Development Ligand-dependent activation of the ESR1/AP-1 pathway
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 mainpathways: a ligand-dependent and ligand-independent . Activated by aligand, ESR1 stimulates transcription directly (classical pathway), or byactivation of other transcription factors in ligand-dependent manner (non-classicalpathway ). Members of AP-1 family Jun oncogene ( c-Jun ) and v-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ) are a one of these transfactors, , . Active ESR1 is a dimer bound to DNA at specific target sequences calledestrogen response elements . 17beta-estradiol is a physiological ligand of the ESR1. In the absenceof the 17beta-estradiol, ESR1 resides primarily in the nucleus, with somepresence in cytoplasm. Ligand-bound ESR1 moves to the nucleus. In the present of 17beta-estradiol, ESR1 recruits ATP-dependentchromatin remodeling complex BAF ,  toestrogen-responsive promoters. Chromatin remodeling allows recruiting co-activators suchas Nuclear receptor co-activator 1 ( NCOA1 (SRC1) )  and Nuclearreceptor co-activator 2 ( NCOA2 (GRIP1/TIF2) ) , . 17beta-estradiol/ ESR1/ co-activator complex then recruits integratorproteins and histone modifying enzymes such as CREB binding protein ( CBP ) andE1A binding protein p300 ( p300 ) , , . Then, ESR1 directly binds to c-Jun protein. This interaction isstabilized by the coactivator NCOA2 (GRIP1/TIF2), which interacts with bothc-Jun and ESR1 , . In addition, NCOA1(SRC1) may participate in this process interacting with c-Jun, c-Fosand ESR1 . Nuclear receptor interacting protein 1 ( RIP140 ) is a regulator in ESR1/ AP-1 pathway. RIP140 physically interacts with c-Jun and ESR1 andinhibits estradiol-induced AP-1-mediated transcription. In addition, RIP140directly binds to histone deacetylases (e.g, Histone deacetylase 4, HDAC4 ) and toco-repressor C-terminal binding protein 1 ( CtBP1 ) which itself interacts withhistone deacetylases (e.g, Histone deacetylase 1, HDAC1 ). Deacetylation ofchromatin proteins by histone deacetylases leads to inhibition of ESR1/AP-1-induced transcription . In addition, CtBP1 repressesp300 -mediated transcriptional activation by direct association with itsbromodomain . ESR1 may activate transcription of RIP140, thus establishing aregulatory feedback loop .