KEGG   PATHWAY: rno04110
Entry
rno04110                    Pathway                                
Name
Cell cycle - Rattus norvegicus (rat)
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
rno04110  Cell cycle
rno04110

Other DBs
GO: 0000278
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
100360427  E2f4; transcription factor E2F4 [KO:K04682]
100360936  Anapc16; anaphase-promoting complex subunit 16 isoform 1 [KO:K25229]
100362453  Ppp2cal1; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform-like [KO:K04382] [EC:3.1.3.16]
103690862  [KO:K06644]
114212  Chek2; serine/threonine-protein kinase Chk2 [KO:K06641] [EC:2.7.11.1]
114483  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
114494  Ccna2; cyclin-A2 [KO:K06627]
114592  Aurkb; aurora kinase B [KO:K11479] [EC:2.7.11.1]
114851  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
116651  E2f5; transcription factor E2F5 [KO:K04682]
117281  Ppp2r1a; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
140583  Chek1; serine/threonine-protein kinase Chk1 [KO:K02216] [EC:2.7.11.1]
170915  Ep300; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
171102  Cdc25a; M-phase inducer phosphatase 1 [KO:K06645] [EC:3.1.3.48]
171103  Cdc25b; M-phase inducer phosphatase 2 isoform 1 [KO:K05866] [EC:3.1.3.48]
171150  Cdk7; cyclin-dependent kinase 7 isoform 1 [KO:K02202] [EC:2.7.11.22 2.7.11.23]
171576  Bub1b; mitotic checkpoint serine/threonine-protein kinase BUB1 beta [KO:K06637] [EC:2.7.11.1]
24577  Myc; myc proto-oncogene protein [KO:K04377]
246060  Cdkn1c; cyclin-dependent kinase inhibitor 1C isoform 1 [KO:K09993]
246284  Atrx; transcriptional regulator ATRX [KO:K10779]
24672  Ppp2ca; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
24673  Ppp2cb; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
24708  Rb1; retinoblastoma-associated protein [KO:K06618]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
25112  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
25163  Cdkn2a; cyclin-dependent kinase inhibitor 2A [KO:K06621]
25164  Cdkn2b; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
25193  Ccnd3; G1/S-specific cyclin-D3 [KO:K10152]
25203  Ccnb1; G2/mitotic-specific cyclin-B1 [KO:K05868]
25515  Plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:2.7.11.21]
25576  Ywhah; 14-3-3 protein eta [KO:K16198]
25577  Ywhaq; 14-3-3 protein theta [KO:K16197]
25578  Ywhaz; 14-3-3 protein zeta/delta [KO:K16197]
25631  Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]
25717  Tgfb3; transforming growth factor beta-3 proprotein preproprotein [KO:K13377]
25729  Ccne1; G1/S-specific cyclin-E1 [KO:K06626]
25737  Pcna; proliferating cell nuclear antigen [KO:K04802]
287101  Pkmyt1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [KO:K06633] [EC:2.7.11.1]
287280  Skp1; S-phase kinase-associated protein 1 [KO:K03094]
287961  Cdc45; cell division control protein 45 homolog [KO:K06628]
288532  Mcm7; DNA replication licensing factor MCM7 [KO:K02210] [EC:5.6.2.3]
288671  Anapc5; anaphase-promoting complex subunit 5 isoform 1 [KO:K03352]
290577  Wapl; wings apart-like protein homolog [KO:K25163]
290668  Mau2; MAU2 chromatid cohesion factor homolog isoform 1 [KO:K11266]
290875  Cdc16; cell division cycle protein 16 homolog [KO:K03353]
291005  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
291105  E2f3; transcription factor E2F3 [KO:K06620]
291689  Cdc23; cell division cycle protein 23 homolog [KO:K03355]
291885  Mcm5; DNA replication licensing factor MCM5 [KO:K02209] [EC:5.6.2.3]
291927  Orc6; origin recognition complex subunit 6 [KO:K02608]
292071  Cdt1; DNA replication factor Cdt1 [KO:K10727]
292206  Trip13; pachytene checkpoint protein 2 homolog [KO:K22399]
292263  Fbxo5; F-box only protein 5 [KO:K10292]
293155  Anapc15; anaphase-promoting complex subunit 15 [KO:K25228]
29357  Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]
294787  Nipbl; nipped-B-like protein isoform X1 [KO:K06672]
294790  Skp2; S-phase kinase-associated protein 2 [KO:K03875]
29486  Smc3; structural maintenance of chromosomes protein 3 [KO:K06669]
295052  Ccna1; cyclin-A1 [KO:K06627]
295596  Orc4; origin recognition complex subunit 4 [KO:K02606]
296137  Bub1; mitotic checkpoint serine/threonine-protein kinase BUB1 [KO:K02178] [EC:2.7.11.1]
296558  Anapc2; anaphase-promoting complex subunit 2 [KO:K03349]
29685  Mcm6; DNA replication licensing factor MCM6 [KO:K02542] [EC:5.6.2.3]
297176  Mad2l1; mitotic spindle assembly checkpoint protein MAD2A [KO:K02537]
29728  Mcm4; DNA replication licensing factor MCM4 [KO:K02212] [EC:5.6.2.3]
29753  Ywhae; 14-3-3 protein epsilon [KO:K06630]
297893  Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
298795  Sfnl1; stratifin like 1 [KO:K06644]
299147  Ppp2r5e; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
299626  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
300084  Rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
300121  Smc1b; structural maintenance of chromosomes protein 1B [KO:K06636]
300711  Atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
300947  Tfdp2; transcription factor Dp-2 [KO:K09392]
301430  Orc2; origin recognition complex subunit 2 [KO:K02604]
301701  Ndc80; kinetochore protein NDC80 homolog [KO:K11547]
304218  Pds5b; sister chromatid cohesion protein PDS5 homolog B isoform 2 [KO:K11267]
304490  Anapc7; anaphase-promoting complex subunit 7 [KO:K03354]
305343  Pds5a; sister chromatid cohesion protein PDS5 homolog A [KO:K11267]
305420  Anapc4; anaphase-promoting complex subunit 4 [KO:K03351]
307511  Cdc25c; M-phase inducer phosphatase 3 [KO:K05867] [EC:3.1.3.48]
308768  Ticrr; treslin isoform X2 [KO:K26117]
308937  Wee1; wee1-like protein kinase [KO:K06632] [EC:2.7.11.1]
309179  Ppp2r5b; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
310806  Cdc14a; dual specificity protein phosphatase CDC14A isoform 2 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
311327  Knl1; kinetochore scaffold 1 [KO:K11542]
311412  Anapc1; anaphase-promoting complex subunit 1 [KO:K03348]
311860  Abl1; tyrosine-protein kinase ABL1 [KO:K06619] [EC:2.7.10.2]
312046  Dbf4; protein DBF4 homolog A [KO:K06629]
312538  Mcm2; DNA replication licensing factor MCM2 [KO:K02540] [EC:5.6.2.3]
312754  Ppp2r5a; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
313017  Sfn; 14-3-3 protein sigma [KO:K06644]
313138  Orc3; origin recognition complex subunit 3 [KO:K02605]
313304  Stag2; cohesin subunit SA-2 [KO:K06671]
313479  Orc1; origin recognition complex subunit 1 [KO:K02603]
313666  Zbtb17; zinc finger and BTB domain-containing protein 17 [KO:K10500]
313702  Mad2l2; mitotic spindle assembly checkpoint protein MAD2B isoform 2 [KO:K13728]
314642  Fzr1; fizzy-related protein homolog [KO:K03364]
314856  Mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:2.3.2.27]
314949  Rad21; double-strand-break repair protein rad21 homolog [KO:K06670]
315330  Espl1; separin [KO:K02365] [EC:3.4.22.49]
315648  Ppp2r1b; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
315852  Ttk; dual specificity protein kinase TTK isoform 1 [KO:K08866] [EC:2.7.12.1]
315958  Stag1; cohesin subunit SA-1 [KO:K06671]
316237  Mad2l1bp; MAD2L1-binding protein [KO:K26093]
316273  Mcm3; DNA replication licensing factor MCM3 [KO:K02541] [EC:5.6.2.3]
316767  Ddx11; probable ATP-dependent RNA helicase DDX11 isoform X4 [KO:K11273] [EC:5.6.2.7]
317389  Ccnb3; G2/mitotic-specific cyclin-B3 [KO:K21771]
360621  Cdc6; cell division control protein 6 homolog [KO:K02213]
360643  Cdc27; cell division cycle protein 27 homolog isoform 2 [KO:K03350]
360748  Prkdc; DNA-dependent protein kinase catalytic subunit [KO:K06642] [EC:2.7.11.1]
360908  Cdc7; cell division cycle 7-related protein kinase [KO:K02214] [EC:2.7.11.1]
361178  Tfdp1; transcription factor Dp-1 [KO:K04683]
361195  Cdc14b; dual specificity protein phosphatase CDC14B isoform 1 [KO:K06639] [EC:3.1.3.16 3.1.3.48]
361389  Anapc10; anaphase-promoting complex subunit 10 [KO:K03357]
361662  Bub3; mitotic checkpoint protein BUB3 [KO:K02180]
362304  Orc5; origin recognition complex subunit 5 [KO:K02607]
362356  Cul1; cullin-1 [KO:K03347]
362485  Ccne2; G1/S-specific cyclin-E2 [KO:K06626]
362817  Cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
363088  Ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
363174  Sgo1; shugoshin 1 [KO:K11580]
363193  Ppp2r5d; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
363481  Hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
366381  Cdc26; anaphase-promoting complex subunit CDC26 [KO:K03359]
399489  E2f1; transcription factor E2F1 [KO:K17454]
494444  Cdkn2d; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
498030  Anapc11; anaphase-promoting complex subunit 11 [KO:K03358]
500870  Mtbp; mdm2-binding protein [KO:K26116]
502750  Wee2; wee1-like protein kinase 2 [KO:K06632] [EC:2.7.11.1]
50554  Smad4; mothers against decapentaplegic homolog 4 [KO:K04501]
54237  Cdk1; cyclin-dependent kinase 1 [KO:K02087] [EC:2.7.11.22 2.7.11.23]
54238  Cdkn2c; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
54244  Crebbp; histone lysine acetyltransferase CREBBP [KO:K04498] [EC:2.3.1.48]
56010  Ywhag; 14-3-3 protein gamma [KO:K16198]
56011  Ywhab; 14-3-3 protein beta/alpha [KO:K16197]
58919  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
59086  Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
63996  Smc1a; structural maintenance of chromosomes protein 1A [KO:K06636]
64033  Ccnd2; G1/S-specific cyclin-D2 [KO:K10151]
64193  Pttg1; securin [KO:K06635]
64515  Cdc20; cell division cycle protein 20 homolog [KO:K03363]
680006  Mad1l1; mitotic spindle assembly checkpoint protein MAD1 [KO:K06679]
680014  Esco1; N-acetyltransferase ESCO1 [KO:K11268] [EC:2.3.1.-]
680111  Rbl1; retinoblastoma-like protein 1 [KO:K04681]
684111  E2f2; transcription factor E2F2 isoform X2 [KO:K09389]
684771  Cdca5; sororin [KO:K17390]
685029  Anapc13; anaphase-promoting complex subunit 13 [KO:K12456]
685055  Atr; serine/threonine-protein kinase ATR [KO:K06640] [EC:2.7.11.1]
686151  Cdca5l1; sororin-like [KO:K17390]
691318  Ppp2r5c; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform 4 [KO:K11584]
691979  Esco2; N-acetyltransferase ESCO2 [KO:K11268] [EC:2.3.1.-]
81758  Rbl2; retinoblastoma-like protein 2 [KO:K16332]
81809  Tgfb2; transforming growth factor beta-2 proprotein precursor [KO:K13376]
83571  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
84027  Gsk3b; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
84389  Ccnh; cyclin-H [KO:K06634]
84576  Hdac1l; histone deacetylase 1-like [KO:K06067] [EC:3.5.1.98]
84577  Hdac2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
94201  Cdk4; cyclin-dependent kinase 4 isoform 1 [KO:K02089] [EC:2.7.11.22]
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
rno03030  DNA replication
rno04010  MAPK signaling pathway
rno04120  Ubiquitin mediated proteolysis
rno04210  Apoptosis
KO pathway
ko04110   

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