KEGG   PATHWAY: esp04110
Entry
esp04110                    Pathway                                
Name
Cell cycle - Etheostoma spectabile (orangethroat darter)
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
esp04110  Cell cycle
esp04110

Other DBs
GO: 0000278
Organism
Etheostoma spectabile (orangethroat darter) [GN:esp]
Gene
116669462  ccnb3; G2/mitotic-specific cyclin-B3 [KO:K21771]
116669513  hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
116669629  e2f2; transcription factor E2F2 isoform X1 [KO:K09389]
116669886  orc3; origin recognition complex subunit 3 [KO:K02605]
116670004  bub1b; mitotic checkpoint serine/threonine-protein kinase BUB1 beta [KO:K06637] [EC:2.7.11.1]
116670007  atr; serine/threonine-protein kinase ATR [KO:K06640] [EC:2.7.11.1]
116670022  [KO:K04402]
116670042  [KO:K06067] [EC:3.5.1.98]
116670053  tgfb3; transforming growth factor beta-3 proprotein [KO:K13377]
116670130  ywhaq; 14-3-3 protein theta [KO:K16197]
116670143  ppp2r5c; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
116670211  ppp2r5e; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
116670492  stag1; cohesin subunit SA-1 [KO:K06671]
116670786  bub3; mitotic checkpoint protein BUB3 [KO:K02180]
116670804  anapc16; anaphase-promoting complex subunit 16 [KO:K25229]
116671005  [KO:K25163]
116671068  [KO:K04498] [EC:2.3.1.48]
116671287  pkmyt1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [KO:K06633] [EC:2.7.11.1]
116671675  [KO:K06629]
116672005  atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
116672376  myc; myc proto-oncogene protein isoform X1 [KO:K04377]
116672831  [KO:K06624]
116673033  [KO:K06625]
116673210  [KO:K06643] [EC:2.3.2.27]
116673291  orc5; origin recognition complex subunit 5 [KO:K02607]
116673298  ccnd2; G1/S-specific cyclin-D2 [KO:K10151]
116674043  orc4; origin recognition complex subunit 4 [KO:K02606]
116674797  [KO:K06630]
116678376  [KO:K11584]
116678815  cdc27; cell division cycle protein 27 homolog isoform X1 [KO:K03350]
116679016  mad2l1; mitotic spindle assembly checkpoint protein MAD2A isoform X1 [KO:K02537]
116679210  [KO:K11268] [EC:2.3.1.-]
116679238  cul1; cullin-1 [KO:K03347]
116679825  [KO:K02089] [EC:2.7.11.22]
116679842  [KO:K16198]
116679844  [KO:K02206] [EC:2.7.11.22]
116682862  [KO:K13375]
116685783  [KO:K21770]
116685784  [KO:K21770]
116685823  prkdc; DNA-dependent protein kinase catalytic subunit isoform X1 [KO:K06642] [EC:2.7.11.1]
116686014  ccne1; G1/S-specific cyclin-E1 [KO:K06626]
116686128  [KO:K05866] [EC:3.1.3.48]
116686339  [KO:K04451]
116686487  cdk1; cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
116686657  anapc7; anaphase-promoting complex subunit 7 [KO:K03354]
116687079  anapc15; anaphase-promoting complex subunit 15 isoform X1 [KO:K25228]
116687132  ppp2r1b; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
116687243  [KO:K02089] [EC:2.7.11.22]
116687244  [KO:K02206] [EC:2.7.11.22]
116687691  [KO:K10152]
116687706  [KO:K06625]
116688004  [KO:K16197]
116688577  rbl1; LOW QUALITY PROTEIN: retinoblastoma-like protein 1 [KO:K04681]
116688584  mcm2; LOW QUALITY PROTEIN: DNA replication licensing factor MCM2 [KO:K02540] [EC:5.6.2.3]
116688706  espl1; LOW QUALITY PROTEIN: separin [KO:K02365] [EC:3.4.22.49]
116688890  [KO:K06672]
116688903  smad4; mothers against decapentaplegic homolog 4 [KO:K04501]
116689261  cdk7; cyclin-dependent kinase 7 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
116689287  ccnh; cyclin-H [KO:K06634]
116689303  [KO:K03354]
116689441  cdc45; cell division control protein 45 homolog [KO:K06628]
116689452  pcna; proliferating cell nuclear antigen [KO:K04802]
116689559  gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
116689665  [KO:K04500]
116689871  cdc6; cell division control protein 6 homolog [KO:K02213]
116689965  ppp2cb; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
116690039  ndc80; kinetochore protein NDC80 homolog [KO:K11547]
116690081  anapc5; anaphase-promoting complex subunit 5 [KO:K03352]
116690107  [KO:K06639] [EC:3.1.3.16 3.1.3.48]
116690652  [KO:K16197]
116690739  [KO:K06670]
116690851  e2f3; transcription factor E2F3 [KO:K06620]
116691348  mtbp; mdm2-binding protein [KO:K26116]
116691466  trip13; pachytene checkpoint protein 2 homolog isoform X1 [KO:K22399]
116691637  ttk; dual specificity protein kinase TTK isoform X1 [KO:K08866] [EC:2.7.12.1]
116691670  dbf4; protein DBF4 homolog A isoform X1 [KO:K06629]
116692231  smc1a; structural maintenance of chromosomes protein 1A [KO:K06636]
116692488  mad2l2; mitotic spindle assembly checkpoint protein MAD2B [KO:K13728]
116692506  e2f1; transcription factor E2F1 [KO:K17454]
116692769  zbtb17; zinc finger and BTB domain-containing protein 17 isoform X1 [KO:K10500]
116692844  [KO:K04682]
116693135  [KO:K06670]
116693179  [KO:K16197]
116693582  ticrr; treslin isoform X1 [KO:K26117]
116693606  wee1; wee1-like protein kinase [KO:K06632] [EC:2.7.11.1]
116693627  [KO:K06636]
116693641  cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
116693672  anapc13; anaphase-promoting complex subunit 13 [KO:K12456]
116693735  [KO:K06632] [EC:2.7.11.1]
116694001  smad3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
116694156  ddx11; ATP-dependent DNA helicase DDX11 [KO:K11273] [EC:5.6.2.7]
116694399  [KO:K09993]
116694578  [KO:K04503]
116694896  cdkn2c; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
116695010  cdkn2d; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
116695293  mau2; MAU2 chromatid cohesion factor homolog [KO:K11266]
116695921  [KO:K03364]
116695929  [KO:K03351]
116696019  [KO:K04402]
116696394  ccna2; cyclin-A2 [KO:K06627]
116696457  cdt1; DNA replication factor Cdt1 [KO:K10727]
116696569  [KO:K06671]
116696752  [KO:K06635]
116696915  atrx; transcriptional regulator ATRX isoform X1 [KO:K10779]
116697037  [KO:K13376]
116697109  mcm7; DNA replication licensing factor MCM7 isoform X1 [KO:K02210] [EC:5.6.2.3]
116697222  [KO:K04382] [EC:3.1.3.16]
116697305  mad1l1; mitotic spindle assembly checkpoint protein MAD1 [KO:K06679]
116697433  [KO:K06671]
116697574  cdc16; cell division cycle protein 16 homolog [KO:K03353]
116697763  tfdp1; transcription factor Dp-1 [KO:K04683]
116697841  cdkn2b; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
116698089  smc3; structural maintenance of chromosomes protein 3 [KO:K06669]
116698290  gsk3b; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
116698378  [KO:K06671]
116698491  mcm4; DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
116698587  cdc7; cell division cycle 7-related protein kinase isoform X1 [KO:K02214] [EC:2.7.11.1]
116698633  cdc20; cell division cycle protein 20 homolog [KO:K03363]
116698754  mcm6; DNA replication licensing factor MCM6 [KO:K02542] [EC:5.6.2.3]
116698959  [KO:K03364]
116698982  [KO:K04402]
116699085  [KO:K03364]
116699256  e2f5; transcription factor E2F5 [KO:K04682]
116699436  tgfb2; transforming growth factor beta-2 proprotein [KO:K13376]
116699503  orc2; origin recognition complex subunit 2 isoform X1 [KO:K02604]
116699648  [KO:K06639] [EC:3.1.3.16 3.1.3.48]
116699943  [KO:K16198]
116700025  chek1; serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
116700064  cdc23; cell division cycle protein 23 homolog [KO:K03355]
116700112  ccna1; cyclin-A1 [KO:K06627]
116700179  ppp2ca; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
116700182  skp1; LOW QUALITY PROTEIN: S-phase kinase-associated protein 1 [KO:K03094]
116700195  [KO:K10779]
116700414  pds5b; sister chromatid cohesion protein PDS5 homolog B [KO:K11267]
116700591  [KO:K06671]
116700602  rb1; retinoblastoma-associated protein isoform X1 [KO:K06618]
116700739  [KO:K06630]
116701298  [KO:K06620]
116701444  [KO:K06067] [EC:3.5.1.98]
116701587  cdca5; sororin [KO:K17390]
116701774  rad21; double-strand-break repair protein rad21 homolog [KO:K06670]
116701851  cdk6; LOW QUALITY PROTEIN: cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
116701885  ccne2; G1/S-specific cyclin-E2 isoform X1 [KO:K06626]
116702155  [KO:K04501]
116702182  [KO:K16197]
116702195  sgo1; shugoshin 1 isoform X1 [KO:K11580]
116702294  anapc2; anaphase-promoting complex subunit 2 [KO:K03349]
116702369  mcm5; DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
116702633  crebbp; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
116702681  anapc11; anaphase-promoting complex subunit 11 [KO:K03358]
116702780  [KO:K02091] [EC:2.7.11.22]
116702788  [KO:K04498] [EC:2.3.1.48]
116702801  rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
116703064  pds5a; sister chromatid cohesion protein PDS5 homolog A isoform X1 [KO:K11267]
116703090  [KO:K10151]
116703178  ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
116704054  skp2; S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
116704114  [KO:K04501]
116704170  [KO:K04402]
116704321  smad2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
116704379  ccnb1; G2/mitotic-specific cyclin-B1 isoform X1 [KO:K05868]
116704516  [KO:K23605]
116704534  abl1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
116704578  [KO:K06672]
116705068  fbxo5; F-box only protein 5 [KO:K10292]
116705086  wapl; wings apart-like protein homolog [KO:K25163]
116705352  anapc1; anaphase-promoting complex subunit 1 isoform X1 [KO:K03348]
116705707  mad2l1bp; MAD2L1-binding protein isoform X1 [KO:K26093]
116705764  plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
116705851  ppp2r5a; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform isoform X1 [KO:K11584]
116706019  mcm3; LOW QUALITY PROTEIN: DNA replication licensing factor MCM3 [KO:K02541] [EC:5.6.2.3]
116706222  [KO:K13377]
116706615  [KO:K04498] [EC:2.3.1.48]
116706673  bub1; mitotic checkpoint serine/threonine-protein kinase BUB1 [KO:K02178] [EC:2.7.11.1]
116706734  [KO:K11584]
116706749  knl1; kinetochore scaffold 1 [KO:K11542]
116707123  ppp2r5b; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
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
esp03030  DNA replication
esp04010  MAPK signaling pathway
esp04120  Ubiquitin mediated proteolysis
esp04210  Apoptosis
KO pathway
ko04110   

DBGET integrated database retrieval system