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 , .
binds and activates CDK4 and CDK6, which regulate G1/S transition of mitotic cell cycle , . Under
Estradiol action, active
phosphorylate Rb protein. It leads to liberation of
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
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
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 /
Cyclin D1/ CDKs.
Thus the inhibitory activity of p21 and p27KIP1 removes from CDK2 , .
ESR1 (nuclear) may down-regulate
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) , .
can directly suppress transcription of p27KIP1  and
Estradiol action .
It is shown, that ESR1 (membrane) participates in
regulation of G1/S transition of mitotic cell cycle as well.
nuclear export via the ESR1 (membrane)/
ERK2 (MAPK1)/ CRM1 pathway , . In addition, ESR1 (membrane) may stimulate Cyclin D1
through alternative pathways , .
Histone-arginine methyltransferase CARM1
M-phase inducer phosphatase 1
Cyclin-dependent kinase 2
Cyclin-dependent kinase 4
Cyclin-dependent kinase 6
Cyclin-dependent kinases regulatory subunit 1
Cyclin A Protein group
Transcription factor E2F1
E2F1/DP1 complex Complex
E2F4/DP1 complex Complex
Mitogen-activated protein kinase 1
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
Nuclear receptor coactivator 3
S-phase kinase-associated protein 2
Transcription factor Sp1
Transcription factor AP-1
Myc proto-oncogene protein
Retinoblastoma-like protein 2
Cyclin-dependent kinase inhibitor 1
Cyclin-dependent kinase inhibitor 1B
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