KEGG   PATHWAY: hsa04110
hsa04110                    Pathway                                
Cell cycle - Homo sapiens (human)
Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. Precise activation and inactivation of CDKs at specific points in the cell cycle are required for orderly cell division. Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated.
 Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation.
Cellular Processes; Cell growth and death
Pathway map
hsa04110  Cell cycle

N00066  MDM2-p21-Cell cycle G1/S
N00069  p16-Cell cycle G1/S
N00090  p15-Cell cycle G1/S
N00091  p27-Cell cycle G1/S
N00347  p300-p21-Cell cycle G1/S
N00455  CDC25-Cell cycle G2/M
N00459  WEE1-Cell cycle G2/M
N00493  Spindle assembly checkpoint signaling
N00499  ATR-p21-Cell cycle G2/M
N00536  MDM2-p21-Cell cycle G1/S
N01468  DNA replication licensing
N01470  Pre-IC formation
N01471  Origin unwinding and elongation
N01482  Cohesin loading
N01486  Cohesin dissociation in anaphase
N01529  Recruitment and formation of the MCC
N01533  Disassembly of MCC
D05988  Tacedinaline (USAN/INN)
D06320  Vorinostat (JAN/USAN)
D06637  Romidepsin (JAN/USAN/INN)
D08870  Belinostat (USAN/INN)
D09338  Entinostat (JAN/USAN/INN)
D09357  Mocetinostat dihydrobromide (USAN)
D09604  Dinaciclib (USAN/INN)
D09641  Mocetinostat (USAN/INN)
D10019  Panobinostat lactate (JAN)
D10060  Abexinostat (USAN)
D10084  Abexinostat hydrochloride (USAN)
D10154  Rigosertib (USAN)
D10155  Rigosertib sodium (JAN/USAN)
D10182  Volasertib (USAN)
D10183  Volasertib trihydrochloride (USAN)
D10319  Panobinostat (USAN/INN)
D10321  Quisinostat (USAN/INN)
D10322  Quisinostat hydrochloride (USAN)
D10372  Palbociclib (JAN/USAN)
D10397  Rabusertib (USAN/INN)
D10652  Palbociclib isethionate (USAN)
D10688  Abemaciclib (JAN/USAN/INN)
D10883  Ribociclib (USAN/INN)
D10977  Remetinostat (USAN/INN)
D10979  Ribociclib succinate (USAN)
D10993  Tucidinostat (JAN/USAN/INN)
D11130  Trilaciclib (USAN/INN)
D11148  Berzosertib (USAN/INN)
D11182  Tinostamustine (USAN/INN)
D11206  Prexasertib (USAN/INN)
D11319  Fimepinostat (USAN/INN)
D11361  Adavosertib (USAN)
D11442  Nanatinostat (USAN)
D11455  Lerociclib (USAN)
D11458  Onvansertib (USAN)
D11459  Onvansertib fumarate (USAN)
D11599  Zotiraciclib (USAN)
D11600  Zotiraciclib citrate (USAN)
D11787  Ceralasertib (USAN/INN)
D11987  Trilaciclib dihydrochloride
D12176  Simurosertib (USAN/INN)
D12304  Elraglusib (USAN)
D12321  Camonsertib (USAN)
D12394  Inobrodib (USAN)
D12551  Bocodepsin (USAN)
D12552  Bocodepsin besylate (USAN)
D12601  Tagtociclib (USAN)
D12828  Risvodetinib (USAN/INN)
D12829  Risvodetinib succinate (USAN)
D12834  Atirmociclib (USAN)
D12882  Tuvusertib (USAN/INN)
Other DBs
GO: 0000278
Homo sapiens (human) [GN:hsa]
595  CCND1; cyclin D1 [KO:K04503]
894  CCND2; cyclin D2 [KO:K10151]
896  CCND3; cyclin D3 [KO:K10152]
1019  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:]
1021  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:]
5925  RB1; RB transcriptional corepressor 1 [KO:K06618]
5933  RBL1; RB transcriptional corepressor like 1 [KO:K04681]
5934  RBL2; RB transcriptional corepressor like 2 [KO:K16332]
25  ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:]
3065  HDAC1; histone deacetylase 1 [KO:K06067] [EC:]
3066  HDAC2; histone deacetylase 2 [KO:K06067] [EC:]
1869  E2F1; E2F transcription factor 1 [KO:K17454]
1870  E2F2; E2F transcription factor 2 [KO:K09389]
1871  E2F3; E2F transcription factor 3 [KO:K06620]
1874  E2F4; E2F transcription factor 4 [KO:K04682]
1875  E2F5; E2F transcription factor 5 [KO:K04682]
7027  TFDP1; transcription factor Dp-1 [KO:K04683]
7029  TFDP2; transcription factor Dp-2 [KO:K09392]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:]
7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K23605]
4089  SMAD4; SMAD family member 4 [KO:K04501]
4609  MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]
7709  ZBTB17; zinc finger and BTB domain containing 17 [KO:K10500]
1029  CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621]
1030  CDKN2B; cyclin dependent kinase inhibitor 2B [KO:K04685]
1031  CDKN2C; cyclin dependent kinase inhibitor 2C [KO:K06622]
1032  CDKN2D; cyclin dependent kinase inhibitor 2D [KO:K06623]
1027  CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]
1028  CDKN1C; cyclin dependent kinase inhibitor 1C [KO:K09993]
1026  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
898  CCNE1; cyclin E1 [KO:K06626]
9134  CCNE2; cyclin E2 [KO:K06626]
1017  CDK2; cyclin dependent kinase 2 [KO:K02206] [EC:]
6500  SKP1; S-phase kinase associated protein 1 [KO:K03094]
8454  CUL1; cullin 1 [KO:K03347]
9978  RBX1; ring-box 1 [KO:K03868] [EC:]
6502  SKP2; S-phase kinase associated protein 2 [KO:K03875]
890  CCNA2; cyclin A2 [KO:K06627]
8900  CCNA1; cyclin A1 [KO:K06627]
990  CDC6; cell division cycle 6 [KO:K02213]
81620  CDT1; chromatin licensing and DNA replication factor 1 [KO:K10727]
4998  ORC1; origin recognition complex subunit 1 [KO:K02603]
4999  ORC2; origin recognition complex subunit 2 [KO:K02604]
23595  ORC3; origin recognition complex subunit 3 [KO:K02605]
5000  ORC4; origin recognition complex subunit 4 [KO:K02606]
5001  ORC5; origin recognition complex subunit 5 [KO:K02607]
23594  ORC6; origin recognition complex subunit 6 [KO:K02608]
4171  MCM2; minichromosome maintenance complex component 2 [KO:K02540] [EC:]
4172  MCM3; minichromosome maintenance complex component 3 [KO:K02541] [EC:]
4173  MCM4; minichromosome maintenance complex component 4 [KO:K02212] [EC:]
4174  MCM5; minichromosome maintenance complex component 5 [KO:K02209] [EC:]
4175  MCM6; minichromosome maintenance complex component 6 [KO:K02542] [EC:]
4176  MCM7; minichromosome maintenance complex component 7 [KO:K02210] [EC:]
8318  CDC45; cell division cycle 45 [KO:K06628]
90381  TICRR; TOPBP1 interacting checkpoint and replication regulator [KO:K26117]
27085  MTBP; MDM2 binding protein [KO:K26116]
8317  CDC7; cell division cycle 7 [KO:K02214] [EC:]
10926  DBF4; DBF4-CDC7 kinase regulatory subunit [KO:K06629]
80174  DBF4B; DBF4B-CDC7 kinase regulatory subunit [KO:K06629]
983  CDK1; cyclin dependent kinase 1 [KO:K02087] [EC:]
891  CCNB1; cyclin B1 [KO:K05868]
9133  CCNB2; cyclin B2 [KO:K21770]
85417  CCNB3; cyclin B3 [KO:K21771]
994  CDC25B; cell division cycle 25B [KO:K05866] [EC:]
995  CDC25C; cell division cycle 25C [KO:K05867] [EC:]
7534  YWHAZ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta [KO:K16197]
7529  YWHAB; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta [KO:K16197]
10971  YWHAQ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta [KO:K16197]
7531  YWHAE; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon [KO:K06630]
7533  YWHAH; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta [KO:K16198]
7532  YWHAG; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma [KO:K16198]
5347  PLK1; polo like kinase 1 [KO:K06631] [EC:]
7465  WEE1; WEE1 G2 checkpoint kinase [KO:K06632] [EC:]
494551  WEE2; WEE2 oocyte meiosis inhibiting kinase [KO:K06632] [EC:]
9088  PKMYT1; protein kinase, membrane associated tyrosine/threonine 1 [KO:K06633] [EC:]
902  CCNH; cyclin H [KO:K06634]
1022  CDK7; cyclin dependent kinase 7 [KO:K02202] [EC:]
64682  ANAPC1; anaphase promoting complex subunit 1 [KO:K03348]
29882  ANAPC2; anaphase promoting complex subunit 2 [KO:K03349]
996  CDC27; cell division cycle 27 [KO:K03350]
29945  ANAPC4; anaphase promoting complex subunit 4 [KO:K03351]
51433  ANAPC5; anaphase promoting complex subunit 5 [KO:K03352]
8881  CDC16; cell division cycle 16 [KO:K03353]
51434  ANAPC7; anaphase promoting complex subunit 7 [KO:K03354]
8697  CDC23; cell division cycle 23 [KO:K03355]
10393  ANAPC10; anaphase promoting complex subunit 10 [KO:K03357]
51529  ANAPC11; anaphase promoting complex subunit 11 [KO:K03358]
246184  CDC26; cell division cycle 26 [KO:K03359]
25847  ANAPC13; anaphase promoting complex subunit 13 [KO:K12456]
25906  ANAPC15; anaphase promoting complex subunit 15 [KO:K25228]
119504  ANAPC16; anaphase promoting complex subunit 16 [KO:K25229]
991  CDC20; cell division cycle 20 [KO:K03363]
9232  PTTG1; PTTG1 regulator of sister chromatid separation, securin [KO:K06635]
10744  PTTG2; pituitary tumor-transforming 2 [KO:K06635]
9700  ESPL1; extra spindle pole bodies like 1, separase [KO:K02365] [EC:]
8243  SMC1A; structural maintenance of chromosomes 1A [KO:K06636]
27127  SMC1B; structural maintenance of chromosomes 1B [KO:K06636]
9126  SMC3; structural maintenance of chromosomes 3 [KO:K06669]
5885  RAD21; RAD21 cohesin complex component [KO:K06670]
10735  STAG2; STAG2 cohesin complex component [KO:K06671]
10274  STAG1; STAG1 cohesin complex component [KO:K06671]
546  ATRX; ATRX chromatin remodeler [KO:K10779]
1663  DDX11; DEAD/H-box helicase 11 [KO:K11273] [EC:]
25836  NIPBL; NIPBL cohesin loading factor [KO:K06672]
23383  MAU2; MAU2 sister chromatid cohesion factor [KO:K11266]
55869  HDAC8; histone deacetylase 8 [KO:K11405] [EC:]
114799  ESCO1; establishment of sister chromatid cohesion N-acetyltransferase 1 [KO:K11268] [EC:2.3.1.-]
157570  ESCO2; establishment of sister chromatid cohesion N-acetyltransferase 2 [KO:K11268] [EC:2.3.1.-]
23244  PDS5A; PDS5 cohesin associated factor A [KO:K11267]
23047  PDS5B; PDS5 cohesin associated factor B [KO:K11267]
23063  WAPL; WAPL cohesin release factor [KO:K25163]
113130  CDCA5; cell division cycle associated 5 [KO:K17390]
9212  AURKB; aurora kinase B [KO:K11479] [EC:]
151648  SGO1; shugoshin 1 [KO:K11580]
5515  PPP2CA; protein phosphatase 2 catalytic subunit alpha [KO:K04382] [EC:]
5516  PPP2CB; protein phosphatase 2 catalytic subunit beta [KO:K04382] [EC:]
5519  PPP2R1B; protein phosphatase 2 scaffold subunit Abeta [KO:K03456]
5518  PPP2R1A; protein phosphatase 2 scaffold subunit Aalpha [KO:K03456]
5526  PPP2R5B; protein phosphatase 2 regulatory subunit B'beta [KO:K11584]
5527  PPP2R5C; protein phosphatase 2 regulatory subunit B'gamma [KO:K11584]
5528  PPP2R5D; protein phosphatase 2 regulatory subunit B'delta [KO:K11584]
5529  PPP2R5E; protein phosphatase 2 regulatory subunit B'epsilon [KO:K11584]
5525  PPP2R5A; protein phosphatase 2 regulatory subunit B'alpha [KO:K11584]
10403  NDC80; NDC80 kinetochore complex component [KO:K11547]
57082  KNL1; kinetochore scaffold 1 [KO:K11542]
7272  TTK; TTK protein kinase [KO:K08866] [EC:]
8379  MAD1L1; mitotic arrest deficient 1 like 1 [KO:K06679]
4085  MAD2L1; mitotic arrest deficient 2 like 1 [KO:K02537]
10459  MAD2L2; mitotic arrest deficient 2 like 2 [KO:K13728]
701  BUB1B; BUB1 mitotic checkpoint serine/threonine kinase B [KO:K06637] [EC:]
9184  BUB3; BUB3 mitotic checkpoint protein [KO:K02180]
699  BUB1; BUB1 mitotic checkpoint serine/threonine kinase [KO:K02178] [EC:]
9319  TRIP13; thyroid hormone receptor interactor 13 [KO:K22399]
9587  MAD2L1BP; MAD2L1 binding protein [KO:K26093]
51343  FZR1; fizzy and cell division cycle 20 related 1 [KO:K03364]
26271  FBXO5; F-box protein 5 [KO:K10292]
8555  CDC14B; cell division cycle 14B [KO:K06639] [EC:]
8556  CDC14A; cell division cycle 14A [KO:K06639] [EC:]
168448  CDC14C; cell division cycle 14C [KO:K06639] [EC:]
1387  CREBBP; CREB binding protein [KO:K04498] [EC:]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:]
5591  PRKDC; protein kinase, DNA-activated, catalytic subunit [KO:K06642] [EC:]
545  ATR; ATR serine/threonine kinase [KO:K06640] [EC:]
472  ATM; ATM serine/threonine kinase [KO:K04728] [EC:]
4193  MDM2; MDM2 proto-oncogene [KO:K06643] [EC:]
7157  TP53; tumor protein p53 [KO:K04451]
1647  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
4616  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
10912  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
5111  PCNA; proliferating cell nuclear antigen [KO:K04802]
2810  SFN; stratifin [KO:K06644]
1111  CHEK1; checkpoint kinase 1 [KO:K02216] [EC:]
11200  CHEK2; checkpoint kinase 2 [KO:K06641] [EC:]
993  CDC25A; cell division cycle 25A [KO:K06645] [EC:]
Matsuoka S, Yamaguchi M, Matsukage A
D-type cyclin-binding regions of proliferating cell nuclear antigen.
J Biol Chem 269:11030-6 (1994)
Welch PJ, Wang JY
A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle.
Cell 75:779-90 (1993)
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Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes.
Oncogene 25:5263-7 (2006)
Cobrinik D
Pocket proteins and cell cycle control.
Oncogene 24:2796-809 (2005)
Boutros R, Lobjois V, Ducommun B
CDC25 phosphatases in cancer cells: key players? Good targets?
Nat Rev Cancer 7:495-507 (2007)
Diehl JA, Cheng M, Roussel MF, Sherr CJ
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
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Transcriptional regulation of the cyclin D1 gene at a glance.
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CDK inhibitors: positive and negative regulators of G1-phase progression.
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Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
Cell 113:685-700 (2003)
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Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation.
Proc Natl Acad Sci U S A 100:10231-6 (2003)
Bond M, Sala-Newby GB, Wu YJ, Newby AC
Biphasic effect of p21Cip1 on smooth muscle cell proliferation: role of PI 3-kinase and Skp2-mediated degradation.
Cardiovasc Res 69:198-206 (2006)
Harris SL, Levine AJ.
The p53 pathway: positive and negative feedback loops.
Oncogene 24:2899-908 (2005)
Vogelstein B, Lane D, Levine AJ
Surfing the p53 network.
Nature 408:307-10 (2000)
Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ Jr
Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.
Science 266:1376-80 (1994)
Petersen BO, Lukas J, Sorensen CS, Bartek J, Helin K
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
EMBO J 18:396-410 (1999)
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Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression.
Mol Cell 24:101-13 (2006)
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Dual phosphorylation of the T-loop in cdk7: its role in controlling cyclin H binding and CAK activity.
EMBO J 16:343-54 (1997)
Lolli G, Johnson LN
CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?
Cell Cycle 4:572-7 (2005)
Musacchio A, Salmon ED
The spindle-assembly checkpoint in space and time.
Nat Rev Mol Cell Biol 8:379-93 (2007)
Uhlmann F
Chromosome cohesion and separation: from men and molecules.
Curr Biol 13:R104-14 (2003)
Stegmeier F, Amon A
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation.
Annu Rev Genet 38:203-32 (2004)
Moustakas A, Kardassis D
Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members.
Proc Natl Acad Sci U S A 95:6733-8 (1998)
de Boer HR, Guerrero Llobet S, van Vugt MA
Controlling the response to DNA damage by the APC/C-Cdh1.
Cell Mol Life Sci 73:949-60 (2016)
Qiao X, Zhang L, Gamper AM, Fujita T, Wan Y
APC/C-Cdh1: from cell cycle to cellular differentiation and genomic integrity.
Cell Cycle 9:3904-12 (2010)
hsa03030  DNA replication
hsa04010  MAPK signaling pathway
hsa04120  Ubiquitin mediated proteolysis
hsa04210  Apoptosis
KO pathway

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