KEGG   PATHWAY: ko04110Help
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
BRITE hierarchy
Pathway map
ko04110  Cell cycle
ko04110

Ortholog table
Module
M00284  Origin recognition complex [PATH:ko04110]
M00285  MCM complex [PATH:ko04110]
M00297  DNA-PK complex [PATH:ko04110]
M00381  SCF-SKP2 complex [PATH:ko04110]
M00389  APC/C complex [PATH:ko04110]
M00691  DNA damage-induced cell cycle checkpoints [PATH:ko04110]
M00692  Cell cycle - G1/S transition [PATH:ko04110]
M00693  Cell cycle - G2/M transition [PATH:ko04110]
Disease
H00064  Ataxia telangiectasia (AT)
H00409  Type II diabetes mellitus
H00631  Cornelia de Lange syndrome (CdLS)
H00713  Beckwith-Wiedemann syndrome
H00881  Li-Fraumeni syndrome
H00992  Seckel syndrome
H01007  Choroid plexus papilloma
H01023  Juvenile polyposis syndrome
H01102  Pituitary adenomas
H01288  Mosaic variegated aneuploidy (MVA) syndrome
H01385  Rienhoff syndrome
H01509  Tonsillar cancer
H01513  Retinoblastoma
H01889  Meier-Gorlin syndrome
Other DBs
BSID: 463
GO: 0000278
Orthology
K04503  G1/S-specific cyclin-D1
K10151  G1/S-specific cyclin-D2
K10152  G1/S-specific cyclin-D3
K02089  cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  cyclin-dependent kinase 6 [EC:2.7.11.22]
K06618  retinoblastoma-associated protein
K04681  retinoblastoma-like protein 1
K16332  retinoblastoma-like protein 2
K06619  abelson tyrosine-protein kinase 1 [EC:2.7.10.2]
K06067  histone deacetylase 1/2 [EC:3.5.1.98]
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
K04682  transcription factor E2F4/5
K04683  transcription factor Dp-1
K09392  transcription factor Dp-2
K03083  glycogen synthase kinase 3 beta [EC:2.7.11.26]
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04500  mothers against decapentaplegic homolog 2/3
K04501  mothers against decapentaplegic homolog 4
K04377  Myc proto-oncogene protein
K10500  zinc finger and BTB domain-containing protein 17
K06621  cyclin-dependent kinase inhibitor 2A
K04685  cyclin-dependent kinase inhibitor 2B
K06622  cyclin-dependent kinase inhibitor 2C
K06623  cyclin-dependent kinase inhibitor 2D
K06624  cyclin-dependent kinase inhibitor 1B
K09993  cyclin-dependent kinase inhibitor 1C
K06625  cyclin-dependent kinase inhibitor 1A
K06626  G1/S-specific cyclin-E1
K02206  cyclin-dependent kinase 2 [EC:2.7.11.22]
K03094  S-phase kinase-associated protein 1
K03347  cullin 1
K03868  RING-box protein 1 [EC:2.3.2.32]
K03875  F-box and leucine-rich repeat protein 1 (S-phase kinase-associated protein 2)
K06627  cyclin-A
K02213  cell division control protein 6
K06628  cell division control protein 45
K02214  cell division control protein 7 [EC:2.7.11.1]
K06629  activator of S phase kinase
K02087  cyclin-dependent kinase 1 [EC:2.7.11.23 2.7.11.22]
K05868  G2/mitotic-specific cyclin-B1
K21770  G2/mitotic-specific cyclin-B2
K21771  G2/mitotic-specific cyclin-B3
K05866  M-phase inducer phosphatase 2 [EC:3.1.3.48]
K05867  M-phase inducer phosphatase 3 [EC:3.1.3.48]
K16197  14-3-3 protein beta/theta/zeta
K06630  14-3-3 protein epsilon
K16198  14-3-3 protein gamma/eta
K06631  polo-like kinase 1 [EC:2.7.11.21]
K06632  wee1-like protein kinase [EC:2.7.11.1]
K06633  membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [EC:2.7.11.1]
K06634  cyclin H
K02202  cyclin-dependent kinase 7 [EC:2.7.11.23 2.7.11.22]
K03348  anaphase-promoting complex subunit 1
K03349  anaphase-promoting complex subunit 2
K03350  anaphase-promoting complex subunit 3
K03351  anaphase-promoting complex subunit 4
K03352  anaphase-promoting complex subunit 5
K03353  anaphase-promoting complex subunit 6
K03354  anaphase-promoting complex subunit 7
K03355  anaphase-promoting complex subunit 8
K03356  anaphase-promoting complex subunit 9
K03357  anaphase-promoting complex subunit 10
K03358  anaphase-promoting complex subunit 11
K03359  anaphase-promoting complex subunit 12
K12456  anaphase-promoting complex subunit 13
K03363  cell division cycle 20, cofactor of APC complex
K06635  securin
K02365  separase [EC:3.4.22.49]
K06636  structural maintenance of chromosome 1
K06669  structural maintenance of chromosome 3 (chondroitin sulfate proteoglycan 6)
K06671  cohesin complex subunit SA-1/2
K06670  cohesin complex subunit SCC1
K08866  serine/threonine-protein kinase TTK/MPS1 [EC:2.7.12.1]
K02178  checkpoint serine/threonine-protein kinase [EC:2.7.11.1]
K02180  cell cycle arrest protein BUB3
K06637  mitotic checkpoint serine/threonine-protein kinase BUB1 beta [EC:2.7.11.1]
K06638  mitotic spindle assembly checkpoint protein MAD1
K02537  mitotic spindle assembly checkpoint protein MAD2
K13728  mitotic spindle assembly checkpoint protein MAD2B
K03364  cell division cycle 20-like protein 1, cofactor of APC complex
K06639  cell division cycle 14 [EC:3.1.3.48 3.1.3.16]
K06640  serine/threonine-protein kinase ATR [EC:2.7.11.1]
K04728  ataxia telangiectasia mutated family protein [EC:2.7.11.1]
K04451  tumor protein p53
K02216  serine/threonine-protein kinase Chk1 [EC:2.7.11.1]
K06641  serine/threonine-protein kinase Chk2 [EC:2.7.11.1]
K04498  E1A/CREB-binding protein [EC:2.3.1.48]
K06642  DNA-dependent protein kinase catalytic subunit [EC:2.7.11.1]
K06643  E3 ubiquitin-protein ligase Mdm2 [EC:2.3.2.27]
K04402  growth arrest and DNA-damage-inducible protein
K04802  proliferating cell nuclear antigen
K06644  stratifin
K06645  M-phase inducer phosphatase 1 [EC:3.1.3.48]
K02603  origin recognition complex subunit 1
K02604  origin recognition complex subunit 2
K02605  origin recognition complex subunit 3
K02606  origin recognition complex subunit 4
K02607  origin recognition complex subunit 5
K02608  origin recognition complex subunit 6
K02540  DNA replication licensing factor MCM2 [EC:3.6.4.12]
K02541  DNA replication licensing factor MCM3 [EC:3.6.4.12]
K02212  DNA replication licensing factor MCM4 [EC:3.6.4.12]
K02209  DNA replication licensing factor MCM5 [EC:3.6.4.12]
K02542  DNA replication licensing factor MCM6 [EC:3.6.4.12]
K02210  DNA replication licensing factor MCM7 [EC:3.6.4.12]
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
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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
  Authors
Cobrinik D
  Title
Pocket proteins and cell cycle control.
  Journal
Oncogene 24:2796-809 (2005)
DOI:10.1038/sj.onc.1208619
Reference
  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
  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
  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
  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
  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
  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
  Authors
Harris SL, Levine AJ.
  Title
The p53 pathway: positive and negative feedback loops.
  Journal
Oncogene 24:2899-908 (2005)
DOI:10.1038/sj.onc.1208615
Reference
  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.
  Journal
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
  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
  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
  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
  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
  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)
DOI:10.1146/annurev.genet.38.072902.093051
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)
DOI:10.1073/pnas.95.12.6733

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