Ligand-dependent activation of the ESR1/AP-1 pathway
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) ) , .
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 ESR1/ AP-1-induced 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 .