KEGG   PATHWAY: rno04110
rno04110                    Pathway                                

Cell cycle - Rattus norvegicus (rat)
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.
Cellular Processes; Cell growth and death
Pathway map
rno04110  Cell cycle

Other DBs
GO: 0000278
Rattus norvegicus (rat) [GN:rno]
58919  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
64033  Ccnd2; G1/S-specific cyclin-D2 [KO:K10151]
25193  Ccnd3; G1/S-specific cyclin-D3 [KO:K10152]
94201  Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
114483  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:]
24708  Rb1; retinoblastoma-associated protein [KO:K06618]
680111  Rbl1; retinoblastoma-like protein 1 [KO:K04681]
81758  Rbl2; retinoblastoma-like protein 2 [KO:K16332]
311860  Abl1; tyrosine-protein kinase ABL1 [KO:K06619] [EC:]
297893  Hdac1; histone deacetylase 1 [KO:K06067] [EC:]
84576  Hdac1l; histone deacetylase 1-like [KO:K06067] [EC:]
84577  Hdac2; histone deacetylase 2 [KO:K06067] [EC:]
399489  E2f1; transcription factor E2F1 [KO:K17454]
684111  E2f2; transcription factor E2F2 isoform X1 [KO:K09389]
291105  E2f3; transcription factor E2F3 [KO:K06620]
116651  E2f5; transcription factor E2F5 isoform X1 [KO:K04682]
100360427  E2f4; transcription factor E2F4 [KO:K04682]
361178  Tfdp1; transcription factor Dp-1 [KO:K04683]
300947  Tfdp2; transcription factor Dp-2 [KO:K09392]
84027  Gsk3b; glycogen synthase kinase-3 beta [KO:K03083] [EC:]
59086  Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
81809  Tgfb2; transforming growth factor beta-2 proprotein precursor [KO:K13376]
25717  Tgfb3; transforming growth factor beta-3 proprotein preproprotein [KO:K13377]
29357  Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]
25631  Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]
50554  Smad4; mothers against decapentaplegic homolog 4 [KO:K04501]
24577  Myc; myc proto-oncogene protein [KO:K04377]
313666  Zbtb17; zinc finger and BTB domain-containing protein 17 [KO:K10500]
25163  Cdkn2a; cyclin-dependent kinase inhibitor 2A [KO:K06621]
25164  Cdkn2b; cyclin-dependent kinase 4 inhibitor B [KO:K04685]
54238  Cdkn2c; cyclin-dependent kinase 4 inhibitor C [KO:K06622]
494444  Cdkn2d; cyclin-dependent kinase 4 inhibitor D [KO:K06623]
83571  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
246060  Cdkn1c; cyclin-dependent kinase inhibitor 1C isoform 1 [KO:K09993]
114851  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
362485  Ccne2; G1/S-specific cyclin-E2 [KO:K06626]
25729  Ccne1; G1/S-specific cyclin-E1 [KO:K06626]
362817  Cdk2; cyclin-dependent kinase 2 [KO:K02206] [EC:]
287280  Skp1; S-phase kinase-associated protein 1 [KO:K03094]
362356  Cul1; cullin-1 [KO:K03347]
300084  Rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:]
294790  Skp2; S-phase kinase-associated protein 2 [KO:K03875]
114494  Ccna2; cyclin-A2 [KO:K06627]
295052  Ccna1; cyclin-A1 [KO:K06627]
360621  Cdc6; cell division control protein 6 homolog [KO:K02213]
287961  Cdc45; cell division control protein 45 homolog [KO:K06628]
360908  Cdc7; cell division cycle 7-related protein kinase [KO:K02214] [EC:]
312046  Dbf4; protein DBF4 homolog A [KO:K06629]
54237  Cdk1; cyclin-dependent kinase 1 [KO:K02087] [EC:]
25203  Ccnb1; G2/mitotic-specific cyclin-B1 [KO:K05868]
363088  Ccnb2; G2/mitotic-specific cyclin-B2 [KO:K21770]
100364016  G2/mitotic-specific cyclin-B2 [KO:K21770]
317389  Ccnb3; G2/mitotic-specific cyclin-B3 isoform X2 [KO:K21771]
171103  Cdc25b; M-phase inducer phosphatase 2 isoform 1 [KO:K05866] [EC:]
307511  Cdc25c; M-phase inducer phosphatase 3 [KO:K05867] [EC:]
25578  Ywhaz; 14-3-3 protein zeta/delta [KO:K16197]
56011  Ywhab; 14-3-3 protein beta/alpha [KO:K16197]
25577  Ywhaq; 14-3-3 protein theta [KO:K16197]
29753  Ywhae; 14-3-3 protein epsilon [KO:K06630]
25576  Ywhah; 14-3-3 protein eta [KO:K16198]
56010  Ywhag; 14-3-3 protein gamma [KO:K16198]
25515  Plk1; serine/threonine-protein kinase PLK1 [KO:K06631] [EC:]
308937  Wee1; wee1-like protein kinase [KO:K06632] [EC:]
502750  Wee2; wee1-like protein kinase 2 [KO:K06632] [EC:]
287101  Pkmyt1; membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase [KO:K06633] [EC:]
84389  Ccnh; cyclin-H [KO:K06634]
171150  Cdk7; cyclin-dependent kinase 7 [KO:K02202] [EC:]
311412  Anapc1; anaphase-promoting complex subunit 1 [KO:K03348]
296558  Anapc2; anaphase-promoting complex subunit 2 [KO:K03349]
360643  Cdc27; cell division cycle protein 27 homolog [KO:K03350]
305420  Anapc4; anaphase-promoting complex subunit 4 [KO:K03351]
288671  Anapc5; anaphase-promoting complex subunit 5 [KO:K03352]
290875  Cdc16; cell division cycle protein 16 homolog [KO:K03353]
304490  Anapc7; anaphase-promoting complex subunit 7 [KO:K03354]
291689  Cdc23; cell division cycle protein 23 homolog [KO:K03355]
361389  Anapc10; anaphase-promoting complex subunit 10 [KO:K03357]
498030  Anapc11; anaphase-promoting complex subunit 11 [KO:K03358]
366381  Cdc26; anaphase-promoting complex subunit CDC26 [KO:K03359]
685029  Anapc13; anaphase-promoting complex subunit 13 [KO:K12456]
293155  Anapc15; anaphase-promoting complex subunit 15 [KO:K25228]
100360936  Anapc16; anaphase-promoting complex subunit 16 isoform X1 [KO:K25229]
64515  Cdc20; cell division cycle protein 20 homolog [KO:K03363]
64193  Pttg1; securin [KO:K06635]
315330  Espl1; separin [KO:K02365] [EC:]
300121  Smc1b; structural maintenance of chromosomes protein 1B [KO:K06636]
63996  Smc1a; structural maintenance of chromosomes protein 1A [KO:K06636]
29486  Smc3; structural maintenance of chromosomes protein 3 [KO:K06669]
313304  Stag2; cohesin subunit SA-2 [KO:K06671]
315958  Stag1; cohesin subunit SA-1 [KO:K06671]
314949  Rad21; double-strand-break repair protein rad21 homolog [KO:K06670]
315852  Ttk; dual specificity protein kinase TTK [KO:K08866] [EC:]
296137  Bub1; mitotic checkpoint serine/threonine-protein kinase BUB1 [KO:K02178] [EC:]
361662  Bub3; mitotic checkpoint protein BUB3 [KO:K02180]
171576  Bub1b; mitotic checkpoint serine/threonine-protein kinase BUB1 beta [KO:K06637] [EC:]
680006  Mad1l1; mitotic spindle assembly checkpoint protein MAD1 [KO:K06679]
297176  Mad2l1; mitotic spindle assembly checkpoint protein MAD2A [KO:K02537]
313702  Mad2l2; mitotic spindle assembly checkpoint protein MAD2B [KO:K13728]
314642  Fzr1; fizzy-related protein homolog [KO:K03364]
310806  Cdc14a; dual specificity protein phosphatase CDC14A isoform 2 [KO:K06639] [EC:]
361195  Cdc14b; dual specificity protein phosphatase CDC14B [KO:K06639] [EC:]
685055  Atr; serine/threonine-protein kinase ATR isoform X1 [KO:K06640] [EC:]
300711  Atm; serine-protein kinase ATM [KO:K04728] [EC:]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
140583  Chek1; serine/threonine-protein kinase Chk1 [KO:K02216] [EC:]
114212  Chek2; serine/threonine-protein kinase Chk2 [KO:K06641] [EC:]
54244  Crebbp; histone lysine acetyltransferase CREBBP [KO:K04498] [EC:]
170915  Ep300; LOW QUALITY PROTEIN: histone acetyltransferase p300 [KO:K04498] [EC:]
360748  Prkdc; DNA-dependent protein kinase catalytic subunit [KO:K06642] [EC:]
314856  Mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:]
25112  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
291005  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
299626  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
25737  Pcna; proliferating cell nuclear antigen [KO:K04802]
298795  uncharacterized protein LOC298795 [KO:K06644]
171102  Cdc25a; M-phase inducer phosphatase 1 [KO:K06645] [EC:]
313479  Orc1; origin recognition complex subunit 1 [KO:K02603]
301430  Orc2; origin recognition complex subunit 2 [KO:K02604]
313138  Orc3; origin recognition complex subunit 3 [KO:K02605]
295596  Orc4; origin recognition complex subunit 4 [KO:K02606]
362304  Orc5; origin recognition complex subunit 5 [KO:K02607]
291927  Orc6; origin recognition complex subunit 6 [KO:K02608]
312538  Mcm2; DNA replication licensing factor MCM2 [KO:K02540] [EC:]
316273  Mcm3; DNA replication licensing factor MCM3 [KO:K02541] [EC:]
29728  Mcm4; DNA replication licensing factor MCM4 [KO:K02212] [EC:]
291885  Mcm5; DNA replication licensing factor MCM5 [KO:K02209] [EC:]
29685  Mcm6; DNA replication licensing factor MCM6 [KO:K02542] [EC:]
288532  Mcm7; DNA replication licensing factor MCM7 [KO:K02210] [EC:]
Matsuoka S, Yamaguchi M, Matsukage A
D-type cyclin-binding regions of proliferating cell nuclear antigen.
J Biol Chem 269:11030-6 (1994)
Welch PJ, Wang JY
A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle.
Cell 75:779-90 (1993)
Macaluso M, Montanari M, Giordano A
Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes.
Oncogene 25:5263-7 (2006)
Cobrinik D
Pocket proteins and cell cycle control.
Oncogene 24:2796-809 (2005)
Boutros R, Lobjois V, Ducommun B
CDC25 phosphatases in cancer cells: key players? Good targets?
Nat Rev Cancer 7:495-507 (2007)
Diehl JA, Cheng M, Roussel MF, Sherr CJ
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
Genes Dev 12:3499-511 (1998)
Klein EA, Assoian RK
Transcriptional regulation of the cyclin D1 gene at a glance.
J Cell Sci 121:3853-7 (2008)
Sherr CJ, Roberts JM
CDK inhibitors: positive and negative regulators of G1-phase progression.
Genes Dev 13:1501-12 (1999)
Shi Y, Massague J.
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
Cell 113:685-700 (2003)
Kamura T, Hara T, Kotoshiba S, Yada M, Ishida N, Imaki H, Hatakeyama S, Nakayama K, Nakayama KI
Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation.
Proc Natl Acad Sci U S A 100:10231-6 (2003)
Bond M, Sala-Newby GB, Wu YJ, Newby AC
Biphasic effect of p21Cip1 on smooth muscle cell proliferation: role of PI 3-kinase and Skp2-mediated degradation.
Cardiovasc Res 69:198-206 (2006)
Harris SL, Levine AJ.
The p53 pathway: positive and negative feedback loops.
Oncogene 24:2899-908 (2005)
Vogelstein B, Lane D, Levine AJ
Surfing the p53 network.
Nature 408:307-10 (2000)
Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ Jr
Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.
Science 266:1376-80 (1994)
Petersen BO, Lukas J, Sorensen CS, Bartek J, Helin K
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
EMBO J 18:396-410 (1999)
Sheu YJ, Stillman B
Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression.
Mol Cell 24:101-13 (2006)
Martinez AM, Afshar M, Martin F, Cavadore JC, Labbe JC, Doree M
Dual phosphorylation of the T-loop in cdk7: its role in controlling cyclin H binding and CAK activity.
EMBO J 16:343-54 (1997)
Lolli G, Johnson LN
CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?
Cell Cycle 4:572-7 (2005)
Musacchio A, Salmon ED
The spindle-assembly checkpoint in space and time.
Nat Rev Mol Cell Biol 8:379-93 (2007)
Uhlmann F
Chromosome cohesion and separation: from men and molecules.
Curr Biol 13:R104-14 (2003)
Stegmeier F, Amon A
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation.
Annu Rev Genet 38:203-32 (2004)
Moustakas A, Kardassis D
Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members.
Proc Natl Acad Sci U S A 95:6733-8 (1998)
rno04010  MAPK signaling pathway
rno04120  Ubiquitin mediated proteolysis
rno04210  Apoptosis
KO pathway

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