Apoptosis signaling pathway - @ a glance

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 Eukaryotic cell death can take the form of apoptosis (type I), autophagic cell death (type II) and necrosis (type III)1. Apoptosis, a form of programmed cell death, causes cells to shrink, condensation of the nuclei, maintenance of membrane integrity and the rapid elimination by phagocytosis. This process allows the safe removal of defective and unnecessary cells during development and tissue homeostasis2. In the developing nervous system approximately half of all neurons generated are eliminated through apoptosis3. The mammalian immune system removes auto reactive B and T lymphocytes in the same way to prevent autoimmunity4. In contrast, failures in this system are linked to both cancer and degenerative diseases5


Fig 1: Conserved mammalian apoptotic pathway 


Several key protein families are involved in the regulation of apoptosis, most notable the cysteine protease family of caspases6. Each caspase is initially expressed as an inactive precursor. Upon activation by cleavage at specific aspartic residues, heterotetramers assemble to form the active protease7. Initiator caspases (e.g. caspase 9) promote caspase activation and amplification. Effector caspases (e.g. caspase 3 and 7) execute apoptosis through the destruction of vital cell proteins8


The Bcl-2 family consists of one anti-apoptotic (e.g. bcl-2, bcl-xl, bcl-w) and two pro-apoptotic (e.g. Bax, Bak, Box, BH3, bim, bad, bid) subfamilies which function in the regulation of cytochrome C (cyt c) release from mitochondrial outer membrane9. This critical step is essential for the assembly of the apoptosome, a key activator of effector caspases10. Upon activation, the BH3-only family is released from bcl-2 inhibition allowing oligomerisation of Bak-Bax within the mitochondrial outer membrane11. This allows the release of a number of proteins from the mitochondrial outer membrane (including cyt c) 12

Inhibitors of apoptosis (IAPs) 

Unwanted activation of the caspase cascade can have deadly consequences to a cell. Inhibitors of apoptosis (IAP) bind and inhibit caspases, protecting or delaying the cell death response. These evolutionarily conserved proteins are defined by their baculovirus inhibitory repeat (BIR) domain12. Members of this family (e.g. NAIP, cIAP1/2, XIAP, Survivin, Apollon, ML-IAP and ILP2) are important regulators of differentiation, innate immune response and cell mortality14. 


p53 is a well-studied apoptotic protein crucial for inducing cell-cycle arrest in response to cell stress including DNA damage, hypoxia, oncogenes. Under normal conditions p53 orchestrates temporary cell cycle arrest, DNA repair and antioxidant production15. Transcriptional activation domains at the N-terminus allows p53 to recruit components of the transcriptional machinery to DNA16. p53 mutations have been found in huge numbers of human cancers, many causing changes to the DNA binding domain. Although considered a tumour suppressor, over-activation of p53 can prove detrimental to a cell. MDM2, an E3 ubiquitin ligase, negatively regulates p53 by binding and blocking the recruitment of transcriptional machinery17.

Fig 2: p53 and death receptor signaling in apoptosis   

Death receptors

In addition to the evolutionarily conserved pathway of apoptosis, the caspase cascade can also be initiated through activation of death receptors causing oligomerisation of initiator caspase-8 (ref 18). Death receptors are members of the tumour necrosis factor (TNF) family of cytokines and TNF-related apoptosis-inducing ligand (TRAIL) including TNFR, CD95 (Fas/APO-1), TRAILR and NGFR. Activation of these ligands by associated ligands rapidly activates caspase-8 and leads to the destruction of a cell within hours19 

Fig 3: Cellular apoptosis pathway

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Available products   


ProductBiological descriptionPurityReference
Pifithrin-α-HBr p53 inhibitor >98% Sohn et al, 2009
Z-D(OMe)E(OMe)VD(OMe)-FMK Cell permeable caspase-3 inhibitor >90% Stepanichev et al, 2005
Z-LE(OMe)VD(OMe)-FMK Cell permeable derivative of caspase-4 inhibitor Z-LEVD-FMK >90% Bian et al, 2009
Z-VAD-FMK Irreversible general caspase inhibitor >98% Vandenabeele et al, 2006
Signal transduction      
SC-66 Allosteric Akt inhibitor >99% Jo et al, 2011
Luteolin Antioxidant, anti-inflammatory, anti-cancer flavonoid >99% Kim et al, 2011
LY 294002 PI-3 kinase inhibitor >99% Gharbi et al, 2007
Y-27632 dihydrochloride Selective Rho kinase inhibitor >99% Darenfed H et al, 2007
Forskolin Adenylyl cyclase activator >98% Awad JA e al, 1983
Cycloheximide Protein synthesis inhibitor >98% Mattson MP et al, 1997
SB 203580 hydrochloride p38 MAP kinase inhibitor; water soluble >99% Kumar S et al, 1999
FCCP Mitochondrial oxidative phosphorylation inhibitor >99% Benz R et al, 1983
SL 327 MEK inhibitor >99% Wang X et al, 2003
A 769662 AMP-activated protein kinase activator >99% Goransson O et al, 2007

Recomended resources from our technical team

Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell 11;147(4):742-58 (2011). Read more (PubMed: 22078876) »  


  1. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell 11;147(4):742-58 (2011). Read more (PubMed: 22078876) »
  2. Jacobson MD et al. Programmed cell death in animal development. Cell  88(3):347-54 (1997). Read more (PubMed: 9039261) »
  3. Barres BA, Raff MC. Axonal control of oligodendrocyte development. J Cell Biol 147(6):1123-8 (1999). Read more (PubMed: 10601327) »
  4. Opferman JT, Korsmeyer SJ. Apoptosis in the development and maintenance of the immune system. Nat Immunol 4(5):410-5 (2003). Read more (PubMed: 12719730) »
  5. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell 11;147(4):742-58 (2011). Read more (PubMed: 22078876) »
  6. Hengartner MO. The biochemistry of apoptosis. Nature 407(6805):770-6 (2000). Read more (PubMed: 9506977) »
  7. Butt AJ et al. Dimerization and autoprocessing of the Nedd2 (caspase-2) precursor requires both the prodomain and the carboxyl-terminal regions.J Biol Chem 273(12):6763-8 (1998). Read more (PubMed: 11864614) »
  8. Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther 4(2):139-63 (2005). Read more (PubMed: 15725726) » 
  9. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15;15(4):1126-32 (2009). Read more(PubMed: 19228717) » 
  10. Acehan D et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 9(2):423-32 (2002). Read more (PubMed: 11048727) »
  11. Letai A et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.Cancer Cell 2(3):183-92 (2002). Read more (PubMed: 12242151) »
  12. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15;15(4):1126-32 (2009). Read more (PubMed: 19228717) » 
  13. Hinds MG et al. Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol 6(7):648-51 (1999). Read more (PubMed: 10404221) »
  14. Dubrez-Daloz L et al. IAPs: more than just inhibitors of apoptosis proteins. Cell Cycle 7(8):1036-46 (2008). Read more (PubMed: 18414036) » 
  15. Brady CA, Attardi LD. p53 at a glance. J Cell Sci 123(Pt 15):2527-32 (2010). Read more (PubMed: 20940128) » 
  16. Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53 and cancer-associated mutants. Adv Cancer Res 97:1-23 (2007). Read more (PubMed: 17419939) »
  17. Marine JC, Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 17(1):93-102 (2010). Read more (PubMed: 19498444) »
  18. Martin DA et al. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal. J Biol Chem 273(8):4345-9 (1998). Read more (PubMed: 9468483) »
  19. Mahmood Z, Shukla Y. Death receptors: targets for cancer therapy. Exp Cell Res 316(6):887-99 (2009). Read more (PubMed: 20026107) » 

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