Cell Death Mechanisms

Question 1

Describe the extrinsic pathway for cell death

Answer 1

Cell death induced from the outside

Inducer is a ligand which binds with cell receptor, inducing intracellular signal transduction eventually leading to: caspases, mitochondrial permeability transition (MPT), or BCL2 pathway

Question 2

What are the two pathways involved in apoptosis?

Answer 2

Type 1 Pathway - (Extrinsic pathway) Induced by death receptor-ligand interations
Type 2 Pathway - (Intrinsic pathway) Typically initiated by intracellular stress like chemotherapy, radiotherapy

Question 3

Name the two ligands in the Extrinsic Pathway

Answer 3

• Fas ligand (Fas-L)

* Tumor necrosis factor-alpha (TNF-a)

Question 4

Name and describe the death receptors in the Extrinsic Pathway

Answer 4

•Belong to tumor necrosis factor (TNF) receptor family
- TNF-a receptor
- Fas
• Are transmembrane proteins with three domains:
- an extracellular ligand-interacting domain
- a transmembrane domain
- and intracellular death domain

Question 5

The binding of a ligand to its death receptor causes what?

Answer 5

Receptor oligomerization and activation, triggering intracellular signaling pathways

Question 6

Describe the Fas/FasL pathway

Answer 6

• Fas is activated on binding with FasL, allowing formation of Death-Inducing Signaling Complex (DISC)
• DISC contains caspases 8, which initiates process of apoptosis
• Caspase-8 (initiator caspase) activates caspase-3 (an effector caspase) in apoptosis cascade
• Caspase-8 also initiates MPT and ultimately apoptosis

Question 7

Describe the four steps in the TNFa signaling pathway

Answer 7

1. Signaling is initiated by TNFa binding to TNFa receptor
2. TNF-a induces both survival and apoptotic pathways
3. Formation of COMPLEX I, which downstream activates NF-kB (transcription factor that is a master regulator of almost all pro-inflammatory cytokines). Leads to transcription of ANTI-APOPTOTIC GENES
4. Formation of COMPLEX II - includes FADD and pro-caspase-8 (similar to Fas/FasL)

Question 8

What can NF-kB activate?

Answer 8

• Inflammation

* Anti-apoptosis/survival

Question 9

What’s the major difference between TNF-a and Fas-L pathways?

Answer 9

• If you have a cell expressing Fas and you give it Fas-L the cell will die
• If you give it TNF-a the cell will not die - in the beginning the receptor activates a lot of NF-kB anti-apoptotic genes and the cell grows better than normal
• To induce cell death via TNFa you have to block NF-kB pathway