apoptosis Flashcards
reasons for apoptosis
harmful cells eg during DNA damage developmentally defective cells eg self reactive lymphocytes excess cells eg during liver regeneration/embryonic development obsolete cells eg (breast cells once lactation not needed) exploitation (chemotherapy)
necrosis vs apoptosis
unregulated cell death- inflammation associated, cell disruption regulated cell death- no cell disruption, no inflammation
what occurs in necrosis
membrane becomes permeable, cell SWELLS and ruptures (basically explodes), and proteases are released= digestion of cells local inflammation occurs
what occurs in apoptosis
two phases- latent phase where death pathways activated, but cell looks the same execution phase- loss of microvilli, cells SHRINKS (rather than swells, chromatin condenses, and membrane-enclosed bits bud off (membrane remains so NO inflammation) and are removed by macrophages
DNA fragmentation
occurs in apoptosis- cell becomes like blobs
other types of cell death
apoptosis-like PCD (programmed cell death)- some features of apoptosis necrosis-like PCD- some features of apoptosis before cell lysis thus there’s a GRADED responses
mechanisms in apoptosis
executioners- caspases starting death programme (death receptors+mitochondria) Bcl-2 family stopping death programme
caspases
they are proteases than cause proteolysis by cleaving cysteine and aspartate (C and AS= start of word caspase)
initiator and effector caspases- domains
they both have P10 and P20 domains, but initiator caspases have CARD and DED domains, which are cleaved later on
caspase maturation
they are produced as procaspases, which have prodomains eg DED- these are then cleaved
caspase cascade
like kinase cascade, except CLEAVAGE occurs rather than phosphorylation caspase 8/9 (intiator) cleave and activate caspase 3 and 7 (effector), which carry out apoptosis
what effector caspases do
cleave/inactivate proteins or complexes eg nuclear laminins also activate other enzymes by cleavage of inhibitor molecules eg nucleases
how caspase cascade activated
extrinsically (by receptors) or intrinsically (through mitochondria)
DIAGRAM death receptors including domains, procaspase recruited and complex formed
a ligand forms a TRIMERIC receptor (not dimeric like before) with cysteine rich domains, and intracellularly there are death domains (DD) FADD is recruited, and procaspase 8 is recruited to form a DISC COMPLEX- procaspase then activated
adapter proteins in receptor pathway and domains
pathway uses adaptor proteins as well, either FADD (activatory- has DD and DED domain), or FLIP (inhibitory, has only DED domains)
apoptosis via mitochondrial regulation
cell stress/DNA damage through P53 causes loss of mitochondrial membrane potential= cytochrome C release= APOPTOSOME COMPLEX (APAF-1 with caspase 9 and cyt C) forms
DIAGRAM apoptosome and difference between necrosis and apoptosis
known as wheel of death- ring in middle, which has cytochrome C on outside formation of apoptosome requires ATP UNLIKE NECROSIS
DIAGRAMS link between receptor and mitochondrial death pathways
caspase 8 cleaves bid, which enhances intrinsic pathway by causing more release of mitochondrial proteins
what modulates apoptosis and proteins
BCL-2 family proteins, 3 groups which all have BH3 (group 3 has BH3 only)
BCL 2 family proteins- anti-apoptotic and pro-apoptotic with difference between
anti- BCL-2 and BCL-xL- anti are MITOCHONDRIAL pro- Bid, bad, bax and bak: pro move between cytosol and mitochondria
pathway in regulation of cell cycle/apoptosis
same receptor that activates RAS/ERK pathway activates PI3-K, which activates PDK-1, which activates PKB/AKT, causing survival
PI3K vs PKB/AKT
PI3K is a LIPID kinase, PKB/Akt is a PROTEIN kinase
what PKB/Akt does
phosphorylates and thus inactivates Bad AND caspase 9 inactivates FOXOS (they activate apoptosis-promoting genes) cause protein synthesis
what opposes PI3K
PTEN, a lipid phosphatase, thus it’s pro-apoptosis
other things that inhibit apoptosis apart from PI3K
IAPs, which bind to caspases to inhibit EXTRINSIC pathway
summary of anti-apoptotic pathways
inhibition of intrinsic pathway- Bcl-2/Bcl-xL extrinsic- FLIP+IAPS PI3K growth factor pathway
