• note: if you express, FasL then you are fine but if you express FasR then you are at risk

Question 14

caspase 3

Answer 14

• both pathways result in a large amount of activity of this protein
• chief executioner of the cell

Question 15

role of caspases

Answer 15

• activate endonucleases which cleave DNA in linker regions between nucleosome
• cleave cytoskeletal proteins resulting in the formation of blebs (membrane bound cytoplasmic buds containing intact organelles)

Question 16

inhibitors of apoptosis

• function
• when to use

Answer 16

• may be useful in limiting the damage caused by strokes and heart attacks
• mice given a protein inhibitor of apoptosis had more cells survival after artificial induction of a stroke than mice without the apoptosis inhibitor
• Hashimotos disease (severe hypothyroidism), would be helpful to reduce apoptosis of thyroid cells

Question 17

modulating apoptosis pharmaceutically

-examples of uses

Answer 17

• also relevant in cancer, restenosis followed vascular surgery,
• in cancer and restenosis, it would be useful to increase the rate of apoptosis in tumor cells and smooth muscle cells, respectively

Question 18

dysregulated apoptosis is the hallmark of the following diseases

Answer 18

• syndactyly and polydactyly
• expansion of cancer
• the cachexia ( wasting) seen in some late stage cancer patients
• polycystic kidney disease
• hashimotos