KEGG   PATHWAY: cmk04110
Entry
cmk04110                    Pathway                                
Name
Cell cycle - Callorhinchus milii (elephant shark)
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
cmk04110  Cell cycle
cmk04110

Other DBs
GO: 0000278
Organism
Callorhinchus milii (elephant shark) [GN:cmk]
Gene
121850328  ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
103182468  G1/S-specific cyclin-D2 isoform X1 [KO:K10151]
103185578  G1/S-specific cyclin-D2 isoform X1 [KO:K10151]
121852060  G1/S-specific cyclin-D2-like [KO:K10151]
103191316  cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
103185269  cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
103183765  cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
103177409  rb1; retinoblastoma-associated protein isoform X1 [KO:K06618]
103171822  rbl1; retinoblastoma-like protein 1 [KO:K04681]
103176093  rbl2; retinoblastoma-like protein 2 [KO:K16332]
103183028  abl1; tyrosine-protein kinase ABL1 isoform X3 [KO:K06619] [EC:2.7.10.2]
103182606  histone deacetylase 2 isoform X1 [KO:K06067] [EC:3.5.1.98]
103185671  hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
103188611  transcription factor E2F1 [KO:K17454]
103179524  e2f2; transcription factor E2F2 isoform X1 [KO:K09389]
103184907  e2f3; transcription factor E2F3 isoform X1 [KO:K06620]
103184963  transcription factor E2F5 isoform X1 [KO:K04682]
103186667  e2f4; transcription factor E2F4 [KO:K04682]
103178530  transcription factor Dp-1 [KO:K04683]
103178656  transcription factor Dp-2 isoform X1 [KO:K09392]
103180204  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
103185816  tgfb2; transforming growth factor beta-2 proprotein [KO:K13376]
103187354  smad2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
103189587  smad3b; mothers against decapentaplegic homolog 3 [KO:K23605]
103187334  mothers against decapentaplegic homolog 4 [KO:K04501]
103185113  transcriptional regulator Myc-2 [KO:K04377]
103187452  zbtb17; zinc finger and BTB domain-containing protein 17 [KO:K10500]
103182848  cdkn2a/b; cyclin-dependent kinase inhibitor 2A/B (p15, inhibits CDK4) [KO:K04685]
103179336  cdkn1bb; cyclin-dependent kinase inhibitor 1Bb [KO:K06624]
103186015  cdkn1cb; cyclin-dependent kinase inhibitor 1 [KO:K09993]
103179079  cyclin-dependent kinase inhibitor 1 [KO:K06625]
103179335  cdkn1d; cyclin-dependent kinase inhibitor 1D [KO:K06625]
103176046  ccne1; G1/S-specific cyclin-E1 [KO:K06626]
103175366  ccne2; G1/S-specific cyclin-E2 [KO:K06626]
103182904  cyclin-dependent kinase 2-like isoform X1 [KO:K02206] [EC:2.7.11.22]
103189561  cdk2; cyclin-dependent kinase 2 isoform X1 [KO:K02206] [EC:2.7.11.22]
103182116  S-phase kinase-associated protein 1 [KO:K03094]
103183679  S-phase kinase-associated protein 1 [KO:K03094]
103187003  cul1b; cullin-1b [KO:K03347]
103189242  rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
103177192  ccna1; cyclin-A1 [KO:K06627]
103183713  cyclin-A2 [KO:K06627]
103188313  ccna2; cyclin-A2 [KO:K06627]
103189276  cdc6; cell division control protein 6 homolog [KO:K02213]
103175990  cdt1; DNA replication factor Cdt1 [KO:K10727]
103182806  orc1; origin recognition complex subunit 1 [KO:K02603]
121851902  orc2; LOW QUALITY PROTEIN: origin recognition complex subunit 2 [KO:K02604]
103186199  orc3; origin recognition complex subunit 3 isoform X1 [KO:K02605]
103180466  orc4; origin recognition complex subunit 4 isoform X1 [KO:K02606]
103176977  orc5; origin recognition complex subunit 5 isoform X1 [KO:K02607]
103176058  orc6; origin recognition complex subunit 6 isoform X1 [KO:K02608]
103176664  mcm2; DNA replication licensing factor MCM2 [KO:K02540] [EC:5.6.2.3]
103175166  mcm4; LOW QUALITY PROTEIN: DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
103180389  zygotic DNA replication licensing factor mcm6-A [KO:K02542] [EC:5.6.2.3]
103187009  LOW QUALITY PROTEIN: maternal DNA replication licensing factor mcm6-like [KO:K02542] [EC:5.6.2.3]
103171998  mcm7; DNA replication licensing factor MCM7 [KO:K02210] [EC:5.6.2.3]
103188587  cdc45; cell division control protein 45 homolog isoform X1 [KO:K06628]
103188390  ticrr; treslin [KO:K26117]
103187834  mdm2-binding protein [KO:K26116]
103174671  cdc7; cell division cycle 7-related protein kinase isoform X4 [KO:K02214] [EC:2.7.11.1]
103181564  dbf4; protein DBF4 homolog A isoform X1 [KO:K06629]
103183815  protein DBF4 homolog B [KO:K06629]
103180965  cdk1; cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
103177779  G2/mitotic-specific cyclin-B1-like [KO:K05868]
103177778  LOW QUALITY PROTEIN: G2/mitotic-specific cyclin-B1 [KO:K05868]
103187043  ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
103177003  ccnb3; G2/mitotic-specific cyclin-B3 [KO:K21771]
103181515  cdc25b; M-phase inducer phosphatase 2 [KO:K05866] [EC:3.1.3.48]
103177381  M-phase inducer phosphatase 1-B [KO:K05867] [EC:3.1.3.48]
103190535  LOW QUALITY PROTEIN: 14-3-3 protein zeta [KO:K16197]
103187123  14-3-3 protein theta [KO:K16197]
103185650  14-3-3 protein beta/alpha-A [KO:K16197]
103180570  ywhae1; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide 1 isoform X1 [KO:K06630]
103180696  14-3-3 protein gamma-B [KO:K16198]
103188669  LOW QUALITY PROTEIN: 14-3-3 protein eta [KO:K16198]
103186623  plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
103185136  LOW QUALITY PROTEIN: wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
103175091  wee1; wee1-like protein kinase [KO:K06632] [EC:2.7.11.1]
103181896  wee1-like protein kinase 2-A [KO:K06632] [EC:2.7.11.1]
103187217  LOW QUALITY PROTEIN: wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
103171650  pkmyt1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [KO:K06633] [EC:2.7.11.1]
103182666  ccnh; cyclin-H [KO:K06634]
103177774  cdk7; cyclin-dependent kinase 7 isoform X1 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
103178938  anapc1; anaphase-promoting complex subunit 1 [KO:K03348]
103182992  anapc2; LOW QUALITY PROTEIN: anaphase-promoting complex subunit 2 [KO:K03349]
103172429  cdc27; cell division cycle protein 27 homolog isoform X1 [KO:K03350]
103175832  anapc4; anaphase-promoting complex subunit 4 isoform X1 [KO:K03351]
103184308  anapc5; anaphase-promoting complex subunit 5 [KO:K03352]
103177562  cdc16; cell division cycle protein 16 homolog [KO:K03353]
103184310  anapc7; anaphase-promoting complex subunit 7 isoform X1 [KO:K03354]
103177272  cdc23; cell division cycle protein 23 homolog [KO:K03355]
103182244  anapc10; anaphase-promoting complex subunit 10 [KO:K03357]
103175514  anapc11; anaphase-promoting complex subunit 11 [KO:K03358]
103182981  cdc26; anaphase-promoting complex subunit CDC26 [KO:K03359]
103180306  anapc13; anaphase-promoting complex subunit 13 [KO:K12456]
103171933  anapc15; anaphase-promoting complex subunit 15 [KO:K25228]
103181282  anapc16; anaphase-promoting complex subunit 16 isoform X1 [KO:K25229]
103174617  cdc20; cell division cycle protein 20 homolog [KO:K03363]
103177878  cell division cycle protein 20 homolog [KO:K03363]
103187229  pttg1; securin [KO:K06635]
103179412  structural maintenance of chromosomes protein 1B isoform X1 [KO:K06636]
103185247  smc3; structural maintenance of chromosomes protein 3 [KO:K06669]
103181205  rad21b; RAD21 cohesin complex component b isoform X1 [KO:K06670]
103171617  double-strand-break repair protein rad21 homolog isoform X1 [KO:K06670]
103178695  stag2b; LOW QUALITY PROTEIN: cohesin subunit SA-2 [KO:K06671]
103174816  stag1a; cohesin subunit SA-1a [KO:K06671]
103177107  cohesin subunit SA-2 [KO:K06671]
103178858  atrx; transcriptional regulator ATRX isoform X1 [KO:K10779]
103179389  ddx11; ATP-dependent DNA helicase DDX11 [KO:K11273] [EC:5.6.2.7]
103190497  nipblb; nipped-B-like protein isoform X1 [KO:K06672]
103181997  mau2; MAU2 chromatid cohesion factor homolog [KO:K11266]
103177112  hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
103178265  esco2; N-acetyltransferase ESCO2 [KO:K11268] [EC:2.3.1.-]
103183449  N-acetyltransferase ESCO1 isoform X1 [KO:K11268] [EC:2.3.1.-]
103175863  pds5a; sister chromatid cohesion protein PDS5 homolog A [KO:K11267]
103177204  LOW QUALITY PROTEIN: sister chromatid cohesion protein PDS5 homolog B [KO:K11267]
103181153  wings apart-like protein homolog isoform X1 [KO:K25163]
103190908  cdca5; sororin isoform X2 [KO:K17390]
103190377  aurora kinase C [KO:K11479] [EC:2.7.11.1]
103181247  sgo1; shugoshin 1 isoform X1 [KO:K11580]
103186729  serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
103183681  ppp2ca; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
103187684  ppp2r1ba; protein phosphatase 2, regulatory subunit A, beta a [KO:K03456]
103175342  ppp2r5ca; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
103181616  ppp2r5d; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
103186155  ppp2r5a; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
103185387  ppp2r5eb; protein phosphatase 2, regulatory subunit B', epsilon isoform X1 [KO:K11584]
103188657  ndc80; kinetochore protein NDC80 homolog [KO:K11547]
103187516  knl1; LOW QUALITY PROTEIN: kinetochore scaffold 1 [KO:K11542]
103186184  ttk; dual specificity protein kinase Ttk [KO:K08866] [EC:2.7.12.1]
103186608  mad1l1; mitotic spindle assembly checkpoint protein MAD1 isoform X1 [KO:K06679]
103177366  mad2l1; mitotic spindle assembly checkpoint protein MAD2A [KO:K02537]
103181392  mad2l2; mitotic spindle assembly checkpoint protein MAD2B [KO:K13728]
103185439  bub3; mitotic checkpoint protein BUB3 [KO:K02180]
103178944  bub1; mitotic checkpoint serine/threonine-protein kinase BUB1 isoform X1 [KO:K02178] [EC:2.7.11.1]
103176232  trip13; pachytene checkpoint protein 2 homolog [KO:K22399]
103181708  MAD2L1-binding protein [KO:K26093]
103182756  fizzy-related protein homolog [KO:K03364]
103181912  fzr1a; fizzy/cell division cycle 20 related 1a [KO:K03364]
103187024  F-box only protein 5 [KO:K10292]
103182833  dual specificity protein phosphatase CDC14C isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
103184740  cdc14ab; dual specificity protein phosphatase CDC14AB isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
103178725  crebbpb; CREB binding protein b isoform X1 [KO:K04498] [EC:2.3.1.48]
103189241  histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
103175370  prkdc; DNA-dependent protein kinase catalytic subunit [KO:K06642] [EC:2.7.11.1]
103178297  atr; LOW QUALITY PROTEIN: serine/threonine-protein kinase ATR [KO:K06640] [EC:2.7.11.1]
103186517  atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
103185308  mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:2.3.2.27]
103181960  gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
103182857  growth arrest and DNA damage-inducible protein GADD45 gamma isoform X1 [KO:K04402]
103189132  growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
103180289  chek1; serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
103184008  chek2; serine/threonine-protein kinase Chk2 isoform X1 [KO:K06641] [EC:2.7.11.1]
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
  Authors
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.
  Journal
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.
  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
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)
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
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
cmk03030  DNA replication
cmk04010  MAPK signaling pathway
cmk04120  Ubiquitin mediated proteolysis
cmk04210  Apoptosis
KO pathway
ko04110   
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