ESR1 regulation of G1/S transition
Estradiol induces proliferation of estrogen receptor-positive cells. ESR1 (nuclear) activated by Estradiol acts like as ligand-dependent transcription factor and promotes G1/S transition (see G1/S transition of mitotic cell cycle) 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 c-Jun/ c-Fos , 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 CDK4 and CDK6, which regulate G1/S transition of mitotic cell cycle , . Under Estradiol action, active Cyclin D1/ CDK4 and Cyclin D1/ CDK6 complexes phosphorylate Rb protein. It leads to liberation of E2F1/DP1 complex, E2F4/DP1 complex) 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. CARM1 in a 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 of mitotic cell cycle is activation of transcription of c-Myc . ESR1 (nuclear) induction of c-Myc leads activation of CDC25A and CDK4 transcription , . Transcription of CDC25A is also regulated by E2F1 . Active CDC25A dephosphorylates CDK2. It leads to inhibition Rb protein and 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 p21 and 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 of SKP2 transcription by E2F1 . c-Myc activates transcription of Cullin 1 and CKS1 , . CKS1 binds to SKP2 and promotes the recognition of phosphorylated p27KIP1 (on Thr187 by Cyclin E/ CDK2) , .
Finally, c-Myc can directly suppress transcription of p27KIP1  and p21 under Estradiol action .
It is shown, that ESR1 (membrane) participates in regulation of G1/S transition of mitotic cell cycle as well. Estradiol down-regulates p27KIP1 by nuclear export via the ESR1 (membrane)/ ERK2 (MAPK1)/ CRM1 pathway , . In addition, ESR1 (membrane) may stimulate Cyclin D1 through alternative pathways , .
| ATF-2/c-Jun || ATF-2/c-Jun Complex |
| CARM1 || Histone-arginine methyltransferase CARM1 |
| CDC25A || M-phase inducer phosphatase 1 |
| CDK2 || Cyclin-dependent kinase 2 |
| CDK4 || Cyclin-dependent kinase 4 |
| CDK6 || Cyclin-dependent kinase 6 |
| CKS1 || Cyclin-dependent kinases regulatory subunit 1 |
| CRM1 || Exportin-1 |
| Cullin 1 || Cullin-1 |
| Cyclin A || Cyclin A Protein group |
| Cyclin D1 || G1/S-specific cyclin-D1 |
| Cyclin E || G1/S-specific cyclin-E1 |
| E2F1 || Transcription factor E2F1 |
| E2F1/DP1 complex || E2F1/DP1 complex Complex |
| E2F4/DP1 complex || E2F4/DP1 complex Complex |
| ERK2 (MAPK1) || Mitogen-activated protein kinase 1 |
| ESR1 (nuclear) || Estrogen receptor |
| Estradiol || Chemical IUPAC name (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol |
| NCOA3 (pCIP/SRC3) || Nuclear receptor coactivator 3 |
| Rb protein || Retinoblastoma-associated protein |
| SKP2 || S-phase kinase-associated protein 2 |
| SP1 || Transcription factor Sp1 |
| c-Fos || Proto-oncogene c-Fos |
| c-Jun || Transcription factor AP-1 |
| c-Myc || Myc proto-oncogene protein |
| p130 || Retinoblastoma-like protein 2 |
| p21 || Cyclin-dependent kinase inhibitor 1 |
| p27KIP1 || Cyclin-dependent kinase inhibitor 1B |
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