KEGG   PATHWAY: hhip04110
Entry
hhip04110                   Pathway                                
Name
Cell cycle - Hippoglossus hippoglossus (Atlantic halibut)
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
hhip04110  Cell cycle
hhip04110

Other DBs
GO: 0000278
Organism
Hippoglossus hippoglossus (Atlantic halibut) [GN:hhip]
Gene
117751952  hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
117752035  ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
117752065  tp53; cellular tumor antigen p53 [KO:K04451]
117752253  ppp2r5b; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
117752647  waplb; wings apart-like protein homolog [KO:K25163]
117752742  pkmyt1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [KO:K06633] [EC:2.7.11.1]
117752910  anapc16; anaphase-promoting complex subunit 16 [KO:K25229]
117752984  dbf4b; protein DBF4 homolog B [KO:K06629]
117753048  bub3; mitotic checkpoint protein BUB3 isoform X1 [KO:K02180]
117753189  ep300a; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
117753418  [KO:K04682]
117753552  [KO:K03347]
117753752  ccne1; G1/S-specific cyclin-E1 [KO:K06626]
117754053  myca; transcriptional regulator Myc-A isoform X1 [KO:K04377]
117754282  prkdc; DNA-dependent protein kinase catalytic subunit isoform X1 [KO:K06642] [EC:2.7.11.1]
117754489  cdkn1ca; cyclin-dependent kinase inhibitor 1Ca [KO:K09993]
117754537  si:ch211-269e2.1; cohesin subunit SA-2 isoform X1 [KO:K06671]
117754796  cdc16; cell division cycle protein 16 homolog [KO:K03353]
117754821  [KO:K11580]
117754984  tfdp1a; transcription factor Dp-1a isoform X1 [KO:K04683]
117755469  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
117755596  cdc25b; M-phase inducer phosphatase 2 [KO:K05866] [EC:3.1.3.48]
117755612  stag1a; cohesin subunit SA-1a [KO:K06671]
117755691  [KO:K04402]
117755873  [KO:K16197]
117756055  ppp2r5ca; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
117756094  e2f2; transcription factor E2F2 isoform X1 [KO:K09389]
117756153  orc3; origin recognition complex subunit 3 isoform X1 [KO:K02605]
117756333  smad3a; mothers against decapentaplegic homolog 3a [KO:K23605]
117756595  [KO:K06067] [EC:3.5.1.98]
117756622  bub1bb; mitotic checkpoint serine/threonine-protein kinase BUB1 beta [KO:K06637] [EC:2.7.11.1]
117756644  tgfb3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
117756651  atr; serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:2.7.11.1]
117756719  ppp2r5eb; protein phosphatase 2, regulatory subunit B', epsilon [KO:K11584]
117756987  cdkn1ba; cyclin-dependent kinase inhibitor 1Ba [KO:K06624]
117757032  mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:2.3.2.27]
117757187  orc5; origin recognition complex subunit 5 [KO:K02607]
117757192  [KO:K10151]
117757274  cdkn1d; cyclin-dependent kinase inhibitor 1D [KO:K06625]
117758032  esco2; N-acetyltransferase ESCO2 [KO:K11268] [EC:2.3.1.-]
117758206  [KO:K06067] [EC:3.5.1.98]
117758213  ppp2r5a; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
117758325  ppp2r5cb; protein phosphatase 2, regulatory subunit B', gamma b isoform X1 [KO:K11584]
117758433  knl1; uncharacterized protein knl1 isoform X1 [KO:K11542]
117758509  mcm3; DNA replication licensing factor MCM3 [KO:K02541] [EC:5.6.2.3]
117758516  [KO:K13377]
117758790  bub1; mitotic checkpoint serine/threonine-protein kinase BUB1 [KO:K02178] [EC:2.7.11.1]
117759437  ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
117759618  [KO:K04681]
117759694  anapc11; anaphase-promoting complex subunit 11 [KO:K03358]
117759833  cdc14ab; LOW QUALITY PROTEIN: dual specificity protein phosphatase CDC14AB [KO:K06639] [EC:3.1.3.16 3.1.3.48]
117759869  anapc4; anaphase-promoting complex subunit 4 [KO:K03351]
117760254  cdkn2c; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
117760361  [KO:K11266]
117760470  orc1; origin recognition complex subunit 1 isoform X1 [KO:K02603]
117760516  [KO:K03364]
117760569  gadd45ab; growth arrest and DNA-damage-inducible, alpha, b [KO:K04402]
117760651  [KO:K04402]
117761231  ccnd3; LOW QUALITY PROTEIN: G1/S-specific cyclin-D3 [KO:K10152]
117761251  ywhaba; 14-3-3 protein beta/alpha-A [KO:K16197]
117761398  crebbpa; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
117761425  cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
117761550  mcm2; DNA replication licensing factor MCM2 [KO:K02540] [EC:5.6.2.3]
117761588  mych; myelocytomatosis oncogene homolog [KO:K04377]
117761594  cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
117761629  pds5a; sister chromatid cohesion protein PDS5 homolog A isoform X1 [KO:K11267]
117761857  cdkn1a; cyclin-dependent kinase inhibitor 1 isoform X1 [KO:K06625]
117761872  espl1; separin [KO:K02365] [EC:3.4.22.49]
117762217  rbl1; retinoblastoma-like protein 1 [KO:K04681]
117762639  rbl2; retinoblastoma-like protein 2 isoform X1 [KO:K16332]
117762712  ddx11; ATP-dependent DNA helicase DDX11 isoform X1 [KO:K11273] [EC:5.6.2.7]
117762757  [KO:K04503]
117762777  e2f4; transcription factor E2F4 [KO:K04682]
117762828  cdkn1bb; cyclin-dependent kinase inhibitor 1Bb [KO:K06624]
117762856  smc1b; structural maintenance of chromosomes protein 1B isoform X1 [KO:K06636]
117763257  wee2; wee1-like protein kinase 2 isoform X1 [KO:K06632] [EC:2.7.11.1]
117763402  wee1; wee1-like protein kinase [KO:K06632] [EC:2.7.11.1]
117763466  smad3b; mothers against decapentaplegic homolog 3b [KO:K23605]
117763553  cdkn1cb; cyclin-dependent kinase inhibitor 1C [KO:K09993]
117763644  ticrr; treslin [KO:K26117]
117763749  ccnd2a; G1/S-specific cyclin-D2a isoform X1 [KO:K10151]
117763771  anapc13; anaphase-promoting complex subunit 13 [KO:K12456]
117764007  cdc6; cell division control protein 6 homolog [KO:K02213]
117764084  rad21l1; double-strand-break repair protein rad21-like protein 1 [KO:K06670]
117764408  [KO:K16197]
117764461  mad2l2; mitotic spindle assembly checkpoint protein MAD2B isoform X1 [KO:K13728]
117764691  smc1a; structural maintenance of chromosomes protein 1A [KO:K06636]
117764782  zbtb17; zinc finger and BTB domain-containing protein 17 isoform X1 [KO:K10500]
117765303  e2f1; transcription factor E2F1 [KO:K17454]
117765838  cdkn2a/b; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
117765976  anapc2; anaphase-promoting complex subunit 2 [KO:K03349]
117766128  cdc27; cell division cycle protein 27 homolog isoform X1 [KO:K03350]
117766184  mcm5; DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
117766207  ep300b; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
117766292  rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
117766356  ccndx; cyclin Dx [KO:K10151]
117766770  cdkn2d; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
117766859  crebbpb; CREB binding protein b isoform X1 [KO:K04498] [EC:2.3.1.48]
117767048  cdk21; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
117767268  cdk7; cyclin-dependent kinase 7 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
117767308  [KO:K04501]
117767363  [KO:K03363]
117767590  cdc45; cell division control protein 45 homolog [KO:K06628]
117767744  [KO:K06641] [EC:2.7.11.1]
117767746  [KO:K06641] [EC:2.7.11.1]
117767782  [KO:K04500]
117767785  ccnh; cyclin-H [KO:K06634]
117768017  pcna; proliferating cell nuclear antigen [KO:K04802]
117768172  nipbla; nipped-B-like protein A isoform X1 [KO:K06672]
117768196  anapc7; anaphase-promoting complex subunit 7 [KO:K03354]
117768221  gadd45ga; growth arrest and DNA-damage-inducible, gamma a [KO:K04402]
117768224  anapc5; anaphase-promoting complex subunit 5 [KO:K03352]
117768335  cdc14b; dual specificity protein phosphatase CDC14B isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
117768386  [KO:K04382] [EC:3.1.3.16]
117768402  ndc80; kinetochore protein NDC80 homolog [KO:K11547]
117768828  stag2b; cohesin subunit SA-2 [KO:K06671]
117768831  mcm7; DNA replication licensing factor MCM7 isoform X1 [KO:K02210] [EC:5.6.2.3]
117768834  aurkb; aurora kinase B isoform X1 [KO:K11479] [EC:2.7.11.1]
117769078  atrx; transcriptional regulator ATRX isoform X1 [KO:K10779]
117769176  pttg1; securin [KO:K06635]
117769402  [KO:K04382] [EC:3.1.3.16]
117769453  [KO:K06671]
117769532  smc3; structural maintenance of chromosomes protein 3 [KO:K06669]
117769581  ccna2; cyclin-A2 [KO:K06627]
117769623  tgfb5; transforming growth factor beta-2 proprotein [KO:K13376]
117770083  [KO:K06670]
117770209  e2f3; transcription factor E2F3 isoform X1 [KO:K06620]
117770325  [KO:K16197]
117770331  mad1l1; mitotic spindle assembly checkpoint protein MAD1 [KO:K06679]
117770363  cdca5; sororin [KO:K17390]
117770384  plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
117770418  hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
117770461  cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
117770624  sgo1; shugoshin 1 isoform X1 [KO:K11580]
117770976  [KO:K06626]
117771112  si:dkey-222b8.1; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
117771273  abl1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
117771392  cdc26; anaphase-promoting complex subunit CDC26 [KO:K03359]
117771425  skp2; S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
117771484  smad4a; mothers against decapentaplegic homolog 4a [KO:K04501]
117771671  ccnb1; G2/mitotic-specific cyclin-B1 isoform X1 [KO:K05868]
117771721  smad2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
117771744  [KO:K06672]
117772062  [KO:K04402]
117772065  [KO:K04402]
117772338  ccnp; cyclin N-terminal domain-containing protein 2 isoform X1 [KO:K21770]
117772384  tgfb1a; transforming growth factor, beta 1a isoform X1 [KO:K13375]
117772410  ywhag2; 14-3-3 protein gamma-2 [KO:K16198]
117772557  ywhae1; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide 1 isoform X1 [KO:K06630]
117772580  atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
117772748  anapc15; anaphase-promoting complex subunit 15 [KO:K25228]
117772763  ppp2r1bb; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
117773951  [KO:K10779]
117774111  ywhag1; 14-3-3 protein gamma-1 [KO:K16198]
117774152  stag2a; cohesin subunit SA-2a isoform X1 [KO:K06671]
117774183  chek1; serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
117774290  skp1; S-phase kinase-associated protein 1 [KO:K03094]
117774431  ccna1; cyclin-A1 [KO:K06627]
117774459  ppp2cab; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
117774464  rb1; retinoblastoma-associated protein [KO:K06618]
117774551  [KO:K06630]
117774911  cdc23; cell division cycle protein 23 homolog [KO:K03355]
117774930  pds5b; sister chromatid cohesion protein PDS5 homolog B isoform X1 [KO:K11267]
117775168  fbxo5; F-box only protein 5 [KO:K10292]
117775173  mad2l1bp; MAD2L1-binding protein [KO:K26093]
117775442  wapla; wings apart-like protein homolog [KO:K25163]
117775734  ppp2r5d; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
117775896  cdt1; DNA replication factor Cdt1 [KO:K10727]
117775916  cdk1; cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
117776032  anapc1; anaphase-promoting complex subunit 1 [KO:K03348]
117776165  orc4; origin recognition complex subunit 4 isoform X1 [KO:K02606]
117776374  ccne2; G1/S-specific cyclin-E2 [KO:K06626]
117776434  trip13; pachytene checkpoint protein 2 homolog [KO:K22399]
117776502  [KO:K06670]
117776532  [KO:K16197]
117776628  [KO:K04501]
117776902  ttk; dual specificity protein kinase Ttk isoform X1 [KO:K08866] [EC:2.7.12.1]
117777073  mtbp; mdm2-binding protein [KO:K26116]
117777108  tgfb2; transforming growth factor beta-2 proprotein [KO:K13376]
117777132  [KO:K06620]
117777484  dbf4; protein DBF4 homolog A isoform X1 [KO:K06629]
117777680  [KO:K03364]
117778022  mcm4; DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
117778049  fzr1b; fizzy-related protein homolog [KO:K03364]
117778247  cdc7; cell division cycle 7-related protein kinase isoform X1 [KO:K02214] [EC:2.7.11.1]
117778472  mau2; MAU2 chromatid cohesion factor homolog isoform X1 [KO:K11266]
117778646  mcm6; LOW QUALITY PROTEIN: DNA replication licensing factor MCM6 [KO:K02542] [EC:5.6.2.3]
117778664  gadd45aa; growth arrest and DNA-damage-inducible, alpha, a [KO:K04402]
117778681  e2f5; transcription factor E2F5 [KO:K04682]
117778701  cdc20; cell division cycle protein 20 homolog [KO:K03363]
117778953  orc2; origin recognition complex subunit 2 [KO:K02604]
117779200  mad2l1; mitotic spindle assembly checkpoint protein MAD2A [KO:K02537]
117779239  anapc10; anaphase-promoting complex subunit 10 isoform X1 [KO:K03357]
Reference
PMID:7908906
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Matsuoka S, Yamaguchi M, Matsukage A
  Title
D-type cyclin-binding regions of proliferating cell nuclear antigen.
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J Biol Chem 269:11030-6 (1994)
Reference
PMID:8242749
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Welch PJ, Wang JY
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A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle.
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Cell 75:779-90 (1993)
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Reference
PMID:16936746
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Macaluso M, Montanari M, Giordano A
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Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes.
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Oncogene 25:5263-7 (2006)
DOI:10.1038/sj.onc.1209680
Reference
PMID:15838516
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Cobrinik D
  Title
Pocket proteins and cell cycle control.
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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?
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Nat Rev Cancer 7:495-507 (2007)
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Reference
PMID:9832503
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Diehl JA, Cheng M, Roussel MF, Sherr CJ
  Title
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
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Genes Dev 12:3499-511 (1998)
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Reference
PMID:19020303
  Authors
Klein EA, Assoian RK
  Title
Transcriptional regulation of the cyclin D1 gene at a glance.
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J Cell Sci 121:3853-7 (2008)
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Reference
PMID:10385618
  Authors
Sherr CJ, Roberts JM
  Title
CDK inhibitors: positive and negative regulators of G1-phase progression.
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Genes Dev 13:1501-12 (1999)
DOI:10.1101/gad.13.12.1501
Reference
PMID:12809600
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Shi Y, Massague J.
  Title
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
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Cell 113:685-700 (2003)
DOI:10.1016/S0092-8674(03)00432-X
Reference
PMID:12925736
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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.
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Proc Natl Acad Sci U S A 100:10231-6 (2003)
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Reference
PMID:16212951
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Bond M, Sala-Newby GB, Wu YJ, Newby AC
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Biphasic effect of p21Cip1 on smooth muscle cell proliferation: role of PI 3-kinase and Skp2-mediated degradation.
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Cardiovasc Res 69:198-206 (2006)
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Reference
PMID:15838523
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Harris SL, Levine AJ.
  Title
The p53 pathway: positive and negative feedback loops.
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Oncogene 24:2899-908 (2005)
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Reference
PMID:11099028
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Vogelstein B, Lane D, Levine AJ
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Surfing the p53 network.
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Nature 408:307-10 (2000)
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PMID:7973727
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Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ Jr
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Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.
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Science 266:1376-80 (1994)
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Reference
PMID:9889196
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Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
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EMBO J 18:396-410 (1999)
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Reference
PMID:17018296
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Sheu YJ, Stillman B
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Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression.
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Mol Cell 24:101-13 (2006)
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Reference
PMID:9029154
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Martinez AM, Afshar M, Martin F, Cavadore JC, Labbe JC, Doree M
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Dual phosphorylation of the T-loop in cdk7: its role in controlling cyclin H binding and CAK activity.
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EMBO J 16:343-54 (1997)
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Reference
PMID:15876871
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  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)
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Reference
PMID:17426725
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Musacchio A, Salmon ED
  Title
The spindle-assembly checkpoint in space and time.
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Nat Rev Mol Cell Biol 8:379-93 (2007)
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Reference
PMID:12573239
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Uhlmann F
  Title
Chromosome cohesion and separation: from men and molecules.
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Curr Biol 13:R104-14 (2003)
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Reference
PMID:15568976
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Stegmeier F, Amon A
  Title
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation.
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Annu Rev Genet 38:203-32 (2004)
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Reference
PMID:9618481
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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.
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Proc Natl Acad Sci U S A 95:6733-8 (1998)
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Reference
PMID:26650195
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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
hhip03030  DNA replication
hhip04010  MAPK signaling pathway
hhip04120  Ubiquitin mediated proteolysis
hhip04210  Apoptosis
KO pathway
ko04110   

DBGET integrated database retrieval system