Apoptosis Flashcards
Name 3 tissues where apoptosis is especially important
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
Name a pathology caused by failure of apoptosis
NEW***
autoimmune lymphoproliferative syndrome
Name a pathology caused by inappropriate apoptosis
Alzheimer’s
Describe necrosis
- Mitochondria fail - can no longer maintain ionic gradient needed for oxidative phosphorylation.
- Cell runs out of ATP - membrane ion pumps fail, water floods into cell - swells
- Cell bursts- small intracellular molecules are intensely pro inflammatory
- Immune response - wbc, especially macrophages arrive and remove debris- resolve injury- form scar (if stroma damaged)
What causes necrosis?
ischemia
physical/ chemical trauma
infection
How is apoptosis different from necrosis?
normal and predictable: result of relatively minor injury
physiological death- not mechanical
expected and implies renewal (like leaves off trees in fall)
What is the defining feature of apoptosis?
collapse of the nucleus
What happens during nuclear collapse?
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!
What are the cytoplasmic and plasma membrane events of apoptosis?
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
Why are apoptotic cells phagocytose d?
so they cannot spill their dangerous contents
Describe the phospholipid phosphatidylserine (PS) system of apoptosis
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
What is the function of flipase
returns PS to inner leaflet of lipid bilayer in healthy cells
What are the key differenced between phagocytosis of apoptitic cells and necrotic cells?
APOPTOSIS:
0 inflammatory response
normal
physiological & silent
NECROSIS:
opposite
How is apoptosis related to tumor formation/ progression?
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
What initiates the intrinsic pathway of apoptosis?
Mitochondrial outer membrane function compromised (withdraw growth factor/ other signal)
What are the “anti-apoptotic” proteins?
Bcl-2
Bcl- XL
Ususally guard outer mitochondrial membrane
What are the “pro-apoptotic” proteins?
Bim
PUMA
replace Bcl-‘s
allowing Bak and Bax to act on membrane
what effect do Bak and Bax have on the cell membrane?
Make it permeable -> cytochrome C released into cytoplasm
Describe the signaling cascade once cytochrome C enters cytoplasm
cytochrome C -> Apaf-1 activated -> protease caspase-9 activated -> caspase 3 activated => APOPTOSIS
What are the nicknames of caspase 9 and caspase 3?
caspase-9: signal caspase
caspase-3: executioner
How do cytotoxic killer T (CTL) cells induce extrinsic apoptosis?
CTL -> activate Fas/CD95 -> transduces signal across membrane -> recruits FADD-> activates caspase 8 -> activates caspase 3 -> APOPTOSIS
What is the root cause of autoimmune lymphoproliferative syndrome?
failure of cells to die (v. uncontrolled proliferation)
What is the importance of hte FLIP family of enzymes in viral infections?
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
Why are mutations to lymphocytes especially dangerous?
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"
