Competition between ARF and E2F1 to bind DP1. PMID: 16135794 ARF relocalize DP1 from the cytoplasm to the nucleolus PMID: 12446760
Notes by CellDesigner PMID: 12909625 reaction: direct
PMID: 12459251 PMID: 10385618 T286 phosphorylation promote association of cyclin D1 with its nuclear exporter CRM1, leading to cytoplasmic translocation of cylcin D1 PMID: 12851486
Inhibition of E2F binding by phosphorylation at several of the 7 C-terminal sites or at one of the two serines 807 and 811. PMID : 9315635
Inactivated by CHEK1 and CHEK2 PMID: 12478465
Nuclear translocation during the G2 to M transition. PMID: 8348613 Translocation via the proteins of the 14-3-3 group. PMID: 12814430 (ref REACTOME) PMID: 9836640 PMID: 9889122 (from REACTOME) PMID: 11063929
Notes by CellDesigner PMID: 12438307 reaction: direct
Notes by CellDesigner PMID: 15782160 reaction: direct
PMID: 10373560 The NES (Nuclear Export Signal) of cyclin B induces its active export. This export seems to be done via a CRM1 complex and could need the GTPaseRan/TC4. PMID: 9679058 (ref REACTOME) PMID: 9670027 PMID: 9679058
The native protein is first correctly folded by HSP90 and CDC37 before being able to bind to the D-type cyclins. PMID: 10385618 PMID: 10498883 (NF = non folded)
Notes by CellDesigner PMID: 16135806 reaction: direct
E2F1 sequestrated by ARF in the nucleolus. PMID: 16135794 PMID: 12446760
Notes by CellDesigner PMID: 12771133 reaction: direct
CDC2 phosphorylation at Tyr15 by WEE1, only when CDC2 is bound to a cyclin. PMID: 12814430 WEE1 allows CDC2 to stay in an inactive state after its translocation during G2. PMID: 10373560 PMID: 8348613 PMID: 9001210 (ref REACTOME) PMID: 1384126 PMID: 15037762
Notes by CellDesigner PMID: 11564866 PMID: 12150994 reaction: direct
PMID: 15024084 ATM phosphorylates p53 in case of DNA double-strand breaks. ATR phosphorylates p53 in case of other types of DNA damages. PMID: 15140942 E2F1 stimulates ATM to phosphorylate p53 (and Chk2) PMID: 15140942 (ref REACTOME) PMID: 9843217 PMID: 9733515 PMID: 9733514
Upon DNA damage and ATM phosphorylation, the transcriptional activity, the apoptotic and the S phase-inducing activites of E2F1 are inhibited by binding to TopBP1 (inhibition RB-independant). Induce damage repair. PMID: 15838517 PMID: 12697828
Notes by CellDesigner PMID: 12004135 reaction: direct
Needs verification: which form of CDC25 gets phosphorylated on Ser216 by Chek1,2???
Phosphorylated CDC25 interacts with the 14-3-3 proteins which keep CDC25 outside of the nucleus. PMID: 12814430 PMID: 11313932 PMID: 11897663
Notes by CellDesigner PMID: 15510213 reaction: direct
Shuttling of p130 between the nucleus and cytoplasm PMID: 11756542
p130 binds to and inhibits cyclinE-CDK2, independantly of its phosphorylation state. PMID: 15456871 PMID: 12006580 PMID: 11237530
Inhibition of PCNA by p21. PMID: 12814430
Notes by CellDesigner PMID: 8760872 reaction: direct PMID: 10766737PMID: 10733529
All three Cip/Kip family members direct the accumulation of cylinD-CDK complexes in the nucleus. PMID: 10385618
Phosphorylation of E2F1 leads to the end of transcription stimulation. PMID: 15840440 Phosphorylation of DP-1 induce the diminution of the binding of E2F to the DNA (leading to the end of its activation). PMID: 15133492 PMID: 9556498 PMID: 15123636 Phosphorylation of both DP-1 and E2F1 PMID: 16135794 Phosphorylation of E2F-1, 2, 3a and 3b by cyclin A/CDK2 induce E2F degradation. PMID: 11980909 Phosphorylation of E2F1 on Ser-375 increases its binding affinity for pRb. PMID: 16213134
pRB phosphorylation PMID: 9315635 PMID: 12006580 Brg1 phosphorylation PMID: 11420722 Brg1 (in the SWI/SNF complex) and pRB are phosphorylated, simultaneously with the complex dissociation. Phosphorylation of pRB PMID: 9315635 PMID: 12006580 Phosphorylation of Brg1 (SWI/SNF complex) PMID: 11420722
Phosphorylation at T145 is catalyzed by the protein serine/threonine kinase Akt PMID: 16775416 PMID: 15798220
HDAC1 and Sin3B associate to the promoteurs via E2F4 and p130/p107 PMID: 11959842 HDAC1 and SUV39H1 associate to the promoteurs via E2F4 and p130/p107 PMID: 15769944
Phosphorylation of p27 at Thr-157 by AKT-1 induce its cytoplasmic localization. PMID: 12851486 Phosphorylation of p21 at Thr-145 by AKT-1 induce its cytoplasmic localization. PMID: 11231573
PMID: 10373560 The NES (Nuclear Export Signal) of cyclin B induces its active export. This export seems to be done via a CRM1 complex and would need the GTPaseRan/TC4 PMID: 9679058 (ref REACTOME) PMID: 9670027 PMID: 9679058
Like CDK4, CDK6 has first to be folded by HSP90 and CDC37 before being able to bind D-type cyclins. PMID: 10385618 PMID: 10498883
Notes by CellDesigner PMID: 14688249 reaction: direct
Notes by CellDesigner PMID: 14532106 reaction: direct
Notes by CellDesigner PMID: 15105433 reaction: directPMID: 15510213
Notes by CellDesigner PMID: 15711575 PMID: 12110166 reaction: direct
Acetylation of E2F1 (or activators E2Fs) on 3 lysine residues by PCAF increases its DNA-binding activity, stabilizes the protein and stimulates its transactivation potentiel. PMID: 15126619 Stabilisation of E2F1 by acetylation of Lys-117, Lys-120 and Lys-125 by PCAF and, to a lesser extent, p300 acetyltransferases. PMID: 15123636 Acetylated lysines on E2F1 are conserved and acetylated on E2F2 and E2F3. Acetylation by p300/CBP. PMID: 10753885
Notes by CellDesigner PMID: 15210709 reaction: direct
Notes by CellDesigner PMID: 15510213 PMID: 16135806 reaction: direct
CDK activity stimulated by its CAK-complex phosphorylation. PMID: 12459251 PMID: 12814430 (ref REACTOME) PMID: 7629134
Notes by CellDesigner PMID: 14633988 reaction: direct
Phosphorylation of p27 by cyclin E/CDK2 at Thr-187 results in targeting p27 for its degradation by proteolysis PMID: 10385618
Notes by CellDesigner CCND3 induced by E2F3a PMID: 12611887
Notes by CellDesigner PMID: 15271987 reaction: direct
Notes by CellDesigner PMID: 15574595 reaction: direct
CDK activity stimulated by its CAK-complex phosphorylation. PMID: 12459251 (ref REACTOME) PMID: 16782892
Notes by CellDesigner PMID: 15195143 reaction: direct
PMID: 10373560 (from REACTOME) PMID: 11063929
Cell cycle inhibition by sequestration of DP1 in the nucleolus. PMID: 16135794 PMID: 12446760
The recruitment of SUV39H1 allows that of HP1 PMID: 11484059 PMID: 15126619 PMID: 11420729 PMID: 15838516
Notes by CellDesigner PMID: 14990995 reaction: indirect intermediate: MYC
dephosphorylation of CDC2 induce its activation PMID: 10373560 PMID: 8348613 PMID: 12814430
Notes by CellDesigner PMID: 11564866 reaction: direct
Notes by CellDesigner PMID: 10733529 PMID: 15014447 reaction: direct
Notes by CellDesigner PMID: 14532106 reaction: directPMID: 15574337
Notes by CellDesigner PMID: 14990995 reaction: direct
Cyclin E phosphorylation by CDK2 at Thr-380. PMID: 8861947 Autophosphorylation of the complex cyclinE/CDK2 at Thr-380 and Thr-62. Phosphorylation at Thr-380 also by GSK-3B. Two other sites of regulation: Ser-372 et Ser-384 PMID: 16131838
Cytoplasmic binding PMID: 9001210 (ref REACTOME) PMID: 1717476
Protein stabilized by phosphorylation. PMID: 15838517 PMID: 15140942
Phosphorylation only when CDC2 is bound to the cyclin D. PMID: 10373560 PMID: 9001210 PMID: 12814430
Degradation depends upon ubiquitination. E3: F-box protein p45Skp2 PMID: 16213134
Notes by CellDesigner PMID: 15014447 reaction: direct
Notes by CellDesigner PMID: 11799067 reaction: direct
Notes by CellDesigner PMID: 16158053 reaction: direct
Notes by CellDesigner PMID: 10766737 reaction: direct
Notes by CellDesigner PMID: 12150994 reaction: direct
Complex cyclinE-CDK2 inhibited by its interaction with CKI. PMID: 10385618
Phosphorylation of pRB PMID: 9315635 dissociation of HDAC1 (during the G1 to S transition) PMID: 10778858 PMID: 11520855 PMID: 7736585, PMID: 9425340 weinberg CycD phosphorylates RB (ref REACTOME) PMID: 9190208
sequestration of CDK4 to prevent its association with Cyclins D and RB phosphorylation. PMID: 11960696 (ref REACTOME) PMID: 8078588 PMID: 8741839 PMID: 8001816 PMID: 8259215
PMID: 15126619 PMID: 15838516 The recruitment of SWI/SNF seems to be necessary for the recrutement de HDAC1 PMID: 11420729 PMID: 15105433
Notes by CellDesigner PMID: 12766778 reaction: direct
Degradation via the ubiquitin/proteasome system. PMID: 8861947
Notes by CellDesigner PMID: 12748276 PMID: 15574595 reaction: direct
Degradation during G1 by APC/C(FZR1) PMID: 15840442 PMID: 15577895 Degradation during M by APC/C(CDC20) PMID: 15577895
Notes by CellDesigner PMID: 12446714 reaction: direct
The complex cyclinD-CDK stability increases when bound to a Cip/Kip family member. PMID: 10385618
CDK7 activation by its phosphorylation at Thr-170 PMID: 11355576
Notes by CellDesigner PMID: 10733529 PMID: 15574595 reaction: direct
Notes by CellDesigner PMID: 15574337 reaction: direct
Dephosphorylation of CDC2 induces its activation. PMID: 10373560 PMID: 8348613 PMID: 12814430
Notes by CellDesigner PMID: 12077144 reaction: direct
Inactivated by phosphorylation by CHEK1 and CHEK2 PMID: 12478465 PMID: 12814430 (ref REACTOME) PMID: 9278512 PMID: 9836640 PMID: 9889122 Phosphorylation by CyclinB-CDC2 PMID: 11313986 ? => concerns CDC25A
Notes by CellDesigner PMID: 16144839PMID: 14990995
Phosphorylation initiated by E2F1. PMID: 15024084 E2F1 stimulates ATM to phosphorylate p53 (and Chk2) PMID: 15140942 (ref REACTOME) PMID: 12773400 PMID: 10973490
Notes by CellDesigner p14 ARF repressed by E2F3b PMID: 15177020 PMID: 15175242 reaction: direct
Notes by CellDesigner PMID: 15580623 reaction: direct
CDK activity stimulated by its CAK-complex phosphorylation. PMID: 12459251 PMID: 12814430 (ref REACTOME) PMID: 16782892
MDM2 = ubiquitin-ligase, regulates p53 stability: induice its degradation via the proteasome. PMID: 15024084
Induce the G0 to G1 transition: phosphorylated pocket proteins stop repressing ribosomal RNA and tRNA gene expression. PMID: 15838516
p14ARF induce the degradation of E2F1, E2F2 and E2F3 via the proteasome PMID: 11274364
PMID: 10373560 The NES (nuclear export signal) of the cyclin B allows its active export. Export via the CRM1 complex, seems to need GTPaseRan/TC4 PMID: 9679058 (ref REACTOME) PMID: 9670027 PMID: 9679058
degradation of cyclin D via the ubiquitin-proteasome system PMID: 9736735
Notes by CellDesigner PMID: 15033491 reaction: direct
PMID: 10548110 (ref REACTOME) PMID: 11598127 (CycB phosphorylates CDH1)
Inactivated by phosphorylation by CHEK1 and CHEK2 PMID: 12478465 PMID: 12814430 Phosphorylation by CyclinB-CDC2 PMID: 11313986 ? => concerns CDC25A
Notes by CellDesigner PMID: 10766737 PMID: 8760872 reaction: direct
p107 binds to and inhibits cyclinA-CDK2, independantly of its phosphorylation state. PMID: 15456871 PMID: 12006580 PMID: 11237530
Notes by CellDesigner PMID: 12789259 reaction: direct
Phosphorylation of p27 at Thr-157 in its NLS, which impair its nuclear import. PMID: 12851486 (from REACTOME) PMID: 9632134
Upon DNA damage, E2F is stabilized by ATM phosphorylation. PMID: 15838517 PMID: 15140942 14-3-3 tau mediates E2F1 stabilization. 14-3-3 tau interacts with ATM-phosphorylated E2F1 during DNA damage and inhibits E2F1 ubiquitination. 14-3-3 tau is also required for expression and induction of E2F1 apoptotic targets, such as p73, Apaf-1, and caspases, during DNA damage. PMID: 15494392
(from REACTOME) PMID: 8515817 phosphorylation and inactivation of Wee1 kinase PMID: 15070733 PMID: 7681363 (yeast) PMID: 9268380 Cyclin B phosphorylates Myt1 in vitro
Dephosphorylation of CDC2 induces its activation. PMID: 10373560 PMID: 8348613 PMID: 12814430 (ref REACTOME) PMID: 1828290
Once the process of methylation has started, pRB is detached from the DNA. PMID: 15126619 OR phosphorylation of RB destroy its binding with SUV39H1 PMID: 11533237
Notes by CellDesigner PMID: 16179649 reaction: direct
Phosphorylation at the Ser-403 in S phase by the TFIIH kinase targets E2F1 for its rapid ubiquitination and degradation through the ubiquitin-proteasome pathway. PMID: 15123636 Phosphorylation at Ser-403 and Thr-433 by the basal TF TFHII triggers E2F1 degradation. PMID: 16213134
Phosphorylation only when CDC2 is bound to the cyclin B PMID: 10373560 PMID: 9001210 PMID: 12814430 (ref REACTOME) PMID: 9268380
Notes by CellDesigner PMID: 12139485 reaction: direct
Phosphorylations on p53 prevent its binding to MDM2. PMID: 15140942 MDM2 phosphorylation by AKT favors the binding of MDM2 to p53 and its following degradation. PMID: 15574337
MDM2 phosphorylation by ATM inhibits its interaction with p53 PMID: 15140942 (ref REACTOME) PMID: 11331603 phosphorylation at Ser395
E2F4 does not possess the NLS (nuclear localisation signal). Translocation in the nucleus only when bound to DP2 and/or p130/p107. Located in the nucleus only during G0 and G1. PMID: 9372959 PMID: 11959842
Notes by CellDesigner PMID: 10733529 PMID: 15510213 reaction: direct
Notes by CellDesigner PMID: 10766737 PMID: 14576826 reaction: direct
Relocalization of p21 from the nucleus to the cytosol PMID: 16775416 (from REACTOME) PMID: 9632134
p130 binds to and inhibits cyclinA-CDK2, independantly of its phosphorylation state. PMID: 15456871 PMID: 12006580 PMID: 11237530
Proteolysis degradation via the SCF(SKP2) system. PMID: 10385618 PMID: 12814430 PMID: 12851486 Preliminary phosphorylation and cytoplasm export needed for degradation. PMID: 11355576
CDC2 phosphorylation at Tyr15 by WEE1, only when CDC2 is bound to a cyclin. PMID: 12814430 WEE1 allows CDC2 to stay in an inactive state after its translocation in late G2 PMID: 10373560 PMID: 8348613 PMID: 9001210 (from REACTOME) PMID: 15037762
CDK activity stimulated by its CAK-complex phosphorylation. PMID: 12459251 PMID: 12814430 (ref REACTOME) PMID: 7799941
Notes by CellDesigner PMID: 10733529 PMID: 10766737 reaction: direct
Protein names are HUGO names or usual names. In the latter case, they are identified with a star (*) and the HUGO name is given in notes. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
relatively low nuclear levels of E2F4 is maintained by efficient CRM1-dependent nuclear export. PMID: 11158323 E2F-5 is exported from the nucleus through leptomycin B-sensitive, CRM1-mediated transport, through a region corresponding to amino acid residues 130-154. PMID: 12089160
E2F1 deacetylated by pRB/HDAC PMID: 15126619 Deacetylation by HDAC1 PMID: 10753885
Complex cyclinA-CDK2 inhibited by its interaction with CKI PMID: 10385618
PMID: 15829956 PMID: 15140942 Auto-phosphorylation catalysed by E2F1 PMID: 15024084 (ref REACTOME) PMID: 12556884 Autophosphorylation of ATM within dimeric ATM complexes
CDK activity activated by its phosphorylation by CAK-complex PMID: 11959850
sequestration of CDK6 to prevent its association with Cyclins D and RB phosphorylation PMID: 11960696 (ref REACTOME) PMID: 8078588 PMID: 8741839 PMID: 8001816 PMID: 8259215
Notes by CellDesigner PMID: 14597855 reaction: direct
Notes by CellDesigner PMID: 12566389 reaction: direct
Degradation via the ubiquitin-proteasome system. PMID: 10773440 Degradation via SCF(SKP2) (=SKP1-Culin1-SKP2) PMID: 12717421
Notes by CellDesigner PMID: 16135806 reaction: directPMID: 15574595