Ligand-dependent activation of the ESR1/SP
Estrogen receptor 1 (ESR1) is a major ligand-activated
transcription factor, member of the family nuclear receptors .
ESR1 acts via two main pathways: a ligand-dependent and
ligand-independent manner . Activated by a ligand,
ESR1 stimulates transcription directly (classical pathway),
or by activation of other transcription factors in ligand-dependent manner (non-classical
pathway). Sp1 transcription factor (SP1) is one of
transcription factors participating in the latter pathway . Active
ESR1 is a dimer bound to DNA at specific target sequences
called estrogen response elements .
17beta-estradiol is a physiological ligand of the
ESR1. In the absence of the
17beta-estradiol, ESR1 resides
primarily in the nucleus, with some presence in cytoplasm. Ligand-bound
ESR1 moves to the nucleus.
In the present of 17beta-estradiol,
ESR1 recruits ATP-dependent chromatin remodeling complex
BAF ,  to
estrogen-responsive promoters. Chromatin remodeling allows recruiting co-activators such
as Nuclear receptor co-activator 1 (NCOA1) .
co-activator complex recruits integrator proteins and histone modifying enzymes such as
CREB binding protein (CBP), E1A binding protein p300
(p300) and K(lysine) acetyltransferase 2B
(PCAF) , .
ESR1 forms a complex with
SP1 in a
ligand-dependent-manner. In most cases, non-classical pathways that involve ligand
activation of ESR1 / SP1 do not
require interactions of ESR1 with promoter DNA but with
DNA-bound transcription factor SP1 . For
example, v-fos FBJ murine osteosarcoma viral oncogene homolog
(c-Fos) , Epidermal growth factor receptor
(EGFR) , DNA polymerase
alpha/primase , Thymidylate synthetase
(TYSY) , Adenosine deaminase
(ADA) , Retinoic acid receptor, alpha
(RARalpha)  and Low density lipoprotein
receptor (LDLR)  are regulated via
Some additional transcription factors participate in activation some genes via
non-classical ESR1/ SP1
pathway. Thus, ESR1/
SP1 complex interacts with Nuclear transcription factor Y,
alpha (NFYA) for a hormone-induced E2F transcription factor
1 (E2F1) transcription . ESR1
/ SP1 and
SP1-bound NFYA and E2F1
are involved in activation of Cell division cycle 25A
(CDC25A) by 17beta-estradiol
. Ligand-induced ESR1
stimulates Prolactin receptor transcription via direct
activation of SP1/ Sp3 transcription factor
(SP3) (SP1/ SP3 complex) and
CCAAT/enhancer binding protein beta (C/EBPbeta)
transcription factors . Cooperative interactions of ESR1
/ SP1, ESR1 /
SP3 and Hypoxia-inducible factor 1
(HIF-1) are required for a
17beta-estradiol-induced Vascular endothelial growth factor
A (VEGF-A) transcription , .
In a number of cases, both ESR1- and
SP1-DNA interactions are required for transcription activation. Both
ESR1 and SP1 are bound to
promoters of Carbamoyl-phosphate synthetase 2 aspartate transcarbamylase and
dihydroorotase (CAD)  and
Cyclin D1 .
The genes regulated by ESR1 /
SP1 play a role in cell cycle regulation and proliferation
(e.g., CDC25A, c-Fos,
Cyclin D1, DNA polymerase
EGFR, Prolactin receptor and
VEGF-A), purine/pyrimidine biosynthesis and metabolism
(e.g., ADA, CAD,
DNA polymerase alpha/primase and
TYSY), immune response (e.g., Prolactin
receptor), regulation of lipid metabolism (e.g.,
LDLR and RARalpha) and
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