KEGG   PATHWAY: ko04110
Entry
ko04110                     Pathway                                
Name
Cell cycle
Description
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.
Class
Cellular Processes; Cell growth and death
Pathway map
ko04110  Cell cycle
ko04110

Other DBs
GO: 0000278
Orthology
K02087  CDK1, CDC2; cyclin-dependent kinase 1 [EC:2.7.11.22 2.7.11.23]
K02089  CDK4; cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  CDK6; cyclin-dependent kinase 6 [EC:2.7.11.22]
K02178  BUB1; checkpoint serine/threonine-protein kinase [EC:2.7.11.1]
K02180  BUB3; cell cycle arrest protein BUB3
K02202  CDK7; cyclin-dependent kinase 7 [EC:2.7.11.22 2.7.11.23]
K02206  CDK2; cyclin-dependent kinase 2 [EC:2.7.11.22]
K02209  MCM5, CDC46; DNA replication licensing factor MCM5 [EC:5.6.2.3]
K02210  MCM7, CDC47; DNA replication licensing factor MCM7 [EC:5.6.2.3]
K02212  MCM4, CDC54; DNA replication licensing factor MCM4 [EC:5.6.2.3]
K02213  CDC6; cell division control protein 6
K02214  CDC7; cell division control protein 7 [EC:2.7.11.1]
K02216  CHEK1; serine/threonine-protein kinase CHEK1 [EC:2.7.11.1]
K02365  ESP1; separase [EC:3.4.22.49]
K02537  MAD2; mitotic spindle assembly checkpoint protein MAD2
K02540  MCM2; DNA replication licensing factor MCM2 [EC:5.6.2.3]
K02541  MCM3; DNA replication licensing factor MCM3 [EC:5.6.2.3]
K02542  MCM6; DNA replication licensing factor MCM6 [EC:5.6.2.3]
K02603  ORC1; origin recognition complex subunit 1
K02604  ORC2; origin recognition complex subunit 2
K02605  ORC3; origin recognition complex subunit 3
K02606  ORC4; origin recognition complex subunit 4
K02607  ORC5; origin recognition complex subunit 5
K02608  ORC6; origin recognition complex subunit 6
K03083  GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26]
K03094  SKP1, CBF3D; S-phase kinase-associated protein 1
K03347  CUL1, CDC53; cullin 1
K03348  APC1, ANAPC1; anaphase-promoting complex subunit 1
K03349  APC2, ANAPC2; anaphase-promoting complex subunit 2
K03350  APC3, CDC27; anaphase-promoting complex subunit 3
K03351  APC4, ANAPC4; anaphase-promoting complex subunit 4
K03352  APC5, ANAPC5; anaphase-promoting complex subunit 5
K03353  APC6, CDC16; anaphase-promoting complex subunit 6
K03354  APC7, ANAPC7; anaphase-promoting complex subunit 7
K03355  APC8, CDC23; anaphase-promoting complex subunit 8
K03357  APC10, ANAPC10, DOC1; anaphase-promoting complex subunit 10
K03358  APC11, ANAPC11; anaphase-promoting complex subunit 11
K03359  APC12, CDC26; anaphase-promoting complex subunit 12
K03363  CDC20; cell division cycle 20, cofactor of APC complex
K03364  CDH1, FZR1; cell division cycle 20-like protein 1, cofactor of APC complex
K03456  PPP2R1; serine/threonine-protein phosphatase 2A regulatory subunit A
K03868  RBX1, ROC1; E3 ubiquitin-protein ligase RBX1 [EC:2.3.2.32]
K03875  SKP2, FBXL1; F-box and leucine-rich repeat protein 1 (S-phase kinase-associated protein 2)
K04377  MYC; Myc proto-oncogene protein
K04382  PPP2C; serine/threonine-protein phosphatase 2A catalytic subunit [EC:3.1.3.16]
K04402  GADD45; growth arrest and DNA-damage-inducible protein
K04451  TP53, P53; tumor protein p53
K04498  EP300, CREBBP, KAT3; E1A/CREB-binding protein [EC:2.3.1.48]
K04500  SMAD2; mothers against decapentaplegic homolog 2
K04501  SMAD4; mothers against decapentaplegic homolog 4
K04503  CCND1; G1/S-specific cyclin-D1
K04681  RBL1; retinoblastoma-like protein 1
K04682  E2F4_5; transcription factor E2F4/5
K04683  TFDP1; transcription factor Dp-1
K04685  CDKN2B, P15, INK4B; cyclin-dependent kinase inhibitor 2B
K04728  ATM, TEL1; serine-protein kinase ATM [EC:2.7.11.1]
K04802  PCNA; proliferating cell nuclear antigen
K05866  CDC25B; M-phase inducer phosphatase 2 [EC:3.1.3.48]
K05867  CDC25C; M-phase inducer phosphatase 3 [EC:3.1.3.48]
K05868  CCNB1; G2/mitotic-specific cyclin-B1
K06067  HDAC1_2; histone deacetylase 1/2 [EC:3.5.1.98]
K06618  RB1; retinoblastoma-associated protein
K06619  ABL1; abelson tyrosine-protein kinase 1 [EC:2.7.10.2]
K06620  E2F3; transcription factor E2F3
K06621  CDKN2A, P16, INK4A; cyclin-dependent kinase inhibitor 2A
K06622  CDKN2C, P18, INK4C; cyclin-dependent kinase inhibitor 2C
K06623  CDKN2D, P19, INK4D; cyclin-dependent kinase inhibitor 2D
K06624  CDKN1B, P27, KIP1; cyclin-dependent kinase inhibitor 1B
K06625  CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A
K06626  CCNE; G1/S-specific cyclin-E1
K06627  CCNA; cyclin-A
K06628  CDC45; cell division control protein 45
K06629  DBF4, ASK; protein DBF4
K06630  YWHAE; 14-3-3 protein epsilon
K06631  PLK1; polo-like kinase 1 [EC:2.7.11.21]
K06632  WEE1; wee1-like protein kinase [EC:2.7.11.1]
K06633  PKMYT; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [EC:2.7.11.1]
K06634  CCNH; cyclin H
K06635  PTTG; securin
K06636  SMC1; structural maintenance of chromosome 1
K06637  BUB1B, BUBR1, MAD3L; mitotic checkpoint serine/threonine-protein kinase BUB1 beta [EC:2.7.11.1]
K06639  CDC14; cell division cycle 14 [EC:3.1.3.16 3.1.3.48]
K06640  ATR; serine/threonine-protein kinase ATR [EC:2.7.11.1]
K06641  CHEK2; serine/threonine-protein kinase CHEK2 [EC:2.7.11.1]
K06642  PRKDC; DNA-dependent protein kinase catalytic subunit [EC:2.7.11.1]
K06643  MDM2; E3 ubiquitin-protein ligase Mdm2 [EC:2.3.2.27]
K06644  SFN; stratifin
K06645  CDC25A; M-phase inducer phosphatase 1 [EC:3.1.3.48]
K06669  SMC3, CSPG6; structural maintenance of chromosome 3 (chondroitin sulfate proteoglycan 6)
K06670  SCC1, MCD1, RAD21; cohesin complex subunit SCC1
K06671  STAG1_2, SCC3, IRR1; cohesin complex subunit SA-1/2
K06672  SCC2, NIPBL; cohesin loading factor subunit SCC2
K06679  MAD1; mitotic spindle assembly checkpoint protein MAD1
K08866  TTK, MPS1; serine/threonine-protein kinase TTK/MPS1 [EC:2.7.12.1]
K09389  E2F2; transcription factor E2F2
K09392  TFDP2; transcription factor Dp-2
K09993  CDKN1C, P57, KIP2; cyclin-dependent kinase inhibitor 1C
K10151  CCND2; G1/S-specific cyclin-D2
K10152  CCND3; G1/S-specific cyclin-D3
K10292  FBXO5, EMI1; F-box protein 5
K10500  ZBTB17, MIZ1; zinc finger and BTB domain-containing protein 17
K10727  CDT1; chromatin licensing and DNA replication factor 1
K10779  ATRX; transcriptional regulator ATRX
K11266  MAU2; MAternally affected uncoordination
K11267  PDS5; sister chromatid cohesion protein PDS5
K11268  ESCO, ECO1; N-acetyltransferase [EC:2.3.1.-]
K11273  DDX11, CHL1, CTF1; chromosome transmission fidelity protein 1 [EC:5.6.2.7]
K11405  HDAC8; histone deacetylase 8 [EC:3.5.1.98]
K11479  AURKB; aurora kinase B [EC:2.7.11.1]
K11542  CASC5, KNL1; protein CASC5
K11547  NDC80, HEC1, TID3; kinetochore protein NDC80
K11580  SGOL1; shugoshin-like 1
K11584  PPP2R5; serine/threonine-protein phosphatase 2A regulatory subunit B'
K12456  APC13, ANAPC13; anaphase-promoting complex subunit 13
K13375  TGFB1; transforming growth factor beta-1
K13376  TGFB2; transforming growth factor beta-2
K13377  TGFB3; transforming growth factor beta-3
K13728  MAD2L2; mitotic spindle assembly checkpoint protein MAD2B
K16197  YWHAB_Q_Z; 14-3-3 protein beta/theta/zeta
K16198  YWHAG_H; 14-3-3 protein gamma/eta
K16332  RBL2; retinoblastoma-like protein 2
K17390  CDCA5; sororin
K17454  E2F1; transcription factor E2F1
K21770  CCNB2; G2/mitotic-specific cyclin-B2
K21771  CCNB3; G2/mitotic-specific cyclin-B3
K22399  TRIP13; pachytene checkpoint protein 2
K23605  SMAD3; mothers against decapentaplegic homolog 3
K25163  WAPL; wings apart-like protein
K25228  APC15, ANAPC15; anaphase-promoting complex subunit 15
K25229  APC16, ANAPC16; anaphase-promoting complex subunit 16
K26093  MAD2L1BP; MAD2L1-binding protein
K26116  MTBP; Mdm2-binding protein
K26117  TICRR; Treslin
Reference
PMID:7908906
  Authors
Matsuoka S, Yamaguchi M, Matsukage A
  Title
D-type cyclin-binding regions of proliferating cell nuclear antigen.
  Journal
J Biol Chem 269:11030-6 (1994)
Reference
PMID:8242749
  Authors
Welch PJ, Wang JY
  Title
A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle.
  Journal
Cell 75:779-90 (1993)
DOI:10.1016/0092-8674(93)90497-E
Reference
PMID:16936746
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Macaluso M, Montanari M, Giordano A
  Title
Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes.
  Journal
Oncogene 25:5263-7 (2006)
DOI:10.1038/sj.onc.1209680
Reference
PMID:15838516
  Authors
Cobrinik D
  Title
Pocket proteins and cell cycle control.
  Journal
Oncogene 24:2796-809 (2005)
DOI:10.1038/sj.onc.1208619
Reference
PMID:17568790
  Authors
Boutros R, Lobjois V, Ducommun B
  Title
CDC25 phosphatases in cancer cells: key players? Good targets?
  Journal
Nat Rev Cancer 7:495-507 (2007)
DOI:10.1038/nrc2169
Reference
PMID:9832503
  Authors
Diehl JA, Cheng M, Roussel MF, Sherr CJ
  Title
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
  Journal
Genes Dev 12:3499-511 (1998)
DOI:10.1101/gad.12.22.3499
Reference
PMID:19020303
  Authors
Klein EA, Assoian RK
  Title
Transcriptional regulation of the cyclin D1 gene at a glance.
  Journal
J Cell Sci 121:3853-7 (2008)
DOI:10.1242/jcs.039131
Reference
PMID:10385618
  Authors
Sherr CJ, Roberts JM
  Title
CDK inhibitors: positive and negative regulators of G1-phase progression.
  Journal
Genes Dev 13:1501-12 (1999)
DOI:10.1101/gad.13.12.1501
Reference
PMID:12809600
  Authors
Shi Y, Massague J.
  Title
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
  Journal
Cell 113:685-700 (2003)
DOI:10.1016/S0092-8674(03)00432-X
Reference
PMID:12925736
  Authors
Kamura T, Hara T, Kotoshiba S, Yada M, Ishida N, Imaki H, Hatakeyama S, Nakayama K, Nakayama KI
  Title
Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation.
  Journal
Proc Natl Acad Sci U S A 100:10231-6 (2003)
DOI:10.1073/pnas.1831009100
Reference
PMID:16212951
  Authors
Bond M, Sala-Newby GB, Wu YJ, Newby AC
  Title
Biphasic effect of p21Cip1 on smooth muscle cell proliferation: role of PI 3-kinase and Skp2-mediated degradation.
  Journal
Cardiovasc Res 69:198-206 (2006)
DOI:10.1016/j.cardiores.2005.08.020
Reference
PMID:15838523
  Authors
Harris SL, Levine AJ.
  Title
The p53 pathway: positive and negative feedback loops.
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Oncogene 24:2899-908 (2005)
DOI:10.1038/sj.onc.1208615
Reference
PMID:11099028
  Authors
Vogelstein B, Lane D, Levine AJ
  Title
Surfing the p53 network.
  Journal
Nature 408:307-10 (2000)
DOI:10.1038/35042675
Reference
PMID:7973727
  Authors
Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ Jr
  Title
Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.
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Science 266:1376-80 (1994)
DOI:10.1126/science.7973727
Reference
PMID:9889196
  Authors
Petersen BO, Lukas J, Sorensen CS, Bartek J, Helin K
  Title
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
  Journal
EMBO J 18:396-410 (1999)
DOI:10.1093/emboj/18.2.396
Reference
PMID:17018296
  Authors
Sheu YJ, Stillman B
  Title
Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression.
  Journal
Mol Cell 24:101-13 (2006)
DOI:10.1016/j.molcel.2006.07.033
Reference
PMID:9029154
  Authors
Martinez AM, Afshar M, Martin F, Cavadore JC, Labbe JC, Doree M
  Title
Dual phosphorylation of the T-loop in cdk7: its role in controlling cyclin H binding and CAK activity.
  Journal
EMBO J 16:343-54 (1997)
DOI:10.1093/emboj/16.2.343
Reference
PMID:15876871
  Authors
Lolli G, Johnson LN
  Title
CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?
  Journal
Cell Cycle 4:572-7 (2005)
DOI:10.4161/cc.4.4.1607
Reference
PMID:17426725
  Authors
Musacchio A, Salmon ED
  Title
The spindle-assembly checkpoint in space and time.
  Journal
Nat Rev Mol Cell Biol 8:379-93 (2007)
DOI:10.1038/nrm2163
Reference
PMID:12573239
  Authors
Uhlmann F
  Title
Chromosome cohesion and separation: from men and molecules.
  Journal
Curr Biol 13:R104-14 (2003)
DOI:10.1016/S0960-9822(03)00039-3
Reference
PMID:15568976
  Authors
Stegmeier F, Amon A
  Title
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation.
  Journal
Annu Rev Genet 38:203-32 (2004)
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Reference
PMID:9618481
  Authors
Moustakas A, Kardassis D
  Title
Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members.
  Journal
Proc Natl Acad Sci U S A 95:6733-8 (1998)
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Reference
PMID:26650195
  Authors
de Boer HR, Guerrero Llobet S, van Vugt MA
  Title
Controlling the response to DNA damage by the APC/C-Cdh1.
  Journal
Cell Mol Life Sci 73:949-60 (2016)
DOI:10.1007/s00018-015-2096-7
Reference
PMID:20935501
  Authors
Qiao X, Zhang L, Gamper AM, Fujita T, Wan Y
  Title
APC/C-Cdh1: from cell cycle to cellular differentiation and genomic integrity.
  Journal
Cell Cycle 9:3904-12 (2010)
DOI:10.4161/cc.9.19.13585
Related
pathway
ko03030  DNA replication
ko04010  MAPK signaling pathway
ko04120  Ubiquitin mediated proteolysis
ko04210  Apoptosis

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