Entry |
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Name |
Cell cycle - Homo sapiens (human)
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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.
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Class |
Cellular Processes; Cell growth and death
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Pathway map |

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Network |
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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 |
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Disease |
H00409 | Type 2 diabetes mellitus |
H00631 | Cornelia de Lange syndrome |
H00713 | Beckwith-Wiedemann syndrome |
H01007 | Choroid plexus papilloma |
H01023 | Juvenile polyposis syndrome |
H01288 | Mosaic variegated aneuploidy syndrome |
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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) |
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 (USAN/INN) |
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Other DBs |
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Organism |
Homo sapiens (human) [GN: hsa]
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Gene |
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] |
25 | ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase [KO:K06619] [EC:2.7.10.2] |
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] |
4609 | MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377] |
7709 | ZBTB17; zinc finger and BTB domain containing 17 [KO:K10500] |
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] |
1027 | CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624] |
1028 | CDKN1C; cyclin dependent kinase inhibitor 1C [KO:K09993] |
1026 | CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625] |
6500 | SKP1; S-phase kinase associated protein 1 [KO:K03094] |
6502 | SKP2; S-phase kinase associated protein 2 [KO:K03875] |
7534 | YWHAZ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta [KO:K16197] |
7529 | YWHAB; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta [KO:K16197] |
10971 | YWHAQ; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta [KO:K16197] |
7531 | YWHAE; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon [KO:K06630] |
7533 | YWHAH; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta [KO:K16198] |
7532 | YWHAG; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma [KO:K16198] |
9088 | PKMYT1; protein kinase, membrane associated tyrosine/threonine 1 [KO:K06633] [EC:2.7.11.1] |
64682 | ANAPC1; anaphase promoting complex subunit 1 [KO:K03348] |
29882 | ANAPC2; anaphase promoting complex subunit 2 [KO:K03349] |
996 | CDC27; cell division cycle 27 [KO:K03350] |
29945 | ANAPC4; anaphase promoting complex subunit 4 [KO:K03351] |
51433 | ANAPC5; anaphase promoting complex subunit 5 [KO:K03352] |
51434 | ANAPC7; anaphase promoting complex subunit 7 [KO:K03354] |
10393 | ANAPC10; anaphase promoting complex subunit 10 [KO:K03357] |
51529 | ANAPC11; anaphase promoting complex subunit 11 [KO:K03358] |
25847 | ANAPC13; anaphase promoting complex subunit 13 [KO:K12456] |
991 | CDC20; cell division cycle 20 [KO:K03363] |
9232 | PTTG1; PTTG1 regulator of sister chromatid separation, securin [KO:K06635] |
10744 | PTTG2; pituitary tumor-transforming 2 [KO:K06635] |
8243 | SMC1A; structural maintenance of chromosomes 1A [KO:K06636] |
27127 | SMC1B; structural maintenance of chromosomes 1B [KO:K06636] |
9126 | SMC3; structural maintenance of chromosomes 3 [KO:K06669] |
5885 | RAD21; RAD21 cohesin complex component [KO:K06670] |
9184 | BUB3; BUB3 mitotic checkpoint protein [KO:K02180] |
701 | BUB1B; BUB1 mitotic checkpoint serine/threonine kinase B [KO:K06637] [EC:2.7.11.1] |
8379 | MAD1L1; mitotic arrest deficient 1 like 1 [KO:K06679] |
4085 | MAD2L1; mitotic arrest deficient 2 like 1 [KO:K02537] |
10459 | MAD2L2; mitotic arrest deficient 2 like 2 [KO:K13728] |
51343 | FZR1; fizzy and cell division cycle 20 related 1 [KO:K03364] |
1647 | GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402] |
4616 | GADD45B; growth arrest and DNA damage inducible beta [KO:K04402] |
10912 | GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402] |
5111 | PCNA; proliferating cell nuclear antigen [KO:K04802] |
4998 | ORC1; origin recognition complex subunit 1 [KO:K02603] |
4999 | ORC2; origin recognition complex subunit 2 [KO:K02604] |
23595 | ORC3; origin recognition complex subunit 3 [KO:K02605] |
5000 | ORC4; origin recognition complex subunit 4 [KO:K02606] |
5001 | ORC5; origin recognition complex subunit 5 [KO:K02607] |
23594 | ORC6; origin recognition complex subunit 6 [KO:K02608] |
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Reference |
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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 |
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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 |
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Reference |
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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 |
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Reference |
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Authors |
Cobrinik D |
Title |
Pocket proteins and cell cycle control. |
Journal |
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Reference |
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Authors |
Boutros R, Lobjois V, Ducommun B |
Title |
CDC25 phosphatases in cancer cells: key players? Good targets? |
Journal |
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Reference |
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Authors |
Diehl JA, Cheng M, Roussel MF, Sherr CJ |
Title |
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. |
Journal |
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Reference |
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Authors |
Klein EA, Assoian RK |
Title |
Transcriptional regulation of the cyclin D1 gene at a glance. |
Journal |
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Reference |
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Authors |
Sherr CJ, Roberts JM |
Title |
CDK inhibitors: positive and negative regulators of G1-phase progression. |
Journal |
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Reference |
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Authors |
Shi Y, Massague J. |
Title |
Mechanisms of TGF-beta signaling from cell membrane to the nucleus. |
Journal |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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Authors |
Harris SL, Levine AJ. |
Title |
The p53 pathway: positive and negative feedback loops. |
Journal |
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Reference |
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Authors |
Vogelstein B, Lane D, Levine AJ |
Title |
Surfing the p53 network. |
Journal |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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Authors |
Sheu YJ, Stillman B |
Title |
Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Lolli G, Johnson LN |
Title |
CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs? |
Journal |
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Reference |
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Authors |
Musacchio A, Salmon ED |
Title |
The spindle-assembly checkpoint in space and time. |
Journal |
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Reference |
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Authors |
Uhlmann F |
Title |
Chromosome cohesion and separation: from men and molecules. |
Journal |
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Reference |
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Authors |
Stegmeier F, Amon A |
Title |
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. |
Journal |
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Reference |
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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 |
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Related pathway |
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KO pathway |
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LinkDB |
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