Green - Apoptosis Flashcards
Blebbing
Cell shrinks and breaks up into membrane enclosed fragments
What is the fate of an apoptic cell?
Recognized and phagocytosed by macrophages and neighboring cells
Caspases
Cleave proteins; present as inactive precursors–activated by cleavage by other caspases
What are the two types of caspases and what are their roles?
Initiators and Executioners
Initiator caspases activate executioner caspases, which can activate other executioner caspases (cascade)
What are the main targets of caspases?
Inhibitor of DNase
Lamins
Cytoskeletal proteins
Inhibitors of apoptosis (Bcl-2, Bcl-xL, FLIP, IAM, XIAP)
What are two main pathways for apoptosis?
- Intrinsic/Stress
- Extrinsic/Death Receptor
What family of proteins determine if apoptosis occurs?
Bcl-2
Both activators and inhibitors
Antiapoptotic Proteins
Inhibit apoptosis by sequestering pro-apoptotic proteins
Bcl-2
Bcl-xL
Bcl-2
Antiapoptotic
Bcl-xL
Antiapoptotic
Propaptotic (non mitochondrial)
Bad
Bid
Proapoptotic (Mitochondrial Migration)
Bak
Bax
How do Bcl-2 proteins interact?
Pro-apoptotic (Bid, Bad) inactivate anti-apoptotic (Bcl-2, Bcl-xL)
Allows other pro-apoptotic (Bax, Bak) to activate apoptosis
What can trigger the mitocondrial/intrinsic pathway of apoptosis?
Disruption of electron transport or production of reactive oxygen species
If damage to DNA or mitochondria occurs, what results?
- Cytochrome C moves to cytosol
- Apaf-1 + ATP + Cytochrome C form Apoptosome
- Caspase-9 binds, activated
4. Downstream caspases activated (3/7)
Death Receptor/Extrinsic Pathway
Immune System
Fas Receptor
What is the process of the Extrinsic or Death Receptor pathway?
- Fas-Ligand (FasL) binds Fas receptor on another cell
- Fas trimerization
- FADD binds via Death Domains on Fas
4. Caspase 8 binds at Death Effector Domain (DED) of FADD
5. Caspase 8 activated
- Downstream activation
What is the interection of the two pathways?
Caspase 8 can cleave Bid which can enter mitochondria to induce the Intrinsic (mitochondrial) pathway
How is apoptosis regulated?
- Positive Feedback and Amp Loops
- Buffers/Dampeners
- FLIPs
- Decoy Receptors
- p53
IAPs
Inhibitors of Apoptosis Proteins
Bind to procaspases to prevent their activation
Bind to caspases to inhibit their activity
Inhibited by Smac/Diablo
Smac/Diablo
Ibhibitor of IAPs
FLIPs
Similar structure as caspase-8, but lack catalytic domain; compete for binding to FADD
Decoy Receptors
Bind to apoptosis0inducing ligand, but don’t transduce signal
p53
Tumor suppressor protein, mediates cell cycle/arrest/apoptosis
DNA damage activates ATM/Chk2
Initiates TX of PUMA/Noxa (pro apoptotic genes)
What are some clinical presentations or excessive/inappropriate apoptosis?
Neurodegenerative Disease
Immune Deficiency Disease
Cardiovascular Disease
Emphysema
AIDS
What are some clinical presentations of deficient apoptosis?
Cancer
Autoimmune Disease
What is the malfunction in apoptosis in many cancers?
- IAP expression increased (inhibit apoptosis)
- Anti-apoptotic Bcl-2 expression increased
What are some possible strategies to reactivate apoptosis in treating cancers?
- BH3 (BID) mimetics
- XIAP Antagonists
- FasL mimetics and Fas Activators
What are the 5 main inhibitors of Apoptosis?
- Bcl-2
- Bcl-xL
- FLIP
- IAP
- XIAP