KEGG   PATHWAY: lav04110
Entry
lav04110                    Pathway                                
Name
Cell cycle - Loxodonta africana (African savanna elephant)
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
lav04110  Cell cycle
lav04110

Other DBs
GO: 0000278
Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100669703  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100668070  CCND2; G1/S-specific cyclin-D2 [KO:K10151]
100668683  CCND3; G1/S-specific cyclin-D3 isoform X1 [KO:K10152]
104847103  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
100655429  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
100673196  RB1; retinoblastoma-associated protein [KO:K06618]
100673003  RBL1; retinoblastoma-like protein 1 isoform X1 [KO:K04681]
100660308  RBL2; retinoblastoma-like protein 2 [KO:K16332]
100677152  ABL1; tyrosine-protein kinase ABL1 isoform X1 [KO:K06619] [EC:2.7.10.2]
100673540  HDAC2; LOW QUALITY PROTEIN: histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
100666845  HDAC1; histone deacetylase 1 isoform X2 [KO:K06067] [EC:3.5.1.98]
100664468  E2F1; LOW QUALITY PROTEIN: transcription factor E2F1 [KO:K17454]
100665816  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
100656140  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
100658600  E2F4; transcription factor E2F4 [KO:K04682]
100661991  E2F5; transcription factor E2F5 isoform X1 [KO:K04682]
100658220  TFDP1; transcription factor Dp-1 isoform X2 [KO:K04683]
100655382  TFDP2; transcription factor Dp-2 isoform X5 [KO:K09392]
100675105  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100667634  TGFB1; transforming growth factor beta-1 [KO:K13375]
100656534  TGFB2; transforming growth factor beta-2 isoform X2 [KO:K13376]
100653832  TGFB3; transforming growth factor beta-3 isoform X1 [KO:K13377]
100663495  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100659509  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100665874  MYC; myc proto-oncogene protein [KO:K04377]
100654604  ZBTB17; zinc finger and BTB domain-containing protein 17 isoform X1 [KO:K10500]
104845647  cyclin-dependent kinase inhibitor 2A-like [KO:K06621]
100664726  CDKN2B; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
100669475  CDKN2C; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
100661356  CDKN2D; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
100674125  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100671706  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100668342  CCNE2; G1/S-specific cyclin-E2 isoform X1 [KO:K06626]
100659451  CCNE1; G1/S-specific cyclin-E1 isoform X1 [KO:K06626]
100668134  CDK2; cyclin-dependent kinase 2 isoform X2 [KO:K02206] [EC:2.7.11.22]
100663845  SKP1; S-phase kinase-associated protein 1 [KO:K03094]
100664600  CUL1; cullin-1 [KO:K03347]
100657479  RBX1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
100676976  SKP2; S-phase kinase-associated protein 2 isoform X1 [KO:K03875]
100667107  CCNA1; cyclin-A1 [KO:K06627]
100654979  CCNA2; cyclin-A2 [KO:K06627]
100666475  CDC6; cell division control protein 6 homolog [KO:K02213]
100674179  CDT1; DNA replication factor Cdt1 [KO:K10727]
100654416  ORC1; LOW QUALITY PROTEIN: origin recognition complex subunit 1 [KO:K02603]
100661691  ORC2; origin recognition complex subunit 2 isoform X2 [KO:K02604]
100671809  ORC3; origin recognition complex subunit 3 isoform X4 [KO:K02605]
100658931  ORC4; LOW QUALITY PROTEIN: origin recognition complex subunit 4 [KO:K02606]
100670785  ORC5; LOW QUALITY PROTEIN: origin recognition complex subunit 5 [KO:K02607]
100668093  ORC6; origin recognition complex subunit 6 [KO:K02608]
100671272  MCM2; DNA replication licensing factor MCM2 isoform X2 [KO:K02540] [EC:5.6.2.3]
100672480  MCM3; DNA replication licensing factor MCM3 isoform X1 [KO:K02541] [EC:5.6.2.3]
100667013  MCM4; DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
100673228  MCM5; DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
100661316  MCM6; DNA replication licensing factor MCM6 [KO:K02542] [EC:5.6.2.3]
100656457  MCM7; DNA replication licensing factor MCM7 isoform X2 [KO:K02210] [EC:5.6.2.3]
100668577  CDC45; cell division control protein 45 homolog [KO:K06628]
100663906  TICRR; LOW QUALITY PROTEIN: treslin [KO:K26117]
100661246  MTBP; LOW QUALITY PROTEIN: mdm2-binding protein [KO:K26116]
100671783  CDC7; cell division cycle 7-related protein kinase [KO:K02214] [EC:2.7.11.1]
100661043  DBF4; protein DBF4 homolog A [KO:K06629]
100655281  DBF4B; protein DBF4 homolog B [KO:K06629]
100668529  CDK1; cyclin-dependent kinase 1 isoform X1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
100654684  CCNB1; G2/mitotic-specific cyclin-B1 [KO:K05868]
100659655  CCNB2; G2/mitotic-specific cyclin-B2 [KO:K21770]
100673511  CCNB3; G2/mitotic-specific cyclin-B3 [KO:K21771]
100664658  CDC25B; M-phase inducer phosphatase 2 [KO:K05866] [EC:3.1.3.48]
100670954  CDC25C; M-phase inducer phosphatase 3 [KO:K05867] [EC:3.1.3.48]
100664090  YWHAQ; 14-3-3 protein theta [KO:K16197]
100672224  YWHAZ; 14-3-3 protein zeta/delta [KO:K16197]
100658856  YWHAB; LOW QUALITY PROTEIN: 14-3-3 protein beta/alpha [KO:K16197]
100658987  YWHAE; 14-3-3 protein epsilon isoform X1 [KO:K06630]
100653674  YWHAG; 14-3-3 protein gamma [KO:K16198]
104846772  YWHAH; LOW QUALITY PROTEIN: 14-3-3 protein eta [KO:K16198]
100675411  PLK1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
100676894  WEE1; wee1-like protein kinase [KO:K06632] [EC:2.7.11.1]
100663265  WEE2; wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
100657179  PKMYT1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase isoform X1 [KO:K06633] [EC:2.7.11.1]
100655150  CCNH; cyclin-H [KO:K06634]
100655537  CDK7; cyclin-dependent kinase 7 isoform X1 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
100676448  ANAPC1; anaphase-promoting complex subunit 1 isoform X1 [KO:K03348]
100656382  ANAPC2; anaphase-promoting complex subunit 2 isoform X1 [KO:K03349]
100660117  CDC27; LOW QUALITY PROTEIN: cell division cycle protein 27 homolog [KO:K03350]
100677309  ANAPC5; anaphase-promoting complex subunit 5 [KO:K03352]
100663426  CDC16; cell division cycle protein 16 homolog [KO:K03353]
100654071  ANAPC7; LOW QUALITY PROTEIN: anaphase-promoting complex subunit 7 [KO:K03354]
100670672  CDC23; cell division cycle protein 23 homolog [KO:K03355]
100668375  ANAPC10; anaphase-promoting complex subunit 10 isoform X1 [KO:K03357]
100674745  ANAPC11; anaphase-promoting complex subunit 11 [KO:K03358]
100659806  CDC26; anaphase-promoting complex subunit CDC26 [KO:K03359]
100669891  ANAPC13; anaphase-promoting complex subunit 13 [KO:K12456]
100674848  ANAPC15; anaphase-promoting complex subunit 15 isoform X2 [KO:K25228]
100661424  ANAPC16; anaphase-promoting complex subunit 16 [KO:K25229]
100667610  CDC20; cell division cycle protein 20 homolog isoform X1 [KO:K03363]
100658636  PTTG1; LOW QUALITY PROTEIN: securin [KO:K06635]
100671244  ESPL1; separin isoform X2 [KO:K02365] [EC:3.4.22.49]
100654641  SMC1B; structural maintenance of chromosomes protein 1B [KO:K06636]
100675890  SMC1A; structural maintenance of chromosomes protein 1A isoform X1 [KO:K06636]
100672803  SMC3; structural maintenance of chromosomes protein 3 [KO:K06669]
100659523  RAD21; double-strand-break repair protein rad21 homolog [KO:K06670]
100658226  STAG2; cohesin subunit SA-2 isoform X1 [KO:K06671]
100667629  STAG1; cohesin subunit SA-1 isoform X1 [KO:K06671]
100657543  ATRX; LOW QUALITY PROTEIN: transcriptional regulator ATRX [KO:K10779]
100666740  DDX11; ATP-dependent DNA helicase DDX11 isoform X2 [KO:K11273] [EC:5.6.2.7]
100656482  NIPBL; nipped-B-like protein isoform X1 [KO:K06672]
100675670  MAU2; MAU2 chromatid cohesion factor homolog isoform X3 [KO:K11266]
100662291  HDAC8; histone deacetylase 8 isoform X3 [KO:K11405] [EC:3.5.1.98]
100657126  ESCO1; N-acetyltransferase ESCO1 [KO:K11268] [EC:2.3.1.-]
100657154  ESCO2; N-acetyltransferase ESCO2 [KO:K11268] [EC:2.3.1.-]
100668329  LOW QUALITY PROTEIN: N-acetyltransferase ESCO2-like [KO:K11268] [EC:2.3.1.-]
100669559  PDS5B; sister chromatid cohesion protein PDS5 homolog B isoform X1 [KO:K11267]
100660865  PDS5A; LOW QUALITY PROTEIN: sister chromatid cohesion protein PDS5 homolog A [KO:K11267]
100665918  WAPL; wings apart-like protein homolog isoform X1 [KO:K25163]
100666852  AURKB; aurora kinase B isoform X1 [KO:K11479] [EC:2.7.11.1]
100671109  SGO1; shugoshin 1 [KO:K11580]
100664132  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
100676230  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
100654486  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
100663532  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
100659955  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
100675562  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
100676500  PPP2R5C; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
100660424  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
100659875  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
100661800  NDC80; kinetochore protein NDC80 homolog [KO:K11547]
100670558  KNL1; kinetochore scaffold 1 [KO:K11542]
100654654  TTK; LOW QUALITY PROTEIN: dual specificity protein kinase TTK [KO:K08866] [EC:2.7.12.1]
100675028  MAD1L1; mitotic spindle assembly checkpoint protein MAD1 isoform X3 [KO:K06679]
100667589  mitotic spindle assembly checkpoint protein MAD2A-like [KO:K02537]
100668722  mitotic spindle assembly checkpoint protein MAD2A isoform X1 [KO:K02537]
100661726  MAD2L2; mitotic spindle assembly checkpoint protein MAD2B isoform X1 [KO:K13728]
100668287  BUB1B; mitotic checkpoint serine/threonine-protein kinase BUB1 beta isoform X1 [KO:K06637] [EC:2.7.11.1]
100664974  BUB3; LOW QUALITY PROTEIN: mitotic checkpoint protein BUB3 [KO:K02180]
100660153  BUB1; mitotic checkpoint serine/threonine-protein kinase BUB1 isoform X1 [KO:K02178] [EC:2.7.11.1]
100675718  TRIP13; pachytene checkpoint protein 2 homolog [KO:K22399]
100661958  MAD2L1BP; MAD2L1-binding protein [KO:K26093]
100677598  FZR1; fizzy-related protein homolog [KO:K03364]
100672960  FBXO5; F-box only protein 5 isoform X1 [KO:K10292]
100662091  CDC14B; dual specificity protein phosphatase CDC14B isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
100658387  CDC14A; dual specificity protein phosphatase CDC14A isoform X1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
100661096  EP300; LOW QUALITY PROTEIN: histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
100663731  LOW QUALITY PROTEIN: CREB-binding protein [KO:K04498] [EC:2.3.1.48]
100667300  PRKDC; DNA-dependent protein kinase catalytic subunit isoform X1 [KO:K06642] [EC:2.7.11.1]
100661281  ATR; serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:2.7.11.1]
100663914  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
100669448  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X2 [KO:K06643] [EC:2.3.2.27]
100663725  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
100658253  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100655692  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta isoform X2 [KO:K04402]
100653562  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100661828  PCNA; proliferating cell nuclear antigen [KO:K04802]
100676629  SFN; 14-3-3 protein sigma [KO:K06644]
100658513  CHEK1; LOW QUALITY PROTEIN: serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
100666208  CHEK2; serine/threonine-protein kinase Chk2 isoform X1 [KO:K06641] [EC:2.7.11.1]
100659991  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
lav03030  DNA replication
lav04010  MAPK signaling pathway
lav04120  Ubiquitin mediated proteolysis
lav04210  Apoptosis
KO pathway
ko04110   
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