KEGG   PATHWAY: llv04110
Entry
llv04110                    Pathway                                
Name
Cell cycle - Lutra lutra (Eurasian river otter)
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
llv04110  Cell cycle
llv04110

Other DBs
GO: 0000278
Organism
Lutra lutra (Eurasian river otter) [GN:llv]
Gene
125078419  G1/S-specific cyclin-D1 [KO:K04503]
125105988  G1/S-specific cyclin-D2 isoform X1 [KO:K10151]
125102808  G1/S-specific cyclin-D3 isoform X1 [KO:K10152]
125106397  cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
125080451  LOW QUALITY PROTEIN: cyclin-dependent kinase 6-like [KO:K02091] [EC:2.7.11.22]
125096420  retinoblastoma-associated protein [KO:K06618]
125109399  retinoblastoma-like protein 1 isoform X1 [KO:K04681]
125088702  retinoblastoma-like protein 2 isoform X1 [KO:K16332]
125083176  tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
125102513  histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
125080019  LOW QUALITY PROTEIN: histone deacetylase 1-like [KO:K06067] [EC:3.5.1.98]
125098208  histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
125106802  histone deacetylase 2-like [KO:K06067] [EC:3.5.1.98]
125109172  transcription factor E2F1 isoform X1 [KO:K17454]
125097872  transcription factor E2F2 isoform X1 [KO:K09389]
125102168  transcription factor E2F3 isoform X1 [KO:K06620]
125088949  transcription factor E2F4 isoform X1 [KO:K04682]
125098269  transcription factor E2F5 isoform X1 [KO:K04682]
125094867  LOW QUALITY PROTEIN: transcription factor Dp-1-like [KO:K04683]
125098174  transcription factor Dp-2 isoform X1 [KO:K09392]
125097853  glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
125089683  transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
125085760  LOW QUALITY PROTEIN: transforming growth factor beta-2 proprotein-like [KO:K13376]
125103650  transforming growth factor beta-3 proprotein [KO:K13377]
125081717  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
125105231  mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
125082527  mothers against decapentaplegic homolog 4 [KO:K04501]
125098611  myc proto-oncogene protein [KO:K04377]
125096718  zinc finger and BTB domain-containing protein 17 isoform X1 [KO:K10500]
125083919  cyclin-dependent kinase inhibitor 2A-like isoform X1 [KO:K06621]
125083921  cyclin-dependent kinase 4 inhibitor B-like [KO:K04685]
125098666  cyclin-dependent kinase 4 inhibitor C [KO:K06622]
125084828  cyclin-dependent kinase 4 inhibitor D [KO:K06623]
125106593  cyclin-dependent kinase inhibitor 1B [KO:K06624]
125078905  cyclin-dependent kinase inhibitor 1C-like [KO:K09993]
125102743  cyclin-dependent kinase inhibitor 1 [KO:K06625]
125096979  G1/S-specific cyclin-E2 [KO:K06626]
125089714  G1/S-specific cyclin-E1 isoform X1 [KO:K06626]
125106521  LOW QUALITY PROTEIN: cyclin-dependent kinase 2-like [KO:K02206] [EC:2.7.11.22]
125099904  S-phase kinase-associated protein 1 [KO:K03094]
125083871  S-phase kinase-associated protein 1 [KO:K03094]
125092302  S-phase kinase-associated protein 1-like [KO:K03094]
125093902  S-phase kinase-associated protein 1-like [KO:K03094]
125094285  S-phase kinase-associated protein 1-like [KO:K03094]
125103677  S-phase kinase-associated protein 1 [KO:K03094]
125080113  S-phase kinase-associated protein 1-like [KO:K03094]
125081063  S-phase kinase-associated protein 1-like [KO:K03094]
125105513  S-phase kinase-associated protein 1-like [KO:K03094]
125089125  S-phase kinase-associated protein 1-like [KO:K03094]
125089985  S-phase kinase-associated protein 1-like [KO:K03094]
125098885  S-phase kinase-associated protein 1-like [KO:K03094]
125080978  cullin-1 [KO:K03347]
125106731  RING-box protein 1b isoform X1 [KO:K03868] [EC:2.3.2.32]
125099857  S-phase kinase-associated protein 2 [KO:K03875]
125084483  LOW QUALITY PROTEIN: cyclin-A1-like [KO:K06627]
125093344  cyclin-A2 isoform X1 [KO:K06627]
125095240  cyclin-A1 [KO:K06627]
125087841  cell division control protein 6 homolog [KO:K02213]
125088731  DNA replication factor Cdt1-like isoform X1 [KO:K10727]
125098934  origin recognition complex subunit 1-like [KO:K02603]
125094989  origin recognition complex subunit 2 isoform X1 [KO:K02604]
125102399  origin recognition complex subunit 3 isoform X1 [KO:K02605]
125095864  LOW QUALITY PROTEIN: origin recognition complex subunit 4-like [KO:K02606]
125080756  origin recognition complex subunit 5 isoform X1 [KO:K02607]
125088623  origin recognition complex subunit 6 [KO:K02608]
125107643  DNA replication licensing factor MCM2 isoform X1 [KO:K02540] [EC:5.6.2.3]
125101910  DNA replication licensing factor MCM3 [KO:K02541] [EC:5.6.2.3]
125096735  DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
125107311  DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
125095932  DNA replication licensing factor MCM6 isoform X1 [KO:K02542] [EC:5.6.2.3]
125090228  DNA replication licensing factor MCM7 isoform X1 [KO:K02210] [EC:5.6.2.3]
125082354  cell division control protein 45 homolog [KO:K06628]
125104188  treslin-like [KO:K26117]
125098191  mdm2-binding protein-like isoform X1 [KO:K26116]
125098405  cell division cycle 7-related protein kinase [KO:K02214] [EC:2.7.11.1]
125080997  protein DBF4 homolog A-like isoform X1 [KO:K06629]
125087082  protein DBF4 homolog B-like isoform X1 [KO:K06629]
125084822  cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
125107793  G2/mitotic-specific cyclin-B1 [KO:K05868]
125100785  G2/mitotic-specific cyclin-B1 [KO:K05868]
125100986  G2/mitotic-specific cyclin-B1-like [KO:K05868]
125104007  G2/mitotic-specific cyclin-B2 isoform X1 [KO:K21770]
125092133  G2/mitotic-specific cyclin-B3-like isoform X1 [KO:K21771]
125108201  M-phase inducer phosphatase 2 isoform X1 [KO:K05866] [EC:3.1.3.48]
125100775  M-phase inducer phosphatase 3-like isoform X1 [KO:K05867] [EC:3.1.3.48]
125108359  14-3-3 protein beta/alpha [KO:K16197]
125109228  14-3-3 protein theta [KO:K16197]
125093034  14-3-3 protein theta-like [KO:K16197]
125093393  14-3-3 protein theta-like [KO:K16197]
125093581  14-3-3 protein beta/alpha-like [KO:K16197]
125094736  14-3-3 protein theta-like [KO:K16197]
125097572  14-3-3 protein zeta/delta [KO:K16197]
125107588  14-3-3 protein epsilon [KO:K06630]
125108683  14-3-3 protein epsilon-like [KO:K06630]
125087039  14-3-3 protein epsilon isoform X1 [KO:K06630]
125090912  14-3-3 protein gamma [KO:K16198]
125082247  14-3-3 protein eta [KO:K16198]
125090174  serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
125078253  wee1-like protein kinase isoform X1 [KO:K06632] [EC:2.7.11.1]
125080531  wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
125090682  membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase isoform X1 [KO:K06633] [EC:2.7.11.1]
125100934  cyclin-H isoform X1 [KO:K06634]
125099766  cyclin-dependent kinase 7 isoform X1 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
125108834  anaphase-promoting complex subunit 1 isoform X1 [KO:K03348]
125087135  cell division cycle protein 27 homolog isoform X1 [KO:K03350]
125093599  anaphase-promoting complex subunit 4 isoform X1 [KO:K03351]
125082292  anaphase-promoting complex subunit 5 isoform X1 [KO:K03352]
125094877  cell division cycle protein 16 homolog [KO:K03353]
125096336  cell division cycle protein 16 homolog [KO:K03353]
125082010  anaphase-promoting complex subunit 7 isoform X1 [KO:K03354]
125099798  cell division cycle protein 23 homolog isoform X1 [KO:K03355]
125093000  LOW QUALITY PROTEIN: anaphase-promoting complex subunit 10-like [KO:K03357]
125087911  anaphase-promoting complex subunit 11 isoform X1 [KO:K03358]
125083224  anaphase-promoting complex subunit CDC26 isoform X1 [KO:K03359]
125104156  anaphase-promoting complex subunit 13 [KO:K12456]
125078306  anaphase-promoting complex subunit 15 isoform X1 [KO:K25228]
125085081  anaphase-promoting complex subunit 16 [KO:K25229]
125092371  cell division cycle protein 20 homolog [KO:K03363]
125097971  cell division cycle protein 20 homolog [KO:K03363]
125083646  securin-like [KO:K06635]
125100897  securin isoform X1 [KO:K06635]
125106438  separin-like [KO:K02365] [EC:3.4.22.49]
125092360  structural maintenance of chromosomes protein 1A isoform X1 [KO:K06636]
125106399  structural maintenance of chromosomes protein 1B isoform X1 [KO:K06636]
125084761  structural maintenance of chromosomes protein 3 [KO:K06669]
125093017  LOW QUALITY PROTEIN: double-strand-break repair protein rad21 homolog [KO:K06670]
125097975  double-strand-break repair protein rad21 homolog isoform X1 [KO:K06670]
125091598  cohesin subunit SA-2 isoform X1 [KO:K06671]
125092239  cohesin subunit SA-2-like isoform X1 [KO:K06671]
125104039  cohesin subunit SA-1 isoform X1 [KO:K06671]
125091280  transcriptional regulator ATRX isoform X1 [KO:K10779]
125106626  putative ATP-dependent RNA helicase DDX11-like protein 8 isoform X1 [KO:K11273] [EC:5.6.2.7]
125101322  nipped-B-like protein isoform X1 [KO:K06672]
125081692  MAU2 chromatid cohesion factor homolog isoform X1 [KO:K11266]
125091895  histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
125092966  N-acetyltransferase ESCO2-like [KO:K11268] [EC:2.3.1.-]
125082662  N-acetyltransferase ESCO1-like [KO:K11268] [EC:2.3.1.-]
125093656  sister chromatid cohesion protein PDS5 homolog A isoform X1 [KO:K11267]
125096290  sister chromatid cohesion protein PDS5 homolog B isoform X1 [KO:K11267]
125084606  wings apart-like protein homolog isoform X1 [KO:K25163]
125078167  sororin-like [KO:K17390]
125087423  aurora kinase B isoform X1 [KO:K11479] [EC:2.7.11.1]
125104929  LOW QUALITY PROTEIN: shugoshin 1-like [KO:K11580]
125100552  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
125092347  serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
125080841  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
125078654  LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform-like [KO:K03456]
125088881  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
125102373  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
125078767  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
125086066  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
125104126  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
125104827  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
125082462  kinetochore protein NDC80 homolog [KO:K11547]
125104859  kinetochore scaffold 1-like [KO:K11542]
125102783  dual specificity protein kinase TTK isoform X1 [KO:K08866] [EC:2.7.12.1]
125090585  mitotic spindle assembly checkpoint protein MAD1 isoform X1 [KO:K06679]
125093334  mitotic spindle assembly checkpoint protein MAD2A [KO:K02537]
125098032  mitotic spindle assembly checkpoint protein MAD2B isoform X1 [KO:K13728]
125105161  mitotic checkpoint serine/threonine-protein kinase BUB1 beta [KO:K06637] [EC:2.7.11.1]
125084908  mitotic checkpoint protein BUB3 isoform X1 [KO:K02180]
125079977  mitotic checkpoint protein BUB3-like [KO:K02180]
125109313  mitotic checkpoint serine/threonine-protein kinase BUB1-like [KO:K02178] [EC:2.7.11.1]
125099662  pachytene checkpoint protein 2 homolog [KO:K22399]
125102300  MAD2L1-binding protein [KO:K26093]
125086840  fizzy-related protein homolog isoform X1 [KO:K03364]
125101964  F-box only protein 5-like [KO:K10292]
125083349  dual specificity protein phosphatase CDC14B isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
125097774  dual specificity protein phosphatase CDC14A isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
125091150  CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
125106189  histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
125096736  DNA-dependent protein kinase catalytic subunit isoform X1 [KO:K06642] [EC:2.7.11.1]
125098230  serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:2.7.11.1]
125078433  serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
125107551  E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
125087037  cellular tumor antigen p53 isoform X1 [KO:K04451]
125084011  growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
125087160  growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
125098822  growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
125108355  proliferating cell nuclear antigen [KO:K04802]
125097227  14-3-3 protein sigma [KO:K06644]
125110264  serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
125081641  serine/threonine-protein kinase Chk2 isoform X1 [KO:K06641] [EC:2.7.11.1]
125080840  M-phase inducer phosphatase 1 isoform X1 [KO:K06645] [EC:3.1.3.48]
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.
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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.
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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
llv03030  DNA replication
llv04010  MAPK signaling pathway
llv04120  Ubiquitin mediated proteolysis
llv04210  Apoptosis
KO pathway
ko04110   
LinkDB

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