Apoptosis Flashcards
What occurs during apoptosis?
Irreversible once started
Chromatin and nucleus fragments
Cytoskeleton breaks up
Cell shrinks and breaks up into membrane-enclosed fragments
What is the role of phosphatidylserine in apoptosis?
Flipped to outer leaflet during apoptosis
Recognized by macrophages for phagocytosis
What are caspases?
Protease that is responsible for cleaving many different cell proteins during apoptosis
What are the two types of capsases?
Initiator and executioner capsases
What are the targets of capsases?
ICAD
Nuclear lamins
Cytoskeletal proteins
Golgi matrix proteins
Scramblase
What are the two main pathways of apoptosis/
Intrinsic/Stress
Extrinsic/Death receptors
What are two antiapoptotic proteins?
Bcl-2
Bcl-xL
What is the function of Bad and Bid?
Proapoptotic proteins that block Bcl-2 and Bcl-xL interaction with pro-apoptotic proteins
What is the function of Bak and Bax?
Proapoptotic proteins that translocate to the mitochondria where they are thought to insert in membrane and disrupt its integrity, allowing cytochrome c release
How is the mitochondrial/intrinsic pathway activated?
DNA damage or mitchondrial damage causes Apaf-1 and cytochrome c release from the mitochondria to the cytoplasm
What is an apoptosome?
Multi subunit complex formed by Apaf-1, cytochrome c, and ATP
Caspase-9 binds to this complex and is activated by autocleavage
What is the function of caspase 9?
Proteolytic activation of Caspase-3 and Caspase-7
How is the extrinsic pathway activated?
When membrane bound FasL on the surface of one cell binds to Fas receptor on surface of another cell
What occurs when ligand binds to Fas receptor?
Fas trimerizes and binds to its adaptor FADD, via death domains at the C-terminal of both proteins
What is the function of FADD?
Once it binds to Fas, it binds capsase-8 via death effector domains at its N-terminus
What happens when capsase-8 binds to FADD?
Autocleavage and activation of C-8, diffuses to cytoplasm and activates C-3
How does Capsase-8 combine the two pathways?
Cleaves Bid, which translocates to the mitochondria and disrupts the membrane.
This causes the release of cytochrome c
What are five ways apoptosis is regulated?
Positive feedback and amplification
Buffers/dampeners
FLIPs
Decoy receptors
p53
What is the function of inhibitors-of-apoptosis proteins (IAPs)?
bind to procaspases and caspases
What is the function of Smac/Diablo?
Inhibits IAPs
What is the function of FLIPs?
compete with caspase-8 for binding to FADD
Lacks catalytic residues
What are decoy receptors?
Bind to apoptosis-inducing ligand, but cannot transduce apoptotic signal
What is the role of p53?
Tumpor suppressor protein
Activated via DNa damage
Initiates transcription of pro-apoptotic genes PUMA and Noxa
What types of diseases are caused by excessive apoptosis?
Neurodegenerative
Immune deficieny
Cardiovascular
Emphysema
AIDS
What types of diseases occur with too little apoptosis?
Cancer
Autoimmune disease
What are two ways cancer cells escape apoptosis?
IAPs expression increased
Anti-apoptotic Bcl-2 protein levels increased
What are some apoptotic cancer treatment?
BH3 mimetics
XIAP antagonists
FasL mimetics and Fas activators
