Entry
Name
Apoptosis - Homo sapiens (human)
Description
Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.
Class
Cellular Processes; Cell growth and death
BRITE hierarchy
Pathway map
Network
Element
N00098 Intrinsic apoptotic pathway
N00145 Extrinsic apoptotic pathway
N00146 Crosstalk between extrinsic and intrinsic apoptotic pathways
N00984 mGluR5-Ca2+ -apoptotic pathway
N01056 FAS-JNK signaling pathway
Drug
D03441 Certolizumab pegol (USAN/INN)
D04687 Lenalidomide (JAN/USAN/INN)
D05216 Oblimersen sodium (USAN)
D08954 Obatoclax mesylate (USAN)
D08976 Pomalidomide (JAN/USAN/INN)
D09692 Veliparib (JAN/USAN/INN)
D09730 Olaparib (JAN/USAN/INN)
D09813 Lenalidomide hydrate (JAN)
D10157 Rucaparib phosphate (USAN)
D10382 Afuresertib hydrochloride (USAN)
D10560 Idelalisib (JAN/USAN/INN)
D10679 Venetoclax (JAN/USAN/INN)
D10733 Talazoparib tosylate (USAN)
D10982 Rucaparib camsylate (USAN)
D10988 Selonsertib (JAN/USAN/INN)
D11895 Niraparib tosylate (USAN)
D11962 Murizatoclax (USAN/INN)
D12352 Eclitasertib (USAN/INN)
D12565 Xevinapant (JAN/USAN/INN)
D12746 Brensocatib hydrate (JAN)
D12940 Oditrasertib (USAN/INN)
Other DBs
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
10039 PARP3; poly(ADP-ribose) polymerase family member 3 [KO:K10798 ] [EC:2.4.2.-]
10912 GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402 ]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467 ] [EC:2.7.11.10 ]
142 PARP1; poly(ADP-ribose) polymerase 1 [KO:K24070 ]
143 PARP4; poly(ADP-ribose) polymerase family member 4 [KO:K10798 ] [EC:2.4.2.-]
1439 CSF2RB; colony stimulating factor 2 receptor subunit beta [KO:K04738 ]
1616 DAXX; death domain associated protein [KO:K02308 ]
1647 GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402 ]
1649 DDIT3; DNA damage inducible transcript 3 [KO:K04452 ]
1676 DFFA; DNA fragmentation factor subunit alpha [KO:K02310 ]
1677 DFFB; DNA fragmentation factor subunit beta [KO:K02311 ] [EC:3.-.-.-]
1965 EIF2S1; eukaryotic translation initiation factor 2 subunit alpha [KO:K03237 ]
2081 ERN1; endoplasmic reticulum to nucleus signaling 1 [KO:K08852 ] [EC:2.7.11.1 3.1.26.-]
2353 FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379 ]
317 APAF1; apoptotic peptidase activating factor 1 [KO:K02084 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
329 BIRC2; baculoviral IAP repeat containing 2 [KO:K16060 ]
330 BIRC3; baculoviral IAP repeat containing 3 [KO:K16060 ]
332 BIRC5; baculoviral IAP repeat containing 5 [KO:K08731 ]
355 FAS; Fas cell surface death receptor [KO:K04390 ]
3563 IL3RA; interleukin 3 receptor subunit alpha [KO:K04737 ]
3708 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
3709 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959 ]
3710 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
4170 MCL1; MCL1 apoptosis regulator, BCL2 family member [KO:K02539 ]
4616 GADD45B; growth arrest and DNA damage inducible beta [KO:K04402 ]
468 ATF4; activating transcription factor 4 [KO:K04374 ]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
5366 PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131 ]
55367 PIDD1; p53-induced death domain protein 1 [KO:K10130 ]
56616 DIABLO; diablo IAP-binding mitochondrial protein [KO:K10522 ]
572 BAD; BCL2 associated agonist of cell death [KO:K02158 ]
578 BAK1; BCL2 antagonist/killer 1 [KO:K14021 ]
5783 PTPN13; protein tyrosine phosphatase non-receptor type 13 [KO:K02374 ]
581 BAX; BCL2 associated X, apoptosis regulator [KO:K02159 ]
596 BCL2; BCL2 apoptosis regulator [KO:K02161 ]
597 BCL2A1; BCL2 related protein A1 [KO:K02162 ]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735 ]
637 BID; BH3 interacting domain death agonist [KO:K04726 ]
63970 TP53AIP1; tumor protein p53 regulated apoptosis inducing protein 1 [KO:K13773 ]
6709 SPTAN1; spectrin alpha, non-erythrocytic 1 [KO:K06114 ]
7132 TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158 ]
7185 TRAF1; TNF receptor associated factor 1 [KO:K03172 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210 ]
8717 TRADD; TNFRSF1A associated via death domain [KO:K03171 ]
8739 HRK; harakiri, BCL2 interacting protein [KO:K02512 ]
8743 TNFSF10; TNF superfamily member 10 [KO:K04721 ]
8772 FADD; Fas associated via death domain [KO:K02373 ]
8795 TNFRSF10B; TNF receptor superfamily member 10b [KO:K04722 ]
8797 TNFRSF10A; TNF receptor superfamily member 10a [KO:K04722 ]
8837 CFLAR; CASP8 and FADD like apoptosis regulator [KO:K04724 ]
9131 AIFM1; apoptosis inducing factor mitochondria associated 1 [KO:K04727 ] [EC:1.-.-.-]
9451 EIF2AK3; eukaryotic translation initiation factor 2 alpha kinase 3 [KO:K08860 ] [EC:2.7.11.1 ]
Compound
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference
Authors
Savitskaya MA, Onishchenko GE
Title
Mechanisms of Apoptosis.
Journal
Reference
Authors
Schleich K, Lavrik IN
Title
Mathematical modeling of apoptosis.
Journal
Reference
Authors
Lavrik I, Golks A, Krammer PH
Title
Death receptor signaling.
Journal
Reference
Authors
Jin Z, El-Deiry WS
Title
Overview of cell death signaling pathways.
Journal
Reference
Authors
Benn SC, Woolf CJ
Title
Adult neuron survival strategies--slamming on the brakes.
Journal
Reference
Authors
Orrenius S, Zhivotovsky B, Nicotera P
Title
Regulation of cell death: the calcium-apoptosis link.
Journal
Reference
Authors
Clarke P, Tyler KL
Title
Apoptosis in animal models of virus-induced disease.
Journal
Reference
Authors
Wen X, Lin ZQ, Liu B, Wei YQ
Title
Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer.
Journal
Reference
Authors
Shalini S, Dorstyn L, Dawar S, Kumar S
Title
Old, new and emerging functions of caspases.
Journal
Reference
Authors
Philchenkov A
Title
Caspases: potential targets for regulating cell death.
Journal
Reference
Authors
Stroh C, Schulze-Osthoff K
Title
Death by a thousand cuts: an ever increasing list of caspase substrates.
Journal
Reference
Authors
Safa AR
Title
c-FLIP, a master anti-apoptotic regulator.
Journal
Exp Oncol 34:176-84 (2012)
Reference
Authors
Jeong SY, Seol DW
Title
The role of mitochondria in apoptosis.
Journal
Reference
Authors
Parsons MJ, Green DR
Title
Mitochondria in cell death.
Journal
Reference
Authors
Strasser A
Title
The role of BH3-only proteins in the immune system.
Journal
Reference
Authors
Schonthal AH
Title
Endoplasmic reticulum stress: its role in disease and novel prospects for therapy.
Journal
Reference
Authors
Malhi H, Kaufman RJ
Title
Endoplasmic reticulum stress in liver disease.
Journal
Reference
Authors
Malhotra JD, Kaufman RJ
Title
The endoplasmic reticulum and the unfolded protein response.
Journal
Reference
Authors
Wu J, Kaufman RJ
Title
From acute ER stress to physiological roles of the Unfolded Protein Response.
Journal
Reference
Authors
Repnik U, Stoka V, Turk V, Turk B
Title
Lysosomes and lysosomal cathepsins in cell death.
Journal
Reference
Authors
Cesen MH, Pegan K, Spes A, Turk B
Title
Lysosomal pathways to cell death and their therapeutic applications.
Journal
Reference
Authors
Dashzeveg N, Yoshida K
Title
Cell death decision by p53 via control of the mitochondrial membrane.
Journal
Reference
Authors
Bouchier-Hayes L, Green DR
Title
Caspase-2: the orphan caspase.
Journal
Reference
Authors
Baptiste-Okoh N, Barsotti AM, Prives C
Title
A role for caspase 2 and PIDD in the process of p53-mediated apoptosis.
Journal
Reference
Authors
Aggarwal BB
Title
Signalling pathways of the TNF superfamily: a double-edged sword.
Journal
Reference
Authors
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA.
Title
JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.
Journal
Reference
Authors
Dragovich T, Rudin CM, Thompson CB
Title
Signal transduction pathways that regulate cell survival and cell death.
Journal
Reference
Authors
Sofroniew MV, Howe CL, Mobley WC
Title
Nerve growth factor signaling, neuroprotection, and neural repair.
Journal
Reference
Authors
Kristiansen M, Ham J
Title
Programmed cell death during neuronal development: the sympathetic neuron model.
Journal
Reference
Authors
Logue SE, Martin SJ
Title
Caspase activation cascades in apoptosis.
Journal
Reference
Authors
Boivin WA, Cooper DM, Hiebert PR, Granville DJ
Title
Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma.
Journal
Reference
Authors
Cullen SP, Brunet M, Martin SJ
Title
Granzymes in cancer and immunity.
Journal
Reference
Authors
Liu K, Lan D, Li C, Liu S, Dai X, Song T, Wang X, Kong Q, He Z, Tan J, Zhang J
Title
A double-edged sword: role of apoptosis repressor with caspase recruitment domain (ARC) in tumorigenesis and ischaemia/reperfusion (I/R) injury.
Journal
Related pathway
hsa04141 Protein processing in endoplasmic reticulum
hsa04650 Natural killer cell mediated cytotoxicity
KO pathway