Ligand-dependent activation of the ESR1/AP-1
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 . Activated by a ligand,
ESR1 stimulates transcription directly (classical pathway),
or by activation of other transcription factors in ligand-dependent manner (non-classical
pathway). Members of AP-1 family Jun oncogene (c-Jun) and
v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos)
are a one of these transfactors , , .
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 (SRC1))  and Nuclear receptor co-activator 2 (NCOA2
(GRIP1/TIF2)) , .
co-activator complex then recruits integrator proteins and histone modifying enzymes such
as CREB binding protein (CBP) and E1A binding protein p300
(p300) , , .
Then, ESR1 directly binds to
c-Jun protein. This interaction is stabilized by the
coactivator NCOA2 (GRIP1/TIF2), which interacts with both
c-Jun and ESR1 , . In addition, NCOA1 (SRC1) may
participate in this process interacting with c-Jun,
c-Fos and ESR1 .
Nuclear receptor interacting protein 1 (RIP140) is a
regulator in ESR1/ AP-1
pathway. RIP140 physically interacts with
c-Jun and ESR1 and inhibits
estradiol-induced AP-1-mediated transcription. In addition,
RIP140 directly binds to histone deacetylases (e.g, Histone
deacetylase 4, HDAC4) and to co-repressor C-terminal binding
protein 1 (CtBP1) which itself interacts with histone
deacetylases (e.g, Histone deacetylase 1, HDAC1).
Deacetylation of chromatin proteins by histone deacetylases leads to inhibition of
transcription . In addition, CtBP1 represses
p300-mediated transcriptional activation by direct
association with its bromodomain .
ESR1 may activate transcription of
RIP140, thus establishing a regulatory
feedback loop .
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