Entry
Name
Cell cycle - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Ortholog table
Network
Element
N00066 MDM2-p21-Cell cycle G1/S
N00347 p300-p21-Cell cycle G1/S
N00493 Spindle assembly checkpoint signaling
N00499 ATR-p21-Cell cycle G2/M
N00536 MDM2-p21-Cell cycle G1/S
N01468 DNA replication licensing
N01471 Origin unwinding and elongation
N01486 Cohesin dissociation in anaphase
N01529 Recruitment and formation of the MCC
Drug
D05988 Tacedinaline (USAN/INN)
D06637 Romidepsin (JAN/USAN/INN)
D09338 Entinostat (JAN/USAN/INN)
D09357 Mocetinostat dihydrobromide (USAN)
D09641 Mocetinostat (USAN/INN)
D10019 Panobinostat lactate (JAN)
D10084 Abexinostat hydrochloride (USAN)
D10155 Rigosertib sodium (JAN/USAN)
D10183 Volasertib trihydrochloride (USAN)
D10319 Panobinostat (USAN/INN)
D10322 Quisinostat hydrochloride (USAN)
D10652 Palbociclib isethionate (USAN)
D10688 Abemaciclib (JAN/USAN/INN)
D10977 Remetinostat (USAN/INN)
D10979 Ribociclib succinate (USAN)
D10993 Tucidinostat (JAN/USAN/INN)
D11182 Tinostamustine (USAN/INN)
D11319 Fimepinostat (USAN/INN)
D11459 Onvansertib fumarate (USAN)
D11600 Zotiraciclib citrate (USAN)
D11787 Ceralasertib (JAN/USAN/INN)
D11987 Trilaciclib dihydrochloride
D12176 Simurosertib (USAN/INN)
D12552 Bocodepsin besylate (USAN)
D12828 Risvodetinib (USAN/INN)
D12829 Risvodetinib succinate (USAN)
D12925 Pocenbrodib hydrochloride (USAN)
Other DBs
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624 ]
10274 STAG1; STAG1 cohesin complex component [KO:K06671 ]
1028 CDKN1C; cyclin dependent kinase inhibitor 1C [KO:K09993 ]
1029 CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621 ]
1030 CDKN2B; cyclin dependent kinase inhibitor 2B [KO:K04685 ]
1031 CDKN2C; cyclin dependent kinase inhibitor 2C [KO:K06622 ]
1032 CDKN2D; cyclin dependent kinase inhibitor 2D [KO:K06623 ]
10393 ANAPC10; anaphase promoting complex subunit 10 [KO:K03357 ]
10403 NDC80; NDC80 kinetochore complex component [KO:K11547 ]
10459 MAD2L2; mitotic arrest deficient 2 like 2 [KO:K13728 ]
10735 STAG2; STAG2 cohesin complex component [KO:K06671 ]
10744 PTTG2; pituitary tumor-transforming 2 [KO:K06635 ]
10912 GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402 ]
10926 DBF4; DBF4-CDC7 kinase regulatory subunit [KO:K06629 ]
10971 YWHAQ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta [KO:K16197 ]
114799 ESCO1; establishment of sister chromatid cohesion N-acetyltransferase 1 [KO:K11268 ] [EC:2.3.1.-]
119504 ANAPC16; anaphase promoting complex subunit 16 [KO:K25229 ]
157570 ESCO2; establishment of sister chromatid cohesion N-acetyltransferase 2 [KO:K11268 ] [EC:2.3.1.-]
1647 GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402 ]
23047 PDS5B; PDS5 cohesin associated factor B [KO:K11267 ]
23244 PDS5A; PDS5 cohesin associated factor A [KO:K11267 ]
23383 MAU2; MAU2 sister chromatid cohesion factor [KO:K11266 ]
23594 ORC6; origin recognition complex subunit 6 [KO:K02608 ]
23595 ORC3; origin recognition complex subunit 3 [KO:K02605 ]
25 ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619 ] [EC:2.7.10.2 ]
25847 ANAPC13; anaphase promoting complex subunit 13 [KO:K12456 ]
25906 ANAPC15; anaphase promoting complex subunit 15 [KO:K25228 ]
27127 SMC1B; structural maintenance of chromosomes 1B [KO:K06636 ]
29882 ANAPC2; anaphase promoting complex subunit 2 [KO:K03349 ]
29945 ANAPC4; anaphase promoting complex subunit 4 [KO:K03351 ]
4085 MAD2L1; mitotic arrest deficient 2 like 1 [KO:K02537 ]
4609 MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377 ]
4616 GADD45B; growth arrest and DNA damage inducible beta [KO:K04402 ]
4998 ORC1; origin recognition complex subunit 1 [KO:K02603 ]
4999 ORC2; origin recognition complex subunit 2 [KO:K02604 ]
5000 ORC4; origin recognition complex subunit 4 [KO:K02606 ]
5001 ORC5; origin recognition complex subunit 5 [KO:K02607 ]
5111 PCNA; proliferating cell nuclear antigen [KO:K04802 ]
51343 FZR1; fizzy and cell division cycle 20 related 1 [KO:K03364 ]
51433 ANAPC5; anaphase promoting complex subunit 5 [KO:K03352 ]
51434 ANAPC7; anaphase promoting complex subunit 7 [KO:K03354 ]
51529 ANAPC11; anaphase promoting complex subunit 11 [KO:K03358 ]
546 ATRX; ATRX chromatin remodeler [KO:K10779 ]
5518 PPP2R1A; protein phosphatase 2 scaffold subunit Aalpha [KO:K03456 ]
5519 PPP2R1B; protein phosphatase 2 scaffold subunit Abeta [KO:K03456 ]
5525 PPP2R5A; protein phosphatase 2 regulatory subunit B'alpha [KO:K11584 ]
5526 PPP2R5B; protein phosphatase 2 regulatory subunit B'beta [KO:K11584 ]
5527 PPP2R5C; protein phosphatase 2 regulatory subunit B'gamma [KO:K11584 ]
5528 PPP2R5D; protein phosphatase 2 regulatory subunit B'delta [KO:K11584 ]
5529 PPP2R5E; protein phosphatase 2 regulatory subunit B'epsilon [KO:K11584 ]
5885 RAD21; RAD21 cohesin complex component [KO:K06670 ]
5925 RB1; RB transcriptional corepressor 1 [KO:K06618 ]
5933 RBL1; RB transcriptional corepressor like 1 [KO:K04681 ]
5934 RBL2; RB transcriptional corepressor like 2 [KO:K16332 ]
64682 ANAPC1; anaphase promoting complex subunit 1 [KO:K03348 ]
6500 SKP1; S-phase kinase associated protein 1 [KO:K03094 ]
6502 SKP2; S-phase kinase associated protein 2 [KO:K03875 ]
701 BUB1B; BUB1 mitotic checkpoint serine/threonine kinase B [KO:K06637 ] [EC:2.7.11.1 ]
7040 TGFB1; transforming growth factor beta 1 [KO:K13375 ]
7042 TGFB2; transforming growth factor beta 2 [KO:K13376 ]
7043 TGFB3; transforming growth factor beta 3 [KO:K13377 ]
7529 YWHAB; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta [KO:K16197 ]
7531 YWHAE; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon [KO:K06630 ]
7532 YWHAG; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma [KO:K16198 ]
7533 YWHAH; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta [KO:K16198 ]
7534 YWHAZ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta [KO:K16197 ]
7709 ZBTB17; zinc finger and BTB domain containing 17 [KO:K10500 ]
80174 DBF4B; DBF4B-CDC7 kinase regulatory subunit [KO:K06629 ]
81620 CDT1; chromatin licensing and DNA replication factor 1 [KO:K10727 ]
8243 SMC1A; structural maintenance of chromosomes 1A [KO:K06636 ]
8379 MAD1L1; mitotic arrest deficient 1 like 1 [KO:K06679 ]
90381 TICRR; TOPBP1 interacting checkpoint and replication regulator [KO:K26117 ]
9088 PKMYT1; protein kinase, membrane associated tyrosine/threonine 1 [KO:K06633 ] [EC:2.7.11.1 ]
9126 SMC3; structural maintenance of chromosomes 3 [KO:K06669 ]
9184 BUB3; BUB3 mitotic checkpoint protein [KO:K02180 ]
9232 PTTG1; PTTG1 regulator of sister chromatid separation, securin [KO:K06635 ]
9319 TRIP13; thyroid hormone receptor interactor 13 [KO:K22399 ]
991 CDC20; cell division cycle 20 [KO:K03363 ]
996 CDC27; cell division cycle 27 [KO:K03350 ]
Reference
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
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
Reference
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
Reference
Authors
Cobrinik D
Title
Pocket proteins and cell cycle control.
Journal
Reference
Authors
Boutros R, Lobjois V, Ducommun B
Title
CDC25 phosphatases in cancer cells: key players? Good targets?
Journal
Reference
Authors
Diehl JA, Cheng M, Roussel MF, Sherr CJ
Title
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
Journal
Reference
Authors
Klein EA, Assoian RK
Title
Transcriptional regulation of the cyclin D1 gene at a glance.
Journal
Reference
Authors
Sherr CJ, Roberts JM
Title
CDK inhibitors: positive and negative regulators of G1-phase progression.
Journal
Reference
Authors
Shi Y, Massague J.
Title
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
Journal
Reference
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
Reference
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
Reference
Authors
Harris SL, Levine AJ.
Title
The p53 pathway: positive and negative feedback loops.
Journal
Reference
Authors
Vogelstein B, Lane D, Levine AJ
Title
Surfing the p53 network.
Journal
Reference
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
Reference
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
Reference
Authors
Sheu YJ, Stillman B
Title
Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression.
Journal
Reference
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
Reference
Authors
Lolli G, Johnson LN
Title
CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?
Journal
Reference
Authors
Musacchio A, Salmon ED
Title
The spindle-assembly checkpoint in space and time.
Journal
Reference
Authors
Uhlmann F
Title
Chromosome cohesion and separation: from men and molecules.
Journal
Reference
Authors
Stegmeier F, Amon A
Title
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation.
Journal
Reference
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
Reference
Authors
de Boer HR, Guerrero Llobet S, van Vugt MA
Title
Controlling the response to DNA damage by the APC/C-Cdh1.
Journal
Reference
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
Related pathway
KO pathway
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