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Flashcards in Apoptosis Deck (22):
1

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

More gradual

2

Apoptosis

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

3

What are capspases?

Family of enzyme proteases

Hydrolyzes specific peptide bonds in proteins

Contribute to cells by inactive of important proteins

Tightly regulated

4

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*

5

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

6

What is the fate of an apoptotic cell?

The remains are up taken and digested by macrophages

7

Death receptor pathway

Triggered by members of death receptor superfamily including CD95

8

Death ligand

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

9

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

10

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)

11

Cytochrome C, Caspase pathway- detailed outline

Outside mitochondria

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 ***

12

What regulates the release of Cytochrome C from the mitochondria?

A family of Bcl proteins (about 24 proteins)

13

Anti-apoptotic Bcl proteins

Bcl-2 and Bcl-XL

14

Pro-apoptotic Bcl proteins

Bax and Bak

15

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

16

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

17

Ultimately what determines cell death or survival?

The ratio between anti and pro apoptotic proteins

18

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

19

P53

P53 was first identified as a tumor suppressor protein

Transcription factor that regulates expression of various genes

20

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

21

How is MAPK activated?

The proteins MAPK: mitogenic activated protein kinases are activated by growth factor signals, UV light, radiation

22

What does MAPK do?

MAPK known as Raf phosphorylates Bad, leading to its dissociation from the mitochondrial membrane --> leakage of cytochrome c --> leading to inhibition of apoptosis