SP1, c-Fos, c-Jun/c-Fos, ERK2 (MAPK1), CKS1, c-Myc, p21, CARM1, Estradiol cytoplasm, p130, Cullin 1, CRM1, E2F4, ATF-2/c-Jun, Ubiquitin, E2F4/DP1 complex, NCOA3 (pCIP/SRC3), E2F1, Cyclin D1, c-Jun, ESR1 (nuclear), Rb protein, SKP2, Skp2/TrCP/FBXW, Cyclin A, Cul1/Rbx1 E3 ligase, CDK6, CDK2, Cyclin E, E2F1/DP1 complex, CDK4, p27KIP1, CDC25A
ESR1 regulation of G1/S transition
17beta-estradiol induce s proliferation of estrogen receptor-positive cells. Estrogen receptor 1 ( ESR1 nuclear ) a ctivated by 17beta-estradiol acts like as ligand-dependent transcription factor and promotes G1/S transition through several pathways , .
First, ESR1 nuclear activates transcription of Cyclin D1 by a variety mechanisms , , . ESR1 nuclear can activate transcription of Cyclin D1 acting as co-activator Jun oncogene ( c-Jun )/ V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) , Activating transcription factor 2 ( ATF-2 )/ c-Jun heterodimers . Moreover, ESR1 nuclear regulates transcription of c-Jun and c-Fos , . In addition, ESR1 nuclear may activate transcription of Cyclin D1 via SP1 -dependent pathways , . Finally, Cyclin D1 can bind ESR1 nuclear and activate transcription of ESR1 nuclear -responsible genes including its own gene , .
Cyclin D1 binds and activates Cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ), which regulate G1/S transition , . Under 17beta-estradiol action, active Cyclin D1/ CDK4 and Cyclin D1/ CDK6 complexes phosphorylate Retinoblastoma 1 ( Rb-protein ). It leads to liberation of E2F/ transcription factor DP1 complexes ( E2F1/DP1, E2F4/DP1 ) from inhibitory binding of Rb-protein and transcription of requisite genes for S-phase entry, including Cyclin E and Cyclin A genes , , .
Also, ESR1 nuclear can regulate transcription of E2F1. Coactivator-associated arginine methyltransferase 1 ( CARM1 ) in a Nuclear receptor coactivator 3 ( NCOA3 (pCIP/SRC3) ) - dependent manner activates ligand-bound ESR1 nuclear which binds to SP1 and promotes transcription E2F1 , .
Another way of ESR1 nuclear promoting G1/S transition is activation of transcription V-myc myelocytomatosis viral oncogene homolog ( c-Myc ) . ESR1 nuclear induction of c-Myc leads activation of Cell division cycle 25 homolog A ( CDC25A ) and CDK4 transcription , . Transcription of CDC25A is also regulated by E2F1 . Active CDC25A dephosphorylates Cyclin-dependent kinase 2 ( CDK2 ). It leads to inhibition Rb protein and Retinoblastoma-like 2 ( p130 ) and transcription activation of E2F/DP1 -dependent S-phase genes, including Cyclin E gene , , .
In addition, ESR1 nuclear regulates G1/S transition by redistribution and down-regulation of Cyclin-dependent kinase inhibitor 1A ( p21 ) and Cyclin-dependent kinase inhibitor 1B ( p27KIP1 ). ESR1 nuclear promotes redistribution of p21 and p27KIP1 from Cyclin E/ CDK2 to Cyclin D1/ CDKs. Thus the inhibitory activity of p21 and p27KIP1 removes from CDK2 , .
ESR1 nuclear may down-regulate p27KIP1 activity by targeting it for ubiquitin - proteosome degradation in nucleus . ESR1 nuclear activation of E2F1 leads to activation SKP2 transcription by E2F1 . c-Myc activates transcription of Cullin1 and Cyclin-dependent kinases regulatory subunit 1 ( CKS1 ) , . CKS1 binds to SKP2 and promotes the recognition of phosphorylated p27KIP1 (on Thr187 by Cyclin E/ CDK2) , .
It is shown, that the membrane form of ESR1 participates in G1/S transition regulation as well. 17beta-estradiol down-regulates p27KIP1 by nuclear export via the ESR1 (membrane) / Mitogen-activated protein kinase 1( ERK2 )/ Exportin 1 ( CRM1 ) pathway , . In addition, ESR1 (membrane) may stimulate Cyclin D1 through alternative pathways