Transcription Ligand-dependent activation of the ESR1/SP pathway
Ligand-dependent activation of the ESR1/SP 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 manner . Activated bya ligand, ESR1 stimulates transcription directly (classical pathway), or byactivation of other transcription factors in ligand-dependent manner (non-classicalpathway). Sp1 transcription factor ( SP1 ) is one of transcription factorsparticipating in the latter pathway . Active ESR1 is a dimer boundto DNA at specific target sequences called estrogen 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 ) .17beta-estradiol/ ESR1/ co-activator complex recruits integrator proteinsand histone modifying enzymes such as CREB binding protein ( CBP ), E1A bindingprotein p300 ( p300 ) and K(lysine) acetyltransferase 2B ( PCAF ) , . ESR1 forms a complex with SP1 in a ligand-dependent-manner. In mostcases, non-classical pathways that involve ligand activation of ESR1/ SP1do not require interactions of ESR1 with promoter DNA but with DNA-boundtranscription factor SP1 . For example, v-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ) , Epidermal growthfactor receptor ( EGFR ) , DNA polymerase alpha/primase, Thymidylate synthetase ( TYSY ) , Adenosinedeaminase ( ADA ) , Retinoic acid receptor, alpha ( RARalpha)  and Low density lipoprotein receptor ( LDLR ) are regulated via DNA-bound ESR1 -activated SP1. Some additional transcription factors participate in activation some genes vianon-classical ESR1/ SP1 pathway. Thus, ESR1/ SP1 complexinteracts with Nuclear transcription factor Y, alpha ( NFYA ) for ahormone-induced E2F transcription factor 1 ( E2F1 ) transcription . ESR1/ SP1 and SP1 -bound NFYA and E2F1 areinvolved in activation of Cell division cycle 25A ( CDC25A ) by17beta-estradiol . Ligand-induced ESR1 stimulatesProlactin receptor transcription via direct activation of SP1/ Sp3transcription factor ( SP3 ) ( SP1/ SP3 complex ) and CCAAT/enhancerbinding protein beta ( C/EBPbeta ) transcription factors .Cooperative interactions of ESR1/ SP1, ESR1/ SP3 andHypoxia-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 requiredfor transcription activation. Both ESR1 and SP1 are bound to promoters ofCarbamoyl-phosphate synthetase 2 aspartate transcarbamylase and dihydroorotase (CAD )  and Cyclin D1 . The genes regulated by ESR1/ SP1 play a role in cell cycle regulationand proliferation (e.g., CDC25A, c-Fos, Cyclin D1, DNApolymerase alpha/primase, E2F1, EGFR, Prolactin receptor andVEGF-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 andRARalpha ) and others.