KEGG   PATHWAY: aml04110
Entry
aml04110                    Pathway                                
Name
Cell cycle - Ailuropoda melanoleuca (giant panda)
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
aml04110  Cell cycle
aml04110

Other DBs
GO: 0000278
Organism
Ailuropoda melanoleuca (giant panda) [GN:aml]
Gene
100469787  CCND1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
100471517  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
100479467  CCND3; G1/S-specific cyclin-D3 isoform X4 [KO:K10152]
100481236  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
100476389  CDK6; cyclin-dependent kinase 6 isoform X2 [KO:K02091] [EC:2.7.11.22]
100477714  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
100478297  RBL1; retinoblastoma-like protein 1 isoform X1 [KO:K04681]
100463875  RBL2; retinoblastoma-like protein 2 isoform X1 [KO:K16332]
100466468  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
100477725  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
100478424  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
117795744  E2F1; transcription factor E2F1 [KO:K17454]
100475779  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
100484544  E2F3; transcription factor E2F3 [KO:K06620]
100472101  E2F4; transcription factor E2F4 [KO:K04682]
100477707  E2F5; transcription factor E2F5 [KO:K04682]
100480013  TFDP1; transcription factor Dp-1 [KO:K04683]
100464401  TFDP2; transcription factor Dp-2 isoform X2 [KO:K09392]
100479224  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100470703  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
100463584  TGFB2; transforming growth factor beta-2 proprotein isoform X2 [KO:K13376]
100475861  TGFB3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
100467069  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100479304  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
100465063  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
100464396  MYC; myc proto-oncogene protein [KO:K04377]
100482510  ZBTB17; zinc finger and BTB domain-containing protein 17 [KO:K10500]
100472171  cyclin-dependent kinase inhibitor 2A isoform X3 [KO:K06621]
100473431  cyclin-dependent kinase 4 inhibitor B [KO:K04685]
100470950  CDKN2C; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
100467420  CDKN2D; cyclin-dependent kinase 4 inhibitor D isoform X2 [KO:K06623]
100467824  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100467238  CDKN1C; cyclin-dependent kinase inhibitor 1C isoform X1 [KO:K09993]
100484923  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100471009  CCNE1; G1/S-specific cyclin-E1 [KO:K06626]
100483627  CCNE2; G1/S-specific cyclin-E2 isoform X1 [KO:K06626]
100468314  CDK2; cyclin-dependent kinase 2 isoform X2 [KO:K02206] [EC:2.7.11.22]
100463880  SKP1; S-phase kinase-associated protein 1 [KO:K03094]
100466596  CUL1; cullin-1 isoform X1 [KO:K03347]
100480437  SKP2; S-phase kinase-associated protein 2 [KO:K03875]
100482271  CCNA2; cyclin-A2 [KO:K06627]
100475180  CCNA1; cyclin-A1 [KO:K06627]
100484881  CDC6; cell division control protein 6 homolog isoform X1 [KO:K02213]
100480032  CDT1; DNA replication factor Cdt1 [KO:K10727]
100483738  ORC1; origin recognition complex subunit 1 [KO:K02603]
100472089  ORC2; origin recognition complex subunit 2 [KO:K02604]
100484796  ORC3; origin recognition complex subunit 3 isoform X1 [KO:K02605]
100471280  ORC4; origin recognition complex subunit 4 isoform X2 [KO:K02606]
100464020  ORC5; origin recognition complex subunit 5 [KO:K02607]
100466300  ORC6; origin recognition complex subunit 6 isoform X2 [KO:K02608]
100481582  MCM2; DNA replication licensing factor MCM2 isoform X1 [KO:K02540] [EC:5.6.2.3]
100483243  MCM3; DNA replication licensing factor MCM3 [KO:K02541] [EC:5.6.2.3]
100483038  MCM4; DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
100477923  MCM5; DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
100484404  MCM6; LOW QUALITY PROTEIN: DNA replication licensing factor MCM6 [KO:K02542] [EC:5.6.2.3]
100481298  MCM7; DNA replication licensing factor MCM7 isoform X1 [KO:K02210] [EC:5.6.2.3]
100473186  CDC45; cell division control protein 45 homolog [KO:K06628]
100476642  TICRR; treslin [KO:K26117]
100467259  MTBP; mdm2-binding protein isoform X1 [KO:K26116]
100482872  CDC7; cell division cycle 7-related protein kinase isoform X1 [KO:K02214] [EC:2.7.11.1]
100476446  DBF4; protein DBF4 homolog A isoform X1 [KO:K06629]
100469754  DBF4B; protein DBF4 homolog B [KO:K06629]
100480564  CDK1; cyclin-dependent kinase 1 isoform X2 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
100484338  CCNB1; G2/mitotic-specific cyclin-B1 [KO:K05868]
100475507  CCNB2; G2/mitotic-specific cyclin-B2 isoform X1 [KO:K21770]
100476957  CCNB3; G2/mitotic-specific cyclin-B3 isoform X2 [KO:K21771]
100483177  CDC25B; LOW QUALITY PROTEIN: M-phase inducer phosphatase 2 [KO:K05866] [EC:3.1.3.48]
100482691  CDC25C; M-phase inducer phosphatase 3 isoform X1 [KO:K05867] [EC:3.1.3.48]
100484483  YWHAZ; 14-3-3 protein zeta/delta [KO:K16197]
100466234  YWHAB; 14-3-3 protein beta/alpha [KO:K16197]
100483021  YWHAQ; 14-3-3 protein theta [KO:K16197]
100484851  YWHAE; 14-3-3 protein epsilon isoform X2 [KO:K06630]
100464004  YWHAG; 14-3-3 protein gamma [KO:K16198]
100467650  YWHAH; 14-3-3 protein eta isoform X1 [KO:K16198]
100478763  PLK1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
100468598  WEE2; wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
100479065  WEE1; wee1-like protein kinase [KO:K06632] [EC:2.7.11.1]
100475442  PKMYT1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase isoform X1 [KO:K06633] [EC:2.7.11.1]
100465559  CCNH; cyclin-H isoform X2 [KO:K06634]
100463640  CDK7; cyclin-dependent kinase 7 isoform X2 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
100474475  ANAPC1; anaphase-promoting complex subunit 1 isoform X1 [KO:K03348]
100471139  ANAPC2; anaphase-promoting complex subunit 2 [KO:K03349]
100476006  CDC27; cell division cycle protein 27 homolog isoform X3 [KO:K03350]
100480006  ANAPC4; anaphase-promoting complex subunit 4 [KO:K03351]
100466383  ANAPC5; anaphase-promoting complex subunit 5 isoform X1 [KO:K03352]
100478508  CDC16; cell division cycle protein 16 homolog isoform X3 [KO:K03353]
100477024  ANAPC7; anaphase-promoting complex subunit 7 isoform X1 [KO:K03354]
100482442  CDC23; cell division cycle protein 23 homolog [KO:K03355]
100477128  ANAPC10; anaphase-promoting complex subunit 10 isoform X1 [KO:K03357]
100479297  ANAPC11; anaphase-promoting complex subunit 11 [KO:K03358]
100476624  CDC26; anaphase-promoting complex subunit CDC26 [KO:K03359]
100465022  ANAPC13; anaphase-promoting complex subunit 13 [KO:K12456]
100473315  ANAPC15; anaphase-promoting complex subunit 15 isoform X1 [KO:K25228]
100466282  ANAPC16; anaphase-promoting complex subunit 16 [KO:K25229]
100473900  CDC20; cell division cycle protein 20 homolog [KO:K03363]
100479295  PTTG1; securin isoform X1 [KO:K06635]
100467596  ESPL1; separin [KO:K02365] [EC:3.4.22.49]
100473647  SMC1B; structural maintenance of chromosomes protein 1B [KO:K06636]
100483784  SMC1A; structural maintenance of chromosomes protein 1A [KO:K06636]
100469989  SMC3; structural maintenance of chromosomes protein 3 isoform X1 [KO:K06669]
100482392  RAD21; double-strand-break repair protein rad21 homolog [KO:K06670]
100470776  STAG2; cohesin subunit SA-2 isoform X1 [KO:K06671]
100472533  STAG1; cohesin subunit SA-1 isoform X1 [KO:K06671]
105241804  cohesin subunit SA-2-like isoform X4 [KO:K06671]
100466696  ATRX; transcriptional regulator ATRX isoform X3 [KO:K10779]
100482225  DDX11; ATP-dependent DNA helicase DDX11 isoform X2 [KO:K11273] [EC:5.6.2.7]
100479499  NIPBL; nipped-B-like protein isoform X1 [KO:K06672]
100480298  MAU2; MAU2 chromatid cohesion factor homolog isoform X1 [KO:K11266]
100480623  HDAC8; histone deacetylase 8 isoform X8 [KO:K11405] [EC:3.5.1.98]
100482821  ESCO2; N-acetyltransferase ESCO2 isoform X2 [KO:K11268] [EC:2.3.1.-]
100471473  ESCO1; N-acetyltransferase ESCO1 isoform X1 [KO:K11268] [EC:2.3.1.-]
100465683  PDS5A; sister chromatid cohesion protein PDS5 homolog A [KO:K11267]
100474124  PDS5B; sister chromatid cohesion protein PDS5 homolog B isoform X1 [KO:K11267]
100475548  WAPL; wings apart-like protein homolog isoform X1 [KO:K25163]
100470170  sororin [KO:K17390]
100478843  AURKB; aurora kinase B isoform X2 [KO:K11479] [EC:2.7.11.1]
100481029  SGO1; shugoshin 1 isoform X2 [KO:K11580]
100464293  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
100473021  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
100482129  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
100482604  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
100463538  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
100471672  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
100466685  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
100472488  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
100480070  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
100465936  NDC80; kinetochore protein NDC80 homolog [KO:K11547]
100474010  KNL1; LOW QUALITY PROTEIN: kinetochore scaffold 1 [KO:K11542]
100475792  TTK; dual specificity protein kinase TTK isoform X1 [KO:K08866] [EC:2.7.12.1]
105234697  MAD1L1; mitotic spindle assembly checkpoint protein MAD1 isoform X5 [KO:K06679]
105239272  mitotic spindle assembly checkpoint protein MAD2A isoform X1 [KO:K02537]
100468851  MAD2L2; mitotic spindle assembly checkpoint protein MAD2B isoform X2 [KO:K13728]
100464546  BUB1B; mitotic checkpoint serine/threonine-protein kinase BUB1 beta isoform X3 [KO:K06637] [EC:2.7.11.1]
100469030  BUB3; mitotic checkpoint protein BUB3 isoform X2 [KO:K02180]
100475509  BUB1; mitotic checkpoint serine/threonine-protein kinase BUB1 isoform X2 [KO:K02178] [EC:2.7.11.1]
100484295  TRIP13; pachytene checkpoint protein 2 homolog [KO:K22399]
100473086  MAD2L1BP; MAD2L1-binding protein [KO:K26093]
100475243  FZR1; fizzy-related protein homolog [KO:K03364]
100468703  FBXO5; F-box only protein 5 [KO:K10292]
100477147  CDC14A; dual specificity protein phosphatase CDC14A isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
100473988  CDC14B; dual specificity protein phosphatase CDC14B isoform X8 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
100480008  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
100468694  EP300; LOW QUALITY PROTEIN: histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
100472045  PRKDC; DNA-dependent protein kinase catalytic subunit isoform X1 [KO:K06642] [EC:2.7.11.1]
100464897  ATR; serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:2.7.11.1]
100480638  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
100479481  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:2.3.2.27]
100468516  TP53; cellular tumor antigen p53 [KO:K04451]
100477654  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X1 [KO:K04402]
100482871  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100470600  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100474064  PCNA; proliferating cell nuclear antigen [KO:K04802]
100478201  SFN; 14-3-3 protein sigma [KO:K06644]
100467858  CHEK1; serine/threonine-protein kinase Chk1 isoform X2 [KO:K02216] [EC:2.7.11.1]
100467146  CHEK2; serine/threonine-protein kinase Chk2 [KO:K06641] [EC:2.7.11.1]
100477247  CDC25A; 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.
  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
aml03030  DNA replication
aml04010  MAPK signaling pathway
aml04120  Ubiquitin mediated proteolysis
aml04210  Apoptosis
KO pathway
ko04110   
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