KEGG   PATHWAY: uah04110
Entry
uah04110                    Pathway                                
Name
Cell cycle - Ursus arctos (brown bear)
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
uah04110  Cell cycle
uah04110

Other DBs
GO: 0000278
Organism
Ursus arctos (brown bear) [GN:uah]
Gene
113240795  [KO:K06671]
113240893  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
113241451  CUL1; cullin-1 [KO:K03347]
113241737  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
113241739  RBX1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
113241920  KNL1; kinetochore scaffold 1 [KO:K11542]
113242041  BUB1B; mitotic checkpoint serine/threonine-protein kinase BUB1 beta isoform X2 [KO:K06637] [EC:2.7.11.1]
113242142  ATRX; transcriptional regulator ATRX isoform X1 [KO:K10779]
113242268  BUB1; mitotic checkpoint serine/threonine-protein kinase BUB1 [KO:K02178] [EC:2.7.11.1]
113242372  ANAPC1; anaphase-promoting complex subunit 1 isoform X1 [KO:K03348]
113242768  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
113242785  [KO:K16197]
113242800  FZR1; fizzy-related protein homolog isoform X1 [KO:K03364]
113242994  CDKN2D; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
113243540  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
113243966  CDKN1C; cyclin-dependent kinase inhibitor 1C [KO:K09993]
113243982  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
113244138  CDCA5; sororin [KO:K17390]
113244148  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
113244499  ANAPC11; anaphase-promoting complex subunit 11 [KO:K03358]
113244704  CCNE1; G1/S-specific cyclin-E1 [KO:K06626]
113244997  CHEK2; serine/threonine-protein kinase Chk2 isoform X2 [KO:K06641] [EC:2.7.11.1]
113245070  YWHAH; 14-3-3 protein eta [KO:K16198]
113245420  PKMYT1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase isoform X2 [KO:K06633] [EC:2.7.11.1]
113245775  WEE1; wee1-like protein kinase isoform X1 [KO:K06632] [EC:2.7.11.1]
113245973  CDC45; cell division control protein 45 homolog isoform X1 [KO:K06628]
113246356  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
113247257  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform isoform X1 [KO:K03456]
113247516  SMC1A; structural maintenance of chromosomes protein 1A isoform X2 [KO:K06636]
113247562  CDC16; cell division cycle protein 16 homolog isoform X2 [KO:K03353]
113247569  TFDP1; transcription factor Dp-1 [KO:K04683]
113247728  MAD1L1; mitotic spindle assembly checkpoint protein MAD1 [KO:K06679]
113248437  ANAPC2; anaphase-promoting complex subunit 2 [KO:K03349]
113250599  ORC2; origin recognition complex subunit 2 [KO:K02604]
113250907  ORC4; origin recognition complex subunit 4 isoform X1 [KO:K02606]
113251247  PDS5B; sister chromatid cohesion protein PDS5 homolog B isoform X1 [KO:K11267]
113251259  CCNA1; cyclin-A1 [KO:K06627]
113251325  RB1; retinoblastoma-associated protein [KO:K06618]
113251924  SMC3; structural maintenance of chromosomes protein 3 isoform X1 [KO:K06669]
113251972  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
113252025  BUB3; mitotic checkpoint protein BUB3 isoform X2 [KO:K02180]
113252201  ORC6; origin recognition complex subunit 6 isoform X2 [KO:K02608]
113252236  RBL2; retinoblastoma-like protein 2 isoform X1 [KO:K16332]
113252353  E2F4; transcription factor E2F4 [KO:K04682]
113252726  MYC; myc proto-oncogene protein [KO:K04377]
113252769  MTBP; mdm2-binding protein isoform X1 [KO:K26116]
113252796  RAD21; double-strand-break repair protein rad21 homolog [KO:K06670]
113252869  YWHAZ; 14-3-3 protein zeta/delta [KO:K16197]
113252919  CCNE2; G1/S-specific cyclin-E2 [KO:K06626]
113252989  E2F5; transcription factor E2F5 isoform X1 [KO:K04682]
113253256  NDC80; kinetochore protein NDC80 homolog [KO:K11547]
113253270  ESCO1; N-acetyltransferase ESCO1 isoform X1 [KO:K11268] [EC:2.3.1.-]
113253394  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
113253422  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
113253885  SGO1; shugoshin 1 [KO:K11580]
113253961  ANAPC13; anaphase-promoting complex subunit 13 [KO:K12456]
113253968  STAG1; cohesin subunit SA-1 isoform X2 [KO:K06671]
113254014  TFDP2; transcription factor Dp-2 isoform X1 [KO:K09392]
113254017  ATR; serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:2.7.11.1]
113254350  CDC14A; dual specificity protein phosphatase CDC14A isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
113254416  CDC7; cell division cycle 7-related protein kinase isoform X1 [KO:K02214] [EC:2.7.11.1]
113254548  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
113254668  ORC1; origin recognition complex subunit 1 [KO:K02603]
113254692  CDKN2C; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
113254788  CDC20; cell division cycle protein 20 homolog [KO:K03363]
113255129  CCNH; cyclin-H isoform X2 [KO:K06634]
113255256  CDK7; cyclin-dependent kinase 7 isoform X3 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
113255260  CCNB1; G2/mitotic-specific cyclin-B1 [KO:K05868]
113255618  MAD2L1; mitotic spindle assembly checkpoint protein MAD2A [KO:K02537]
113255629  CCNA2; cyclin-A2 [KO:K06627]
113255720  ANAPC10; anaphase-promoting complex subunit 10 isoform X1 [KO:K03357]
113256007  MCM5; DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
113256295  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
113256363  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
113256451  CDK2; cyclin-dependent kinase 2 isoform X1 [KO:K02206] [EC:2.7.11.22]
113256753  MAU2; MAU2 chromatid cohesion factor homolog isoform X1 [KO:K11266]
113256823  CDC25A; M-phase inducer phosphatase 1 isoform X1 [KO:K06645] [EC:3.1.3.48]
113257273  MCM2; DNA replication licensing factor MCM2 [KO:K02540] [EC:5.6.2.3]
113257870  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
113258003  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
113258026  DDX11; ATP-dependent DNA helicase DDX11 isoform X1 [KO:K11273] [EC:5.6.2.7]
113258272  E2F1; transcription factor E2F1 isoform X2 [KO:K17454]
113258365  PCNA; proliferating cell nuclear antigen [KO:K04802]
113258383  CDC25B; M-phase inducer phosphatase 2 isoform X2 [KO:K05866] [EC:3.1.3.48]
113258573  RBL1; retinoblastoma-like protein 1 isoform X1 [KO:K04681]
113258642  YWHAB; 14-3-3 protein beta/alpha [KO:K16197]
113258845  ORC5; origin recognition complex subunit 5 isoform X4 [KO:K02607]
113259076  CDK1; cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
113259158  ANAPC16; anaphase-promoting complex subunit 16 [KO:K25229]
113259244  WAPL; wings apart-like protein homolog isoform X1 [KO:K25163]
113259531  DBF4; protein DBF4 homolog A isoform X1 [KO:K06629]
113259573  FBXO5; F-box only protein 5 [KO:K10292]
113259903  CHEK1; serine/threonine-protein kinase Chk1 isoform X4 [KO:K02216] [EC:2.7.11.1]
113259981  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
113260072  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
113260096  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
113260574  CDKN2B; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
113260575  [KO:K06621]
113260782  TRIP13; pachytene checkpoint protein 2 homolog [KO:K22399]
113260895  SKP2; S-phase kinase-associated protein 2 [KO:K03875]
113260899  NIPBL; nipped-B-like protein isoform X1 [KO:K06672]
113261080  TTK; dual specificity protein kinase TTK isoform X2 [KO:K08866] [EC:2.7.12.1]
113261196  MCM3; DNA replication licensing factor MCM3 [KO:K02541] [EC:5.6.2.3]
113261255  MAD2L1BP; MAD2L1-binding protein [KO:K26093]
113261281  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
113261302  CCND3; G1/S-specific cyclin-D3 isoform X1 [KO:K10152]
113261495  CDC25C; M-phase inducer phosphatase 3 isoform X1 [KO:K05867] [EC:3.1.3.48]
113261736  SKP1; S-phase kinase-associated protein 1 isoform X2 [KO:K03094]
113261737  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
113261783  CDC23; cell division cycle protein 23 homolog [KO:K03355]
113262137  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
113262428  PDS5A; sister chromatid cohesion protein PDS5 homolog A isoform X1 [KO:K11267]
113262671  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform isoform X1 [KO:K11584]
113263419  MCM6; DNA replication licensing factor MCM6 [KO:K02542] [EC:5.6.2.3]
113263689  TICRR; treslin [KO:K26117]
113264047  PTTG1; securin isoform X1 [KO:K06635]
113264513  E2F3; transcription factor E2F3 isoform X2 [KO:K06620]
113264707  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
113264840  ORC3; origin recognition complex subunit 3 isoform X1 [KO:K02605]
113265245  WEE2; wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
113265311  CDC27; cell division cycle protein 27 homolog isoform X1 [KO:K03350]
113265346  DBF4B; protein DBF4 homolog B [KO:K06629]
113265490  CDC6; cell division control protein 6 homolog [KO:K02213]
113265961  CCNB3; G2/mitotic-specific cyclin-B3 [KO:K21771]
113266311  CDC26; anaphase-promoting complex subunit CDC26 [KO:K03359]
113266525  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
113266758  ANAPC4; anaphase-promoting complex subunit 4 isoform X2 [KO:K03351]
113266948  ANAPC5; anaphase-promoting complex subunit 5 isoform X1 [KO:K03352]
113266956  ANAPC7; anaphase-promoting complex subunit 7 isoform X1 [KO:K03354]
113267251  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X2 [KO:K11584]
113267582  PLK1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
113267814  YWHAG; 14-3-3 protein gamma [KO:K16198]
113267879  MCM7; DNA replication licensing factor MCM7 isoform X1 [KO:K02210] [EC:5.6.2.3]
113268118  MCM4; DNA replication licensing factor MCM4 isoform X2 [KO:K02212] [EC:5.6.2.3]
113268119  PRKDC; DNA-dependent protein kinase catalytic subunit isoform X2 [KO:K06642] [EC:2.7.11.1]
113268357  HDAC1; histone deacetylase 1 isoform X2 [KO:K06067] [EC:3.5.1.98]
113268452  SFN; 14-3-3 protein sigma [KO:K06644]
113268523  E2F2; transcription factor E2F2 [KO:K09389]
113268733  TGFB2; transforming growth factor beta-2 proprotein isoform X2 [KO:K13376]
113269111  YWHAE; 14-3-3 protein epsilon isoform X1 [KO:K06630]
113269268  ANAPC15; anaphase-promoting complex subunit 15 isoform X1 [KO:K25228]
113269684  CCNB2; G2/mitotic-specific cyclin-B2 isoform X1 [KO:K21770]
113269739  YWHAQ; 14-3-3 protein theta [KO:K16197]
113269770  CDC14B; dual specificity protein phosphatase CDC14B isoform X5 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
113269952  ESCO2; N-acetyltransferase ESCO2 [KO:K11268] [EC:2.3.1.-]
113270128  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
113270312  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
113270465  ZBTB17; zinc finger and BTB domain-containing protein 17 isoform X1 [KO:K10500]
113270506  MAD2L2; mitotic spindle assembly checkpoint protein MAD2B [KO:K13728]
113270858  CREBBP; CREB-binding protein isoform X3 [KO:K04498] [EC:2.3.1.48]
113270930  STAG2; cohesin subunit SA-2 isoform X1 [KO:K06671]
113271152  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
113271177  AURKB; aurora kinase B isoform X1 [KO:K11479] [EC:2.7.11.1]
123000788  CDT1; DNA replication factor Cdt1 [KO:K10727]
125281562  [KO:K25163]
130544383  [KO:K06671]
Reference
PMID:7908906
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Matsuoka S, Yamaguchi M, Matsukage A
  Title
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J Biol Chem 269:11030-6 (1994)
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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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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)
DOI:10.1038/nrc2169
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
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Klein EA, Assoian RK
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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
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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.
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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
  Authors
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.
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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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Reference
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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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?
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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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  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
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  Title
Controlling the response to DNA damage by the APC/C-Cdh1.
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Cell Mol Life Sci 73:949-60 (2016)
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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
uah03030  DNA replication
uah04010  MAPK signaling pathway
uah04120  Ubiquitin mediated proteolysis
uah04210  Apoptosis
KO pathway
ko04110   

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