A cytotoxic T lymphocyte (CTL) kills a virally infected cell by expressing Fas-L on its surface. Which apoptosis pathway is activated in the target cell, and what is the first intracellular event?
AIntrinsic pathway; Bcl-2 is displaced from the mitochondrial membrane
BExtrinsic pathway; Fas-L binds the Fas death receptor, recruiting FADD and activating caspase-8
CBoth pathways simultaneously; cytochrome c is released before caspase-8 activation
Fas-L binding to the Fas/CD95 death receptor is the defining feature of the extrinsic pathway. The receptor's intracellular death domain recruits FADD, which recruits procaspase-8 and activates it. Caspase-8 is an initiator caspase — it then activates executioner caspases (3, 6, 7) to execute death. Bcl-2 and Bax belong to the intrinsic (mitochondrial) pathway, not the extrinsic one. Note that caspase-8 can also cleave Bid into tBid, linking the two pathways, but the first event is caspase-8 activation.
Question 2 Multiple Choice
A tumor cell has markedly overexpressed Bcl-2 protein. DNA damage from radiation therapy occurs. What is the most likely outcome, and why?
AThe cell dies rapidly via the extrinsic pathway, since Bcl-2 only affects the intrinsic pathway
BThe cell undergoes necrosis instead of apoptosis, because caspases are blocked
CThe cell survives despite DNA damage, because Bcl-2 prevents cytochrome c release and intrinsic pathway activation
DThe cell activates p53, which overrides Bcl-2 and forces apoptosis regardless
Bcl-2 is an anti-apoptotic protein that maintains the integrity of the outer mitochondrial membrane. When overexpressed, it sequesters pro-apoptotic proteins (Bax, Bak) and prevents them from forming pores that release cytochrome c. Without cytochrome c release, the apoptosome cannot form, caspase-9 is not activated, and the intrinsic pathway is blocked. Although p53 upregulates pro-apoptotic BH3-only proteins (PUMA, Noxa), these must overwhelm Bcl-2 to have effect — with massive Bcl-2 overexpression, this balance tips toward survival. This is precisely the mechanism of venetoclax (a BH3-mimetic) resistance when Bcl-2 expression is extreme.
Question 3 True / False
Apoptosis, like necrosis, triggers inflammation because the dying cell releases cytokines and spills its contents into surrounding tissue.
TTrue
FFalse
Answer: False
This is the defining contrast between apoptosis and necrosis. Necrotic cells swell, lyse, and spill their contents, triggering a robust inflammatory response. Apoptosis is an orderly, contained process: the cell shrinks, packages its contents into membrane-bound apoptotic bodies, and displays 'eat me' signals (phosphatidylserine on the outer membrane leaflet) that attract phagocytes for clean engulfment. No inflammatory mediators are released and no tissue damage occurs. Apoptosis is in fact immunologically silent — it is how the body eliminates billions of cells daily without causing chronic inflammation.
Question 4 True / False
Both the extrinsic (death receptor) and intrinsic (mitochondrial) apoptosis pathways ultimately converge on activation of the same executioner caspases.
TTrue
FFalse
Answer: True
Despite having different initiating events and distinct initiator caspases (caspase-8 for extrinsic, caspase-9 for intrinsic), both pathways converge on caspase-3 (and -6, -7) — the executioner caspases that actually dismantle the cell. This convergence explains why the end-stage of apoptosis looks the same regardless of which pathway triggered it: chromatin condensation, DNA fragmentation into nucleosomal ladders, membrane blebbing, and phosphatidylserine exposure.
Question 5 Short Answer
Why does loss of p53 function allow cancer cells to survive DNA damage that would normally trigger apoptosis?
Think about your answer, then reveal below.
Model answer: p53 is a transcription factor that senses DNA damage and upregulates pro-apoptotic BH3-only proteins such as PUMA and Noxa. These BH3-only proteins tip the Bcl-2 balance toward death by displacing pro-apoptotic Bax/Bak from anti-apoptotic proteins, leading to mitochondrial membrane permeabilization, cytochrome c release, and caspase activation. Without p53, damaged cells cannot upregulate these pro-apoptotic signals, so the Bcl-2 balance stays tilted toward survival and the intrinsic pathway is not triggered.
p53 mutation (present in >50% of cancers) is essentially a disabling of the cell's DNA-damage-to-apoptosis alarm. Cells accumulate further mutations without being eliminated, accelerating cancer progression. This molecular mechanism explains why p53 is called the 'guardian of the genome' and why restoring p53 function (or bypassing the need for it with drugs like venetoclax) is a major therapeutic strategy.