KEGG   PATHWAY: hsa04218
Entry
hsa04218                    Pathway                                
Name
Cellular senescence - Homo sapiens (human)
Description
Cellular senescence is a state of irreversible cellular arrest and can be triggered by a number of factors, such as telomere shortening, oncogene activation, irradiation, DNA damage and oxidative stress. It is characterized by enlarged flattened morphology, senescence-associated beta-galactosidase (SA-b-gal) activity, secretion of inflammatory cytokines, growth factors and matrix metalloproteinases, as part of the senescence-associated secretory phenotype (SASP). Cellular senescence is functionally associated with many biological processes including aging, tumor suppression, placental biology, embryonic development, and wound healing.
Class
Cellular Processes; Cell growth and death
Pathway map
hsa04218  Cellular senescence
hsa04218

Drug
D00107  Tacrolimus (USP/INN)
D00184  Cyclosporine (USP)
D01583  Pirfenidone (JAN/USAN/INN)
D05480  Pimecrolimus (JAN/USAN/INN)
D06160  Tiplasinin (USAN)
D08556  Tacrolimus (INN)
D08656  Aleplasinin (USAN/INN)
D09033  Voclosporin (JAN/USAN/INN)
D10983  Ruclosporin (USAN/INN)
D11148  Berzosertib (USAN/INN)
D11787  Ceralasertib (JAN/USAN/INN)
D12181  Edasalonexent (USAN/INN)
D12237  Zunsemetinib (USAN)
D12321  Camonsertib (USAN)
D12656  Adakitug (USAN)
D12834  Atirmociclib (USAN)
D12882  Tuvusertib (USAN/INN)
D13010  Lartesertib (USAN/INN)
Other DBs
GO: 0090398
Organism
Homo sapiens (human) [GN:hsa]
Gene
10000  AKT3; RAC-gamma serine/threonine-protein kinase isoform 1 [KO:K04456] [EC:2.7.11.1]
10111  RAD50; DNA repair protein RAD50 [KO:K10866] [EC:3.6.-.-]
10114  HIPK3; homeodomain-interacting protein kinase 3 isoform 1 [KO:K08826] [EC:2.7.11.1]
1017  CDK2; cyclin-dependent kinase 2 isoform 1 [KO:K02206] [EC:2.7.11.22]
1019  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
1021  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
1026  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform 1 [KO:K06625]
1029  CDKN2A; cyclin-dependent kinase inhibitor 2A isoform p16INK4a [KO:K06621]
1030  CDKN2B; cyclin-dependent kinase 4 inhibitor B isoform 1 [KO:K04685]
10758  TRAF3IP2; E3 ubiquitin ligase TRAF3IP2 isoform 1 [KO:K21124]
10912  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
110117499  P3R3URF-PIK3R3; LOC110117498-PIK3R3 readthrough [KO:K02649]
1111  CHEK1; serine/threonine-protein kinase Chk1 isoform 1 [KO:K02216] [EC:2.7.11.1]
11200  CHEK2; serine/threonine-protein kinase Chk2 isoform a [KO:K06641] [EC:2.7.11.1]
132660  LIN54; protein lin-54 homolog isoform a [KO:K21776]
1432  MAPK14; mitogen-activated protein kinase 14 isoform 2 [KO:K04441] [EC:2.7.11.24]
144715  RAD9B; cell cycle checkpoint control protein RAD9B isoform b [KO:K10995]
147746  HIPK4; homeodomain-interacting protein kinase 4 [KO:K08826] [EC:2.7.11.1]
163688  CALML6; calmodulin-like protein 6 isoform 1 [KO:K02183]
1647  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform 1 [KO:K04402]
1869  E2F1; transcription factor E2F1 [KO:K17454]
1870  E2F2; transcription factor E2F2 [KO:K09389]
1871  E2F3; transcription factor E2F3 isoform 1 [KO:K06620]
1874  E2F4; transcription factor E2F4 [KO:K04682]
1875  E2F5; transcription factor E2F5 isoform 1 [KO:K04682]
1978  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
204851  HIPK1; homeodomain-interacting protein kinase 1 isoform 1 [KO:K08826] [EC:2.7.11.1]
207  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
208  AKT2; RAC-beta serine/threonine-protein kinase isoform 1 [KO:K04456] [EC:2.7.11.1]
2113  ETS1; protein C-ets-1 isoform 2 [KO:K02678]
22800  RRAS2; ras-related protein R-Ras2 isoform a [KO:K07830]
22808  MRAS; ras-related protein M-Ras isoform 1 precursor [KO:K07831]
2305  FOXM1; forkhead box protein M1 isoform 2 [KO:K09406]
2308  FOXO1; forkhead box protein O1 [KO:K07201]
2309  FOXO3; forkhead box protein O3 isoform 1 [KO:K09408]
23291  FBXW11; F-box/WD repeat-containing protein 11 isoform C [KO:K03362]
23411  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform a [KO:K11411] [EC:2.3.1.286]
2475  MTOR; serine/threonine-protein kinase mTOR isoform 1 [KO:K07203] [EC:2.7.11.1]
2626  GATA4; transcription factor GATA-4 isoform 2 [KO:K09183]
286826  LIN9; protein lin-9 homolog isoform 8 [KO:K21773]
28996  HIPK2; homeodomain-interacting protein kinase 2 isoform 1 [KO:K08826] [EC:2.7.11.1]
291  SLC25A4; ADP/ATP translocase 1 [KO:K05863]
292  SLC25A5; ADP/ATP translocase 2 [KO:K05863]
293  SLC25A6; ADP/ATP translocase 3 [KO:K05863]
3105  HLA-A; HLA class I histocompatibility antigen, A alpha chain isoform A*03:01:01:01 precursor [KO:K06751]
3106  HLA-B; major histocompatibility complex, class I, B precursor [KO:K06751]
3107  HLA-C; HLA class I histocompatibility antigen, C alpha chain precursor [KO:K06751]
3133  HLA-E; HLA class I histocompatibility antigen, alpha chain E precursor [KO:K06751]
3134  HLA-F; HLA class I histocompatibility antigen, alpha chain F isoform 2 precursor [KO:K06751]
3135  HLA-G; HLA class I histocompatibility antigen, alpha chain G isoform 2 precursor [KO:K06751]
3265  HRAS; GTPase HRas isoform 1 [KO:K02833]
3364  HUS1; checkpoint protein HUS1 isoform 1 [KO:K10903]
3486  IGFBP3; insulin-like growth factor-binding protein 3 isoform b precursor [KO:K10138]
3552  IL1A; interleukin-1 alpha precursor [KO:K04383]
3569  IL6; interleukin-6 isoform 1 precursor [KO:K05405]
3576  CXCL8; interleukin-8 isoform 1 precursor [KO:K10030]
3708  ITPR1; inositol 1,4,5-trisphosphate-gated calcium channel ITPR1 isoform 4 [KO:K04958]
3709  ITPR2; inositol 1,4,5-trisphosphate-gated calcium channel ITPR2 isoform 1 [KO:K04959]
3710  ITPR3; inositol 1,4,5-trisphosphate-gated calcium channel ITPR3 [KO:K04960]
3805  KIR2DL4; killer cell immunoglobulin-like receptor 2DL4 isoform c precursor [KO:K24231]
3845  KRAS; GTPase KRas isoform a [KO:K07827]
4087  SMAD2; mothers against decapentaplegic homolog 2 isoform 1 [KO:K04500]
4088  SMAD3; mothers against decapentaplegic homolog 3 isoform 1 [KO:K23605]
4193  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform 2 [KO:K06643] [EC:2.3.2.27]
4361  MRE11; double-strand break repair protein MRE11 isoform 1 [KO:K10865]
4605  MYBL2; myb-related protein B isoform 1 [KO:K21769]
4609  MYC; myc proto-oncogene protein isoform 1 [KO:K04377]
4616  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
4683  NBN; nibrin isoform 1 [KO:K10867]
472  ATM; serine-protein kinase ATM isoform a [KO:K04728] [EC:2.7.11.1]
4772  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform F [KO:K04446]
4773  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform C [KO:K17332]
4775  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform 1 [KO:K17333]
4776  NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 isoform 2 [KO:K17334]
4790  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform 2 proprotein [KO:K02580]
4893  NRAS; GTPase NRas [KO:K07828]
5054  SERPINE1; plasminogen activator inhibitor 1 isoform 2 precursor [KO:K03982]
51806  CALML5; calmodulin-like protein 5 [KO:K02183]
5290  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform 1 [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform 1 [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform 1 [KO:K02649]
5296  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
545  ATR; serine/threonine-protein kinase ATR isoform 1 [KO:K06640] [EC:2.7.11.1]
5481  PPID; peptidyl-prolyl cis-trans isomerase D [KO:K05864] [EC:5.2.1.8]
54822  TRPM7; transient receptor potential cation channel subfamily M member 7 isoform a [KO:K04982] [EC:2.7.11.1]
5499  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
5500  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
5501  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha isoform 1 [KO:K04348] [EC:3.1.3.16]
5532  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform b [KO:K04348] [EC:3.1.3.16]
5533  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform 2 [KO:K04348] [EC:3.1.3.16]
5534  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
5535  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 isoform 1 [KO:K04371] [EC:2.7.11.24]
55957  LIN37; protein lin-37 homolog isoform 1 [KO:K21774]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
5604  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform 1 [KO:K04369] [EC:2.7.12.2]
5606  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform B [KO:K04432] [EC:2.7.12.2]
5608  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform 1 [KO:K04433] [EC:2.7.12.2]
5728  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
5810  RAD1; cell cycle checkpoint protein RAD1 [KO:K02830] [EC:3.1.11.2]
5883  RAD9A; cell cycle checkpoint control protein RAD9A isoform 1 [KO:K10994] [EC:3.1.11.2]
5894  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform b [KO:K04366] [EC:2.7.11.1]
5925  RB1; retinoblastoma-associated protein isoform 1 [KO:K06618]
5928  RBBP4; histone-binding protein RBBP4 isoform a [KO:K10752]
5933  RBL1; retinoblastoma-like protein 1 isoform a [KO:K04681]
5934  RBL2; retinoblastoma-like protein 2 isoform 1 [KO:K16332]
59341  TRPV4; transient receptor potential cation channel subfamily V member 4 isoform a [KO:K04973]
595  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
5970  RELA; transcription factor p65 isoform 1 [KO:K04735]
6009  RHEB; GTP-binding protein Rheb [KO:K07208]
6237  RRAS; ras-related protein R-Ras [KO:K07829]
6300  MAPK12; mitogen-activated protein kinase 12 isoform 1 [KO:K04441] [EC:2.7.11.24]
677  ZFP36L1; mRNA decay activator protein ZFP36L1 isoform 1 [KO:K18753]
678  ZFP36L2; mRNA decay activator protein ZFP36L2 [KO:K18753]
7040  TGFB1; transforming growth factor beta-1 proprotein preproprotein [KO:K13375]
7042  TGFB2; transforming growth factor beta-2 proprotein isoform 2 preproprotein [KO:K13376]
7043  TGFB3; transforming growth factor beta-3 proprotein isoform 1 preproprotein [KO:K13377]
7046  TGFBR1; TGF-beta receptor type-1 isoform 1 precursor [KO:K04674] [EC:2.7.11.30]
7048  TGFBR2; TGF-beta receptor type-2 isoform B precursor [KO:K04388] [EC:2.7.11.30]
7157  TP53; cellular tumor antigen p53 isoform a [KO:K04451]
7248  TSC1; hamartin isoform 1 [KO:K07206]
7249  TSC2; tuberin isoform 1 [KO:K07207]
7416  VDAC1; non-selective voltage-gated ion channel VDAC1 isoform 1 [KO:K05862]
7417  VDAC2; non-selective voltage-gated ion channel VDAC2 isoform 2 [KO:K15040]
7419  VDAC3; non-selective voltage-gated ion channel VDAC3 isoform 1 [KO:K15041]
776  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform b [KO:K04851]
801  CALM1; calmodulin-1 isoform 2 [KO:K02183]
805  CALM2; calmodulin-2 isoform 2 [KO:K02183]
808  CALM3; calmodulin-3 isoform 1 [KO:K02183]
810  CALML3; calmodulin-like protein 3 [KO:K02183]
823  CAPN1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
824  CAPN2; calpain-2 catalytic subunit isoform 1 [KO:K03853] [EC:3.4.22.53]
83447  SLC25A31; ADP/ATP translocase 4 isoform 1 [KO:K05863]
83593  RASSF5; ras association domain-containing protein 5 isoform A [KO:K08015]
8503  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform 1 [KO:K02649]
85417  CCNB3; G2/mitotic-specific cyclin-B3 isoform 3 [KO:K21771]
8878  SQSTM1; sequestosome-1 isoform 1 [KO:K14381]
890  CCNA2; cyclin-A2 [KO:K06627]
8900  CCNA1; cyclin-A1 [KO:K06627]
891  CCNB1; G2/mitotic-specific cyclin-B1 isoform 1 [KO:K05868]
894  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
8945  BTRC; F-box/WD repeat-containing protein 1A isoform 1 [KO:K03362]
896  CCND3; G1/S-specific cyclin-D3 isoform 2 [KO:K10152]
898  CCNE1; G1/S-specific cyclin-E1 isoform 1 [KO:K06626]
90550  MCU; calcium uniporter protein, mitochondrial isoform 1 precursor [KO:K20858]
9133  CCNB2; G2/mitotic-specific cyclin-B2 [KO:K21770]
9134  CCNE2; G1/S-specific cyclin-E2 [KO:K06626]
91750  LIN52; protein lin-52 homolog isoform 1 [KO:K21775]
91860  CALML4; calmodulin-like protein 4 isoform 1 [KO:K02183]
9261  MAPKAPK2; MAP kinase-activated protein kinase 2 isoform 2 [KO:K04443] [EC:2.7.11.1]
983  CDK1; cyclin-dependent kinase 1 isoform 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
993  CDC25A; M-phase inducer phosphatase 1 isoform a [KO:K06645] [EC:3.1.3.48]
Compound
C00027  Hydrogen peroxide
C00076  Calcium cation
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C07909  Sirolimus
C16844  Hydroxyl radical
Reference
PMID:24954210
  Authors
Munoz-Espin D, Serrano M
  Title
Cellular senescence: from physiology to pathology.
  Journal
Nat Rev Mol Cell Biol 15:482-96 (2014)
DOI:10.1038/nrm3823
Reference
PMID:26646499
  Authors
Childs BG, Durik M, Baker DJ, van Deursen JM
  Title
Cellular senescence in aging and age-related disease: from mechanisms to therapy.
  Journal
Nat Med 21:1424-35 (2015)
DOI:10.1038/nm.4000
Reference
PMID:26105537
  Authors
Sharpless NE, Sherr CJ
  Title
Forging a signature of in vivo senescence.
  Journal
Nat Rev Cancer 15:397-408 (2015)
DOI:10.1038/nrc3960
Reference
PMID:26435346
  Authors
Fridlyanskaya I, Alekseenko L, Nikolsky N
  Title
Senescence as a general cellular response to stress: A mini-review.
  Journal
Exp Gerontol 72:124-8 (2015)
DOI:10.1016/j.exger.2015.09.021
Reference
PMID:27417123
  Authors
Lujambio A
  Title
To clear, or not to clear (senescent cells)? That is the question.
  Journal
Bioessays 38 Suppl 1:S56-64 (2016)
DOI:10.1002/bies.201670910
Reference
PMID:26564316
  Authors
Di Mitri D, Alimonti A
  Title
Non-Cell-Autonomous Regulation of Cellular Senescence in Cancer.
  Journal
Trends Cell Biol 26:215-26 (2016)
DOI:10.1016/j.tcb.2015.10.005
Reference
PMID:27574725
  Authors
Francica P, Aebersold DM, Medova M
  Title
Senescence as biologic endpoint following pharmacological targeting of receptor tyrosine kinases in cancer.
  Journal
Biochem Pharmacol 126:1-12 (2017)
DOI:10.1016/j.bcp.2016.08.022
Reference
PMID:23982440
  Authors
Bartling B
  Title
Cellular senescence in normal and premature lung aging.
  Journal
Z Gerontol Geriatr 46:613-22 (2013)
DOI:10.1007/s00391-013-0543-3
Reference
PMID:24238962
  Authors
Munoz-Espin D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, Rodriguez-Baeza A, Varela-Nieto I, Ruberte J, Collado M, Serrano M
  Title
Programmed cell senescence during mammalian embryonic development.
  Journal
Cell 155:1104-18 (2013)
DOI:10.1016/j.cell.2013.10.019
Reference
PMID:26697828
  Authors
Herranz N, Gallage S, Gil J
  Title
TORn about SASP regulation.
  Journal
Cell Cycle 14:3771-2 (2015)
DOI:10.1080/15384101.2015.1105694
Reference
PMID:28410770
  Authors
Martin N, Bernard D
  Title
Calcium signaling and cellular senescence.
  Journal
Cell Calcium S0143-4160(17)30049-0 (2017)
DOI:10.1016/j.ceca.2017.04.001
Reference
PMID:25764980
  Authors
Farfariello V, Iamshanova O, Germain E, Fliniaux I, Prevarskaya N
  Title
Calcium homeostasis in cancer: A focus on senescence.
  Journal
Biochim Biophys Acta 1853:1974-9 (2015)
DOI:10.1016/j.bbamcr.2015.03.005
Reference
PMID:24062309
  Authors
McCarthy DA, Clark RR, Bartling TR, Trebak M, Melendez JA
  Title
Redox control of the senescence regulator interleukin-1alpha and the secretory phenotype.
  Journal
J Biol Chem 288:32149-59 (2013)
DOI:10.1074/jbc.M113.493841
Reference
PMID:27288568
  Authors
Donninger H, Schmidt ML, Mezzanotte J, Barnoud T, Clark GJ
  Title
Ras signaling through RASSF proteins.
  Journal
Semin Cell Dev Biol 58:86-95 (2016)
DOI:10.1016/j.semcdb.2016.06.007
Reference
PMID:28455242
  Authors
Barnoud T, Schmidt ML, Donninger H, Clark GJ
  Title
The role of the NORE1A tumor suppressor in Oncogene-Induced Senescence.
  Journal
Cancer Lett 400:30-36 (2017)
DOI:10.1016/j.canlet.2017.04.030
Reference
PMID:26404840
  Authors
Kang C, Xu Q, Martin TD, Li MZ, Demaria M, Aron L, Lu T, Yankner BA, Campisi J, Elledge SJ
  Title
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
  Journal
Science 349:aaa5612 (2015)
DOI:10.1126/science.aaa5612
Reference
PMID:26777575
  Authors
Cao X, Li M
  Title
A New Pathway for Senescence Regulation.
  Journal
Genomics Proteomics Bioinformatics 13:333-5 (2015)
DOI:10.1016/j.gpb.2015.11.002
Reference
PMID:25564883
  Authors
Gire V, Dulic V
  Title
Senescence from G2 arrest, revisited.
  Journal
Cell Cycle 14:297-304 (2015)
DOI:10.1080/15384101.2014.1000134
Reference
PMID:24981831
  Authors
Mowla SN, Lam EW, Jat PS
  Title
Cellular senescence and aging: the role of B-MYB.
  Journal
Aging Cell 13:773-9 (2014)
DOI:10.1111/acel.12242
Reference
PMID:22546858
  Authors
Yao H, Chung S, Hwang JW, Rajendrasozhan S, Sundar IK, Dean DA, McBurney MW, Guarente L, Gu W, Ronty M, Kinnula VL, Rahman I
  Title
SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice.
  Journal
J Clin Invest 122:2032-45 (2012)
DOI:10.1172/JCI60132
Reference
PMID:23542362
  Authors
Hwang JW, Yao H, Caito S, Sundar IK, Rahman I
  Title
Redox regulation of SIRT1 in inflammation and cellular senescence.
  Journal
Free Radic Biol Med 61:95-110 (2013)
DOI:10.1016/j.freeradbiomed.2013.03.015
Related
pathway
hsa04020  Calcium signaling pathway
hsa04068  FoxO signaling pathway
hsa04110  Cell cycle
hsa04115  p53 signaling pathway
hsa04150  mTOR signaling pathway
KO pathway
ko04218   

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