Apoptosis signaling pathway

Apoptosis is genetically regulated programmed cell death. Extrinsic (death receptor–DISC–caspase-8) and intrinsic (mitochondrial MOMP–cytochrome c–apoptosome–caspase-9) pathways converge on effector caspases (e.g., caspase-3/7) to cleave substrates and dismantle the cell. It is central to development, immunity, and cancer therapy response or resistance.

1. Key targets

Core nodes

  • BCL-2 家族

    Pro-apoptotic (BAX, BAK, BH3-only BIM/PUMA/BID) vs anti-apoptotic (BCL-2, BCL-XL, MCL1) proteins set the MOMP threshold.

  • Caspase 级联

    Initiator caspases-8/9 activate effectors-3/7; cleaved caspase and PARP are common readouts.

  • Death receptors & IAPs

    Fas, TRAIL-Rs (DR4/DR5), TNFR1 recruit FADD to form DISCs; XIAP and cIAPs modulate caspase activity.

Intrinsic branch

  • DNA damage, p53, ER stress upregulate BH3-only proteins
  • MOMP → cytochrome c / SMAC release → apoptosome assembly

Extrinsic branch

  • Ligand–receptor clustering → DISC → caspase-8 activation
  • Type II cells often amplify via tBID / mitochondrial coupling

Supplement: Apoptosis targets (gene symbols)

HGNC symbols grouped by BCL-2 family, caspases, death receptors, apoptosome, and IAP/p53 modules.

BCL-2 family

Pro-apoptotic effectors

BAX, BAK1, BOK, BID, BIM, BBC3, PMAIP1, BAD, BIK, HRK, BNIP3, BNIP3L

Anti-apoptotic BCL-2 family

BCL2, BCL2L1, MCL1, BCL2A1, BCL2L2, BCL2L10, BCL2L11

Caspases

Initiator caspases

CASP8, CASP9, CASP10, CASP2

Effector caspases

CASP3, CASP7, CASP6

Death receptors / DISC

DISC adaptors

FADD, TRADD, RIPK1

Apoptosome

Apoptosome

CYCS, APAF1, CASP9, DIABLO, XIAP

IAPs & p53

IAP family

XIAP, BIRC2, BIRC3, BIRC5, BIRC6, BIRC7, NAIP

p53 & DNA-damage axis

TP53, CDKN1A, BBC3, PMAIP1, GADD45A, MDM2, ATM, ATR, CHEK1, CHEK2

2. Suggested experimental readouts

Pair early (membrane asymmetry loss) vs late (DNA fragmentation) readouts; distinguish from necroptosis, pyroptosis, and ferroptosis.

  • Cleaved caspase-3 / -8 / -9 (model-dependent)
  • Cleaved PARP1; pair with total PARP
  • Cytochrome c release (fractionation or IF colocalization)
  • Annexin V with 7-AAD or PI flow panel
  • DNA fragmentation / TUNEL; nuclear morphology (Hoechst)
  • BH3-only proteins BIM / PUMA / NOXA (stimulus-dependent)

3. Extrinsic vs intrinsic: quick comparison

FeatureExtrinsicIntrinsic
TriggerDeath-ligands (FasL, TRAIL, TNF, etc.)DNA damage, growth-factor withdrawal, ER stress, oncogenic stress
Key complexDISCApoptosome (Apaf-1 + Cyt c + caspase-9)
BCL-2 familyOften couples to MOMP in type II cells (Bid/tBid)BH3 competition and BAX/BAK oligomerization drive MOMP

4. Cancer & therapeutic context

  • BCL-2 / BCL-XL / MCL1: High expression antagonizes many cytotoxic drugs; BCL2 inhibitors (e.g., venetoclax) are established in hematologic malignancies.
  • cIAP / XIAP: IAP antagonists / SMAC mimetics can sensitize by relieving caspase inhibition or modulating receptor complexes (context-dependent).
  • TRAIL 轴: Pro-apoptotic receptor agonism has a long R&D history; resistance often involves FLIP, cIAPs, or mitochondrial thresholds.

Apoptosis-related antibodies (curated)

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5. Product lines & on-site search

Primary & phospho antibodies

BAX, BAK, BCL-2, BCL-XL, MCL1, caspase-3/8/9 (including cleaved), PARP, cytochrome c, XIAP, FADD, DR4/DR5, p53—WB/IHC/IF/FC as applicable.

Functional reagents

Recombinant TRAIL / FasL for extrinsic stimulation (per datasheet and ethics); pan-caspase inhibitors as negative controls.

6. Inhibitors & tool compounds (summary)

For research use; follow lab SOP, compound datasheets, and ethics approvals.

Z-VAD-FMK

Pan-caspase inhibitor; validates caspase dependence.

Q-VD-OPh

Cell-permeable pan-caspase inhibitor with favorable potency.

Venetoclax (ABT-199)

Selective BCL-2 inhibitor; hallmark probe in hematologic models.

ABT-263 (Navitoclax)

Multi-target BCL-2/BCL-XL/BCL-W; watch platelet toxicity.

ABT-737

BH3 mimetic tool; often discussed with MCL1 co-targeting.

SMAC mimetics / IAP antagonists

Promote cIAP degradation or antagonize XIAP; common in combination studies.

7. Pathway schematic

Extrinsic / intrinsic / effector convergence
Apoptosis pathway schematic
Legend
  1. Extrinsic: ligand–death receptor–DISC–caspase-8
  2. Intrinsic: stress–BAX/BAK–MOMP–Cyt c–apoptosome–caspase-9
  3. Effector caspases-3/7 cleave PARP and other substrates
  4. BCL-2 family and XIAP are major regulatory / resistance nodes

8. Pathway biology overview

Apoptosis removes damaged cells, shapes immune tolerance, and participates in tumor surveillance; solid tumors often evade via upstream rewiring, anti-apoptotic upregulation, or caspase antagonism—interpret alongside autophagy and necroptosis.

  • c-FLIP expression can limit full caspase-8 activation at the DISC
  • Post-MOMP SMAC/DIABLO and cytochrome c jointly tune IAP and caspase activity

9. Related pathways on this site

TGF-β/SmadMAPK/ERKPI3K/Akt/mTORNF-κBCell cycleReceptor tyrosine kinase

10. External databases & modification resources

11. References

Mechanisms & BCL-2 family

  • • Adams JM, Cory S. (2007). Nat Rev Cancer. 7(9):680-92.
  • • Chipuk JE, et al. (2010). Nat Rev Mol Cell Biol. 11(9):624-36.

Death receptors & caspases

  • • Ashkenazi A, Dixit VM. (1998). Science. 281(5381):1305-8.
  • • Lavrik IN, Golks A, Krammer PH. (2005). Cell Death Differ. 12(Suppl 2):997-1004.