Pathway Map Details
Transcription_Ligand-dependent activation of the ESR1/SP pathway
Object list (links open in MetaCore):
Cyclin D1, CDC25A, NFYA, Cyclin E, Cyclin E2, Estradiol cytoplasm, PCAF, DNA polymerase alpha/primase, SP1/SP3 (complex), SP1, CBP, E2F1, ADA, CARM1, NCOA3 (pCIP/SRC3), NCOA1 (SRC1), p300, BAF, C/EBPbeta, HIF-1, Prolactin receptor, TYSY, ESR1, CAD, RARalpha, LDLR, EGFR, c-Fos, VEGF-A, SP3
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 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 ) . 17beta-estradiol/ ESR1/ 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 DNA-bound ESR1 -activated SP1.
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 alpha/primase, E2F1, 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 others.
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