Flashcards in Apoptosis Deck (22)
Necrotic cell death
Lysis of cell membrane leads to the release of cell's content into extra cellular space
Occurs in trauma, bacterial/viral infection
Initials of intracellular biochemical, which are not associated with cell lysis
Initiated by signals from damaged DNA, lack of necessary growth factors, forced entrance of the cell to S phase
Leads to the activation of proteases called capspases
What are capspases?
Family of enzyme proteases
Hydrolyzes specific peptide bonds in proteins
Contribute to cells by inactive of important proteins
Activation cascade of Caspase
Procaspase 8, 9, 10 --> auto catalytic just that they can work on themselves --> once bound to adaptor proteins and attached onto membrane, can be active Caspase --> Caspase 8, 9, 10 --> proteolytic activation of effector caspases 3, 6, 7 --> cellular proteins cleavage
*activities are changing, not protein levels*
Characteristics of an apoptotic cell
Changes in plasma membrane protein content causes the membrane to become blabbed (fluidity) and to shed membranous particles that contain intracellular material
Endonucleases (Caspase activated DNase) are activate and they degrade chromosomal DNA into fragments
Degradation and changes in cytoskeletal proteins such as actin, plectin causes a dramatic change in cell shape
What is the fate of an apoptotic cell?
The remains are up taken and digested by macrophages
Death receptor pathway
Triggered by members of death receptor superfamily including CD95
Proteins that activate the death receptor and downstream signaling
Ie; TNF and FAS ligand
Ligand binding to the receptor promotes binding of an intracellular adaptor protein to the cytoplasmic side of the receptor
TNF, FAS ligand pathway
FADD- death domain adaptor protein
TNF (ligand) + Fas receptor + FADD protein --> procaspase 8, 9 ,10 --> Caspase cascade
TNF + FAS increases affinity to FADD
Mitochondrial pathway of apoptosis- Cytochrome C, Caspase pathway (basics)
Mitochondria contains Cytochrome C in the mitochondrial membrane space
Translocation of cytochrome C to the cytosol via pores generated in the outer mitochondrial membrane, leads to apoptosis (Cytochrome C is essentials for cell survival)
Cytochrome C, Caspase pathway- detailed outline
Cytochrome C + Apaf1 + procaspase 9 --> apoptosome --> procaspase 9 activation to Caspase 9 --> released from complex to activate caspases 3, 6, 7
Activation not expression increased ***
What regulates the release of Cytochrome C from the mitochondria?
A family of Bcl proteins (about 24 proteins)
Anti-apoptotic Bcl proteins
Bcl-2 and Bcl-XL
Pro-apoptotic Bcl proteins
Bax and Bak
How does a pro-apoptotic Bcl family protein promote apoptosis?
The pores in the mitochondrial membrane through which Cytochrome C passes are generated by dimers or polymers of Bax and Bak
Bid, Bad, Noxa are pro-apoptotic facilitator proteins that help the formation of these stable dimers
How does Bcl-2 prevent apoptosis?
Anti-apoptotic Bcl-2 and BclXL prevent cytochrome C leakage by binding to Bak and Bax and preventing their self association to form membrane proteins
Ultimately what determines cell death or survival?
The ratio between anti and pro apoptotic proteins
XIAP and Smac/Diablo
XIAP- Caspase inhibitor protein
X linked inhibitor of apoptosis
The protein Smac/Diablo inhibits XIAP and therefore allows activation of the Caspase cascade
Regulated mainly by proteins
P53 was first identified as a tumor suppressor protein
Transcription factor that regulates expression of various genes
How does p53 induce apoptosis?
P53 increases the transcription of pro-apoptotic genes such as Bax and Noxa
Activates cytoplasmic Bax to bind to the mitochondrial membrane
Increases the expression of p21, which leads to cell cycle arrest
How is MAPK activated?
The proteins MAPK: mitogenic activated protein kinases are activated by growth factor signals, UV light, radiation