Pathway Map Details

Transcription_Ligand-dependent activation of the ESR1/SP pathway

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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 [1]. ESR1 acts via two main pathways: a ligand-dependent and ligand-independent manner [2]. 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 [3]. Active ESR1 is a dimer bound to DNA at specific target sequences called estrogen response elements [2].

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 [4], [5] to estrogen-responsive promoters. Chromatin remodeling allows recruiting co-activators such as Nuclear receptor co-activator 1 ( NCOA1 ) [6]. 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 ) [7], [6].

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 [3]. For example, v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [8], Epidermal growth factor receptor ( EGFR ) [9], DNA polymerase alpha/primase [10], Thymidylate synthetase ( TYSY ) [11], Adenosine deaminase ( ADA ) [12], Retinoic acid receptor, alpha ( RARalpha ) [13] and Low density lipoprotein receptor ( LDLR ) [14] 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 [15]. ESR1/ SP1 and SP1 -bound NFYA and E2F1 are involved in activation of Cell division cycle 25A ( CDC25A ) by 17beta-estradiol [16]. 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 [6]. 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 [17], [7].

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 ) [18] and Cyclin D1 [19].

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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