KEGG   PATHWAY: rno04218
Entry
rno04218                    Pathway                                

Name
Cellular senescence - Rattus norvegicus (rat)
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
rno04218  Cellular senescence
rno04218

Other DBs
GO: 0090398
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
59086  Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
81809  Tgfb2; transforming growth factor beta-2 proprotein precursor [KO:K13376]
25717  Tgfb3; transforming growth factor beta-3 proprotein preproprotein [KO:K13377]
29591  Tgfbr1; TGF-beta receptor type-1 precursor [KO:K04674] [EC:2.7.11.30]
81810  Tgfbr2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]
29357  Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]
25631  Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]
25164  Cdkn2b; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
94201  Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
114483  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
58919  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
64033  Ccnd2; G1/S-specific cyclin-D2 [KO:K10151]
25193  Ccnd3; G1/S-specific cyclin-D3 [KO:K10152]
24708  Rb1; retinoblastoma-associated protein [KO:K06618]
680111  Rbl1; retinoblastoma-like protein 1 [KO:K04681]
81758  Rbl2; retinoblastoma-like protein 2 [KO:K16332]
399489  E2f1; transcription factor E2F1 [KO:K17454]
684111  E2f2; transcription factor E2F2 isoform X1 [KO:K09389]
291105  E2f3; transcription factor E2F3 [KO:K06620]
116651  E2f5; transcription factor E2F5 isoform X1 [KO:K04682]
100360427  E2f4; transcription factor E2F4 [KO:K04682]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
84482  Foxo1; forkhead box protein O1 [KO:K07201]
294515  Foxo3; forkhead box protein O3 [KO:K09408]
114851  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
362817  Cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
362485  Ccne2; G1/S-specific cyclin-E2 [KO:K06626]
25729  Ccne1; G1/S-specific cyclin-E1 [KO:K06626]
24747  RT1-M3-1; RT1 class Ib, locus M3-1 precursor [KO:K06751]
24750  RT1-N3; RT1 class Ib, locus N3 [KO:K06751]
24973  RT1-A1; RT1 class Ia, locus A1 precursor [KO:K06751]
24974  RT1-A2; RT1 class Ia, locus A2 precursor [KO:K06751]
24988  RT1-M2; RT1 class Ib, locus M2 precursor [KO:K06751]
294213  RT1-M1-4; RT1 class I, locus M1, gene 4 precursor [KO:K06751]
309600  RT1-CE12; RT1 class I, locus CE12 precursor [KO:K06751]
309603  RT1-CE1; RT1 class I, locus CE1 precursor [KO:K06751]
309607  RT1-CE5; RT1 class I, locus CE5 isoform 1 precursor [KO:K06751]
309627  RT1-A3; RT1 class I, locus A3 precursor [KO:K06751]
361787  RT1-T24-1; RT1 class I, locus T24, gene 1 [KO:K06751]
365527  RT1-M6-2; RT1 class I, locus M6, gene 2 precursor [KO:K06751]
368153  RT1-CE7; RT1 class I, locus CE7 precursor [KO:K06751]
414270  RT1-CE14; RT1 class I, locus CE14 isoform 1 precursor [KO:K06751]
414779  RT1-CE2; RT1 class I, locus CE2 precursor [KO:K06751]
414783  RT1-CE4; RT1 class I, locus CE4 precursor [KO:K06751]
414784  RT1-T24-4; RT1 class I, locus T24, gene 4 [KO:K06751]
414785  RT1-M6-1; RT1 class I, locus M6, gene 1 precursor [KO:K06751]
414786  RT1-M1-2; RT1 class I, locus M1, gene 2 precursor [KO:K06751]
414787  RT1-M10-1; RT1 class I, locus M10, gene 1 precursor [KO:K06751]
414789  RT1-CE15; RT1 class I, locus CE15 precursor [KO:K06751]
414790  RT1-CE13; RT1 class I, locus CE13 precursor [KO:K06751]
414791  RT1-CE11; RT1 class I, locus CE11 precursor [KO:K06751]
414792  RT1-CE10; RT1 class I, locus CE10 precursor [KO:K06751]
414793  RT1-CE3; RT1 class I, locus CE3 precursor [KO:K06751]
414819  RT1-CE16; RT1 class I, locus CE16 precursor [KO:K06751]
24751  RT1-O1; RT1 class Ib, locus O1 [KO:K06751]
406194  RT1-T18; RT1 class Ib, locus T18 precursor [KO:K06751]
294228  RT1-S3; RT1 class Ib, locus S3 precursor [KO:K06751]
309584  RT1-M4; RT1 class Ib, locus M4 precursor [KO:K06751]
360323  RT1-N2; RT1 class Ib, locus N2 precursor [KO:K06751]
414788  RT1-T24-3; RT1 class I, locus T24, gene 3 [KO:K06751]
680842  RT1-M1-5; RT1 class I, M1, gene 5 precursor [KO:K06751]
102546590  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
499400  RT1-M5; RT1 class Ib, locus M5 isoform 2 precursor [KO:K06751]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
361568  Rras; ras-related protein R-Ras [KO:K07829]
365355  Rras2; ras-related protein R-Ras2 [KO:K07830]
25482  Mras; ras-related protein M-Ras [KO:K07831]
293621  Hras; GTPase HRas [KO:K02833]
367858  GTPase HRas [KO:K02833]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
60445  Tsc1; hamartin [KO:K07206]
24855  Tsc2; tuberin [KO:K07207]
26954  Rheb; GTP-binding protein Rheb [KO:K07208]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
50557  Pten; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
309757  Sirt1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
114494  Ccna2; cyclin-A2 [KO:K06627]
295052  Ccna1; cyclin-A1 [KO:K06627]
296344  Mybl2; myb-related protein B [KO:K21769]
689523  Lin9; protein lin-9 homolog isoform X1 [KO:K21773]
292787  Lin37; protein lin-37 homolog [KO:K21774]
362763  Lin52; protein lin-52 homolog isoform X1 [KO:K21775]
305171  Lin54; protein lin-54 homolog [KO:K21776]
313048  Rbbp4; histone-binding protein RBBP4 [KO:K10752]
310511  RGD1563620; histone-binding protein RBBP4 [KO:K10752]
58921  Foxm1; forkhead box protein M1 [KO:K09406]
24577  Myc; myc proto-oncogene protein [KO:K04377]
25163  Cdkn2a; cyclin-dependent kinase inhibitor 2A [KO:K06621]
314856  Mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:2.3.2.27]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
54355  Rassf5; ras association domain-containing protein 5 [KO:K08015]
303024  Fbxw11; F-box/WD repeat-containing protein 11 [KO:K03362]
361765  Btrc; F-box/WD repeat-containing protein 1A [KO:K03362]
362342  Hipk2; homeodomain-interacting protein kinase 2 [KO:K08826] [EC:2.7.11.1]
365895  Hipk1; homeodomain-interacting protein kinase 1 [KO:K08826] [EC:2.7.11.1]
83617  Hipk3; homeodomain-interacting protein kinase 3 [KO:K08826] [EC:2.7.11.1]
308449  Hipk4; homeodomain-interacting protein kinase 4 [KO:K08826] [EC:2.7.11.1]
24668  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
24669  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
25594  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100363225  disks large homolog 5-like isoform X1 [KO:K06269] [EC:3.1.3.16]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
24356  Ets1; protein C-ets-1 [KO:K02678]
303200  Map2k3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
114495  Map2k6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
25112  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
291005  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
299626  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
54237  Cdk1; cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
25203  Ccnb1; G2/mitotic-specific cyclin-B1 [KO:K05868]
363088  Ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
100364016  G2/mitotic-specific cyclin-B2 [KO:K21770]
317389  Ccnb3; G2/mitotic-specific cyclin-B3 isoform X2 [KO:K21771]
64046  Mre11; double-strand break repair protein MRE11 [KO:K10865]
64012  Rad50; DNA repair protein RAD50 [KO:K10866] [EC:3.6.-.-]
85482  Nbn; nibrin [KO:K10867]
300711  Atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
114212  Chek2; serine/threonine-protein kinase Chk2 [KO:K06641] [EC:2.7.11.1]
100361529  Rad9a; cell cycle checkpoint control protein RAD9A isoform X1 [KO:K10994] [EC:3.1.11.2]
363924  Rad9b; cell cycle checkpoint control protein RAD9B [KO:K10995]
294800  Rad1; cell cycle checkpoint protein RAD1 [KO:K02830] [EC:3.1.11.2]
498411  Hus1; checkpoint protein HUS1 [KO:K10903]
685055  Atr; serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:2.7.11.1]
140583  Chek1; serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
171102  Cdc25a; M-phase inducer phosphatase 1 [KO:K06645] [EC:3.1.3.48]
113894  Sqstm1; sequestosome-1 isoform 1 [KO:K14381]
54254  Gata4; transcription factor GATA-4 [KO:K09183]
361857  Traf3ip2; adapter protein CIKS [KO:K21124]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
24493  Il1a; interleukin-1 alpha [KO:K04383]
24498  Il6; interleukin-6 precursor [KO:K05405]
24484  Igfbp3; insulin-like growth factor-binding protein 3 precursor [KO:K10138]
24617  Serpine1; plasminogen activator inhibitor 1 precursor [KO:K03982]
116636  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
289014  Mapkapk2; MAP kinase-activated protein kinase 2 [KO:K04443] [EC:2.7.11.1]
29344  Zfp36l1; mRNA decay activator protein ZFP36L1 [KO:K18753]
298765  Zfp36l2; zinc finger protein 36, C3H1 type-like 2 [KO:K18753]
29716  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
66026  Trpv4; transient receptor potential cation channel subfamily V member 4 [KO:K04973]
679906  Trpm7; transient receptor potential cation channel subfamily M member 7 [KO:K04982] [EC:2.7.11.1]
29153  Capn1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
29154  Capn2; calpain-2 catalytic subunit [KO:K03853] [EC:3.4.22.53]
50663  Calm2; calmodulin-2 [KO:K02183]
24242  Calm1; calmodulin-1 [KO:K02183]
24244  Calm3; calmodulin-3 [KO:K02183]
364774  Calml5; calmodulin-like protein 5 [KO:K02183]
307100  Calml3; calmodulin-like protein 3 [KO:K02183]
691455  Calml4; calmodulin-like protein 4 [KO:K02183]
24674  Ppp3ca; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16]
24675  Ppp3cb; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:3.1.3.16]
171378  Ppp3cc; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16]
29748  Ppp3r1; calcineurin subunit B type 1 [KO:K06268]
29749  Ppp3r2; calcineurin subunit B type 2 [KO:K06268]
100361818  Nfatc1; nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
311658  Nfatc2; nuclear factor of activated T-cells, cytoplasmic 2 [KO:K17332]
361400  Nfatc3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333]
305897  Nfatc4; nuclear factor of activated T-cells, cytoplasmic 4 [KO:K17334]
25262  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform 3 [KO:K04958]
81678  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
25176  Slc25a5; ADP/ATP translocase 2 [KO:K05863]
85333  Slc25a4; ADP/ATP translocase 1 [KO:K05863]
689108  Slc25a31; ADP/ATP translocase 4 [KO:K05863]
361967  Ppid; peptidyl-prolyl cis-trans isomerase D [KO:K05864] [EC:5.2.1.8]
83529  Vdac1; voltage-dependent anion-selective channel protein 1 [KO:K05862]
83531  Vdac2; voltage-dependent anion-selective channel protein 2 [KO:K15040]
83532  Vdac3; voltage-dependent anion-selective channel protein 3 [KO:K15041]
294560  Mcu; calcium uniporter protein, mitochondrial precursor [KO:K20858]
Compound
C00027  Hydrogen peroxide
C00076  Calcium cation
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C07909  Sirolimus
C16844  Hydroxyl radical
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
rno04020  Calcium signaling pathway
rno04068  FoxO signaling pathway
rno04110  Cell cycle
rno04115  p53 signaling pathway
rno04150  mTOR signaling pathway
KO pathway
ko04218   

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