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 [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) [6], [7].

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 [7], [17].

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.

References:

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