Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Transcription Ligand-dependent activation of the ESR1/SP pathway

Log In to Post A Comment

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 mainpathways: a ligand-dependent and ligand-independent manner [2]. 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 [3]. Active ESR1 is a dimer boundto DNA at specific target sequences called estrogen response elements [2].

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

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 [3]. For example, v-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ) [8], Epidermal growthfactor receptor ( EGFR ) [9], DNA polymerase alpha/primase[10], Thymidylate synthetase ( TYSY ) [11], Adenosinedeaminase ( 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 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 [15]. ESR1/ SP1 and SP1 -bound NFYA and E2F1 areinvolved in activation of Cell division cycle 25A ( CDC25A ) by17beta-estradiol [16]. 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 [6].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 [17], [7].

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 ) [18] and Cyclin D1 [19].

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.