Chapter 2 Part 3 Flashcards
Define apoptosis
pathway of cell death that is induced by tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear and cytoplasmic proteins
When does apoptosis occur as a physiological condition?
- destruction of cells during embryogenesis
- involution of hormone-dependent tissues upon hormone withdrawal
- cell loss in proliferating cell populations
- elimination of potentially harmful self-reactive lymphocytes
- death of host cells that have served their useful purpose
When does apoptosis occur in a pathologic condition?
- DNA damage
- accumulation of misfiled proteins
- cell death in certain infections
- pathologic atrophy in parenchymal organs after duct obstruction
Morphologic features associated with apoptosis
- cell shrinkage
- chromatin condensation
- formation of cytoplasmic blebs and apoptotic bodies
- phagocytosis of apoptotic cell or cell bodies, usually by macrophages
Apoptosis results from the activation of…
caspases (cysteine proteases that cleave proteins after aspartic residues)
What two phases are the process of apoptosis divided into?
1) initiation phase- during which some caspases becomes catalytically active
2) execution phase- during which other caspases trigger the degradation of critical cellular components
What two distinct pathways converge on caspase activation?
1) mitochondrial pathway
2) death receptor pathway
What occurs during the mitochondrial (intrinsic) pathway?
-results from increased permeability of the mitochondrial outer membrane with consequent release of death inducing (pro-apoptotic) molecules from the mitochondrial inter membrane space into the cytoplasm
What controls the release of mitochondrial pro-apoptotic proteins?
BCL2 family of proteins
What are the 3 groups the BCL family is divided into?
1) anti-apoptotic: BCL2, BCL-XL, MCL1
2) pro-apoptotic: BAX and BAK
3) Sensors: BAD, BIM, BID, Puma, Noxa
Anti-apoptotic protein functions
keep mitochondrial outer membrane impermeable and prevent leakage of cytochrome c and other death inducing proteins into cytosol
Pro-apoptotic protein functions
promote outer mitochondrial membrane permeability allowing the leakage of cytochrome c from the inter membranous space
Function of sensors
sensors of cellular stress and damage, regulate the balance between the other two groups
What does cytochrome c bind to once released into the cytosol?
APAF-1 (apoptosis activating factor 1) forming a multimeric structure called the apoptosome
What does the apoptosome complex do?
bind caspase 9 to initiate the mitochondrial pathway and sets up an auto amplification process
Mitochondrial (intrinsic) pathway overview
1) cell injury (growth factor withdrawal, DNA damage, protein misfolding)
2) triggers BCL2 family sensors
3) signal BCL2 effectors (BAX and BAK) to promote membrane permeability
4) release of cytochrome c and other pro-apoptotic proteins from the mitochondria
5) singnals initiator caspases (formation of apoptosome)
6) executioner caspases either activate endonucleases leading to nuclear fragmentation of breakdown the cytoskeleton
7) formation of cytoplasmic bleb
8) cytoplasmic bleb becomes apoptotic body
9) apoptotic body binds to phagocytic cell receptors
How is cell viability maintained?
1) survival signal (growth factor) binds to receptor protein
2) production of anti-apoptotic proteins (BCL2, BCL-XL)
3) no leakage of cytochrome c
How is the extrinsic (death receptor initiated) pathway initiated?
engagement of plasma membrane death receptors on a variety of cells
Describe the interactions that occurs during the activation of the extrinsic pathway of apoptosis
1) FasL expressed in T cells binds to Fas, which is a death receptor expressed in many cell types
2) 3 or more molecules of Fas are brought together and their cytoplasmic death domains form a binding site for FADD (Fas-associated death domain)
3) FADD attached to the death receptor binds an inactive caspase-8
4) multiple pro-caspase-8 molecules are brought into close proximity and cleave one another to generate active caspase 8
5) follow the rest of the mitochondrial pathway
What protein inhibits the extrinsic pathway?
FLIP- binds to pro-caspase-8 but cannot activate it
The mitochondrial pathway leads to an activation of what caspase?
9
The death receptor pathway leads to an activation of what caspases?
8 and 10
What are the two executioners caspases?
3 and 6
What are examples of changes that occur in the membranes of apoptotic cells and fragments to promote phagocytosis?
- phosphatidylserine flips to outer leaflet
- secretion of soluble factors that recruit phagocytes
- coated with thrombospondin
- coated with natural antibodies and proteins of complement system (C1q)
